Home  /  Interviews  /  John Allman

# John M. Allman

### Frank P. Hixon Professor of Neurobiology

By David Zierler, Director of the Caltech Heritage Project

September 8, 15, 22, and 24, 2021

DAVID ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Wednesday, September 8th, 2021. I am delighted to be here with Professor John M. Allman. John, it's great to see you. Thank you for joining me today.

JOHN ALLMAN: Good to be with you.

ZIERLER: To start, would you please tell me your title and institutional affiliation?

ALLMAN: My title is officially Frank P. Hixon Professor of Neurobiology. I am at the Division of Biology and Biomedical Engineering at Caltech.

ZIERLER: Tell me about Frank Hixon, and his connection at all to your work.

ALLMAN: Frank Hixon was from Wisconsin. I actually have had some contact with the Hixon family. In fact, they've been nice enough to invite me to several of their family gatherings over the years. Frank Hixon was, I believe, quite successful initially in the lumber business in the 19th century. The family is still quite well-to-do. In one branch of the Hixon family was Adelaide Hixon, who lived here in Pasadena. I had dinner with her on several occasions over the years because we had a mutual friend. I attended a memorial service for her that the family invited me to, just before COVID, back in February of 2020. They've been very friendly.

Hixon gave the money to Caltech in the 1930s to endow the professorship. The first occupant of the chair was George Beadle, who won the Nobel Prize for his work on encoding of genes, the one gene, one protein hypothesis. Beadle became president of University of Chicago when I was a graduate student there, and I occasionally encountered him there. Beadle served on the Biology Division visiting committee when I was an assistant professor, and I had a good chat with him about raising owl monkeys during one of his visits. Beadle had a strong interest in the care of animals having grown up on a farm.

Then the professorship went to Roger Sperry, whom I knew quite well. Roger was instrumental in bringing me to Caltech in 1974. He was very supportive. I now occupy Roger's office. Roger also won a Nobel Prize for his studies of hemispheric differences in function in split brain patients. I was very fortunate to have known Roger well. We even took a trip to Baja, California, exploring and finding ammonite fossils, which is something he loved to do. I'm only the third person to occupy the Hixon chair in about 90 years.

ZIERLER: Another question about your title—how far back does the term "neurobiology" go, and how far back does your title with that name go?

ALLMAN: The occupant of the chair has had some discretion in what to call it. I'm sure that George Beadle was just "Professor of Biology." Roger wanted to have his field known as psychobiology, and so when I first occupied that, I inherited that title: Hixon professor of psychobiology. I was never very comfortable with that, because it doesn't have a very clear referent in terms of academic specialties.

What happened—within the span of my career—was the emergence of the field of neurobiology. That could be seen as being associated with the Society for Neuroscience, which is the organization for neurobiologists which was established - around 1970, over 50 years ago. I was one of the original members. The Society for Neuroscience has had an important role in the formation of neurobiology. I was a little concerned about being professor of something that didn't have a clear referent, so I said, "I really would prefer to be called a neurobiologist." So we did that! That's how it came about.

ZIERLER: Just some historical perspective—what was happening around 1970 that allowed for this field to develop? Was it advances in instrumentation? Were there certain theoretical advances? What was happening around this time?

ALLMAN: I would say that people who studied the nervous system—and there weren't a huge number of them who were doing basic neurobiological research at that time—were in medical schools. They might be neurologists, or they might be neurophysiologists. I was in neurophysiology. There were a very small number of schools that had significant programs. It was a small field. The Society for Neuroscience at its first meeting, which was in 1970 in Washington D.C., had about 1,000 people attending. It now has maybe 50,000 people, so it's a big thing. In 1970, that thousand was probably most of the people who were active in that field.

So it's quite a legitimate question to say, "Well, what happened?" I think part of it—computer technology came to neuroscience earlier than in most other areas of science. For example, at the Laboratory of Neurophysiology where I worked, at University of Wisconsin in the 1960s, we used very early computers. The computer that I first used had 8K of memory—eight K—and it filled a room. In those days, what they called the core were literally iron beads, and you entered data to the thing very laboriously. Everything is machine language programming, which I never learned. Part of it was the early use of computer technology and the quantification of research that followed from that. Also scaling up of the research. What I did early on was recording from single neurons in visual cortex. That is something that lent itself to quantification in the sense that we could control the visual stimuli being presented and measuring the output of the neurons in terms of units of activity, of spikes. You could analyze that in a pretty straightforward manner, by counting spikes and averaging them. So we did a lot of that, and it was quite useful. So an early aspect of it was the successful use of what was then very primitive computer technology. That early and successful application of computer technology would have been part of it.

There were also important techniques that were developed to trace connectivity in the brain, and those came online in the late 1970s. The injection of different tracer substances in the brain that allowed a much better mapping of connectivity, at least within experimental animals. That eventually hooked up with the emergence of brain imaging technology, first PET (positron emission tomography) scanning, and then magnetic resonance imaging, which is one of the things I do today, and there has been an immense revolution in that. That's something that was just getting started around 1980. Michel Ter-Pogossian was doing PET at Washington University, beginning about 1980. I was involved in some of the PET experiments with Mark Raichle that allowed a clear objective mapping of brain activity. In fact, I did some of the experiments mapping my own visual cortex that way. But the PET scanning involves exposure and ionizing radiation, and it's very expensive and cumbersome to do. So while that was a powerful technique, it was hard to do experiments with it. You have to have very specialized facilities, had to have a cyclotron available for the on-the-spot generation of short-lived isotopes, a big, complicated apparatus.

Then Paul Lauterbur, again in the early 1980s, had this tremendous insight about the ability to do spatial NMR to be able to see initially structure within tissue, based on small differences in the NMR signal. This became known as MRI-magnetic resonance imaging. Then in the late 1980s, a group at Bell Labs realized that there was a powerful signal associated with the oxygenation state of hemoglobin that allowed one to record essentially a vascular response in the brain, and that (vascular response, which is called the BOLD (blood exygenation level) signal, was a very powerful tool for brain mapping. There are many thousands of studies based on that now. That was a true revolution.

PET was already underway in 1980, and MRI began very shortly thereafter, and was already picked up as a tool for neurobiology in the late 1980s. Those were things that I think were important. There were also of course revolutions in genetic technology, but those are somewhat more recent, although some of that goes back to that period as well. There was a realization that there were vast new vistas that could be explored.

ZIERLER: We'll explore your educational trajectory in its proper chronological context, but a very broad question now as it relates to your educational background and your current work, and that is, among your contemporaries and peers whose education precedes the development of neurobiology, was anthropology a natural starting point, or was that unique for you?

ALLMAN: It wasn't absolutely unique, but it was rare. It was a kind of curious coincidence, or accident, maybe, that I benefited from, like a lot of things in life. When I was an undergraduate, I was interested in anthropology, and particularly cultural anthropology. I studied Chinese, which was unusual at that time. This is the 1960s. I got an NSF graduate fellowship, which at that time, was for five years. It was a wonderful thing. I was very fortunate to have gotten that because it gave me considerable independence. I went to the University of Chicago, and at that time, I started getting interested in the biological basis of behavior. Particularly I got interested in the question that just came to me as kind of a flash one day—that a powerful way of understanding the brain would be to look at the way the visual input was transformed from the retina through different levels of neural processing in the visual pathways of the brain, which at that time was only known in a very rudimentary way.

There was a group at Harvard who was just at that time beginning to work—David Hubel and Torsten Wiesel. I got to know them pretty well, later on. They eventually won a Nobel Prize for their work in visual cortex. In a sense, they were a beacon of light. It was clear that this idea had legs, so to speak—that you could trace the activity elicited by, say, a visual stimulus at different levels in the brain, and that you could trace that through a microelectrode recording of the neurons involved. There's a straightforward technology for doing that with microelectrode recording, even at that time, and it was quite accessible.

I got interested in microelectrode recording from neurons in the visual system when I was a graduate student and I thought, "Well, anthropologists don't do that sort of stuff." I was fortunate that I had a very broad-minded, biologically oriented advisor named Clark Howell. Clark was unusual in that many senior people would see a prospective student as someone who could advance their own particular agenda. Clark didn't feel that way. Clark liked to work independently. Clark did paleoanthropology. Another one of his students, Don Johanson, became famous for discovering Lucy, Australopithecus afarensis, in Ethiopia.

Clark encouraged me and my interest in the brain. He was basically an anatomist. He said there was another student that had been a few years ahead of me named Carol Welt, and that she was interested in motor cortex and had done a thesis mapping motor cortex in apes at the University of Wisconsin with Clinton Woolsey and Wally Welker. Eventually, she married Wally. She was about five years ahead of me. Clark suggested that I get in touch with Wally.

Well, I did, and Wally was just wonderful. He was very welcoming. And something of course that is hard to imagine in the contemporary world, but it was a small world, then—there were very few students who did this sort of thing, in anthropology or anywhere else for that matter, so they were pleased to see somebody who was interested. I went up to the University of Wisconsin and got going right away and working with Jon Kaas who at that time had just gone from being a postdoc to being assistant professor. Jon and I made a great team. We published a lot of papers on the organization of the visual cortex. I also remained close to Wally. Wally build a large collections of beautifully sectioned and stained comparative mammalian brains, virtually unique in the world, which I have used extensively and are the basis for several of my papers. His collection became part of the collection at the National Museum of Health and Medicine, which is curated by Archie Fobbs, another good friend. I visited Wally in Madison just a few weeks before his death in 2007 and feel fortunate to have spent that time with him.

I was quite impressed with Hubel and Wiesel's findings with respect to the increasing complexity of analysis of visual input in the second-order visual areas in cats. I thought, "Well, we should see what happens in monkeys" because of the importance of the higher-order visual perception in us. I wanted to understand how we see. So we did that, and it worked really well. We were able to delineate quite a few cortical areas on the basis of their visual field maps and brain architecture. That has been an activity that has continued, and I have a former postdoc, now very senior because of the time that has gone by, named Marty Sereno, who still works on that, as well the map of human visual cortex using magnetic resonance imaging. Other people, particularly David Van Essen's group, mapped the cortex in macaque monkeys.

It eventually emerged that there were large number of cortical areas, each of which probably makes its own distinctive contributions to perception. One that we particularly were involved with was an area that we called MT, for middle temporal area. MT is involved in the mechanisms for the perception of direction of motion. It's like a parcellation of perceptual functioning, so we could identify one particular place in the cortex, a uniquely defined map of visual space that was related to the analysis of movement of objects in space. We did quite a bit of work on that that has become foundational. The papers that we generated, beginning back in 1971, are still frequently cited, 50 years later, because they continue to the relevant to contemporary science.

After I came to Caltech, I had this idea which proved to be pretty fruitful, which is that with respect to motion, everything is relative. Objects move with respect to other objects. One of the key things doing this kind of work was the concept of mapping receptive fields. A receptive field was a little place in visual space that activated a particular neuron within a particular map, say MT. A little place within the visual field map in MT was activated by objects moving in a particular direction within that space, very specific, and tuned (differentially responsive) for velocity, as well.

We thought, well, a fundamental question is how the experience of movement is integrated for the whole space, not just for small localities in that space but for the whole - the global perception. We wanted to be able then to look at the interactions of moving objects in space. To do that, we invented a little special purpose computer, because at that time (1979) this was way beyond what could be done with programming in computers at that time. We designed this special computer, together with the electronics shop at Caltech. What our novel little computer did was to present very localized stimuli anywhere on a television screen—and then have other objects moving in other directions in other parts of the screen space, so we could compare the impact of the stimuli within what we eventually called a classical receptive field, with stimuli moving elsewhere in the visual field. That of course is the normal visual experience.

There's the classical receptive field, which is small and subtended only a few degrees of the visual field, and which had very specific properties. However, the classical receptive field was modulated by visual stimuli lots of other places, so that what was happening was a local-global comparison between objects moving within the classical receptive field and things that were happening everywhere else in the visual field. That's important because that's what perception is, a local-global analysis. We're not aware of the individual receptive fields; all we're aware of is their totality.

This gave us a way of bridging from the local to the whole experience. Specifically, what we found was if you had cells within MT that preferred a particular direction of movement within a little location in space, the classical receptive field, that they were powerfully modulated by movement elsewhere, beyond their classical receptive fields. That is to say that if you stimulate out there in these further places, you wouldn't get any apparent response, but if you compared how that impacted on the response within the classical receptive field, it has a huge effect. Generally, they were antagonistic. That is to say that the preferred movement within the classical receptive field was 180 degrees opposite to the preferred movement in the outside space, in the much broader non-classical field. In other words—and this is very basic principle of opponent processing—we experience things by comparisons, often between opposites.

There are many examples of this. Our experience of motion, for example, is really a comparison between movements in opposite directions. That's called opponent processing. It was known for color vision from work that was done in the 19th century by Ewald Hering, when he showed that red/green and blue/yellow and black/white are opposites, but our experience of color is really the product of the interaction of these opposites, which is the opponent color theory of vision, and was subsequently verified in recordings from neurons by Wiesel and Hubel and others. We were able to show opponent process for motion. We also found evidence that it's true for depth as well, for near and far stimuli in recordings from other visual areas. That is to say a similar opponent processing for objects that are close compared to things that are far away. We published the results for depth in Science and Neuron around 20 years ago.

Thus, a very fundamental principle of neurobiology is opponent processing. From that emerges the global experience of the world from opponent mechanisms. You can see that this can be much more general form. For example, you have agonists and antagonists in muscles that work in opposite directions. There are also many examples from the immune system that serve to keep the immune response within bounds. Even in engineering systems, it's commonly used, because it's a way of getting precise control. It's much stronger than having a system that was only one direction, as you get more precision if you're comparing two opposite mechanisms than just a single monotonic function would be. This is a basic principle of homeostatic regulation, which was developed by Walter Cannon in his Wisdom of the Body and has many applications even to the social organization as Cannon recognized back in the 1930's. It even applies to the experience of emotion, that emotions like lust and disgust tend to be opposed; love-hate, gratitude-resentment and other opponent pairs are probably operating under similar principles. It is a powerful general way of looking at the world. Our work of motion in MT culminated in several papers published in the 1980s on the non-classical receptive field. These also continue to be cited quite frequently, even 40 years after they were published, because they expressed general principles that are widely applicable to many systems. (There is "family tree" of mentors and mentees in neurobiology called Neurotree. I'm a direct academic descendant of Walter Cannon's via his student, Philip Bard, and Bard's student, Clinton Woolsey.)

ZIERLER: I'm curious how you see your background in anthropology being valuable for your subsequent interest, in terms of your perspective, in terms of your world view.

ALLMAN: Actually, in the initial time, it wasn't very valuable. I will have to say that at that time, there was also emerging from anthropology and other disciplines a field that's now called behavioral ecology. That roughly has a similar time trajectory to neurobiology. It barely existed when I was a student, but it has become quite an important field in itself, which is aligned with anthropology in that some of its practitioners are in anthropology departments. The understanding of behavior of animals, including especially primates, within an ecological context, is something that's quite interesting to me, and that has been something that has largely emerged in the last 40 years.

There's a whole interesting story associated with that. I have some connection with that because I have a close friend named Pat Wright, who was very interested in owl monkeys. She did some of the early studies of owl monkeys in nature. But she got interested in lemurs in Madagascar. We went out to Madagascar in 1986. There were old reports that indicated the existence of a particular species of bamboo lemur (Hapalemur simus) that might have become extinct in a particular place in Madagascar. So she went to this place, and lo and behold, there were the bamboo lemurs. They were still there. Pat also found that there was a new species, hitherto undescribed, of bamboo lemurs, that lived in the same bamboo groves. I was there in Madagascar, and I took the first pictures of a golden bamboo lemur (Hapalemur aureus), a very irate female who was shaking her tail fiercely at me. What was really incredible about them is that the species that was known, Hapalemur simus, ate the mature leaves of bamboo, but the new species ate the young shoots of bamboo. What's remarkable about that is the young shoots are full of cyanide. So how is it [laughs] that these lemurs can eat huge quantities of cyanide and be fine? [laughs] That's what this new species could do. It could detoxify cyanide, or perhaps their microbiome could do it. In any event, it was remarkable species specialization.

Pat managed to persuade the government of Madagascar to create a national park for the golden bamboo lemurs, so they set aside 40,000 hectares—a lot of land—as a national park at Ranomafana. I've been there a number of times, and I continue to serve on the board of the research institute that's the core of that operation at Ranomafana, today at the Centre ValBio. You could say that in a sense it sprang from my interest in anthropology, but I'll have to say, anthropology circa 1970 didn't have much of that. That's something that came later. There were one or two early investigators, particularly Jane Goodall, who had begun observing chimpanzees at Gombe in the 1960s. But what became a revolution in our understanding of animal behavior and its relations to ecology had yet to come.

I retained an active involvement in it to this day. The Centre ValBio is very much a going concern now, and they have wonderful facilities. They have moved increasingly into molecular biology. They're doing a lot of things. For example, they've studied a natural population of mouse lemurs, 500 of them or so, and they've sequenced all of them, and they have chips implanted and so on, so they're able to monitor them. They know quite a lot about their genetics and behavior. It's a gigantic natural laboratory that's really a unique operation.

ZIERLER: Very broadly conceived, what do you see as the interplay between theory and experimentation in neurobiology?

ALLMAN: I think it's kind of weak. [laughs]

ZIERLER: Meaning that it's almost purely an experimental field?

ALLMAN: I'm an empiricist. [laughs] I tend to be a bit skeptical of overarching theories. But it also is reflective of where we are in the state of maturation of the field. There may be a point where theory may be more productive. But I try to be agnostic about theory. I just go and do it. That has worked pretty well and continues to work pretty well.

I'm doing, with Ryan Cabeen, an analysis of the data collected in the Human Connectome Project, which I can say a bit about later. I must say that in the analysis that we're doing, there are many surprises of things that I'm not aware any theory would predict, but nevertheless quite robust and coherent phenomena. I still think we're at the kind of "this is really surprising" stage [laughs]. There are all kinds of theories about perceptual function, for example, that were around, say, circa 1970. You don't hear much about them, and that's because they didn't lead anywhere.

In that context, I just want to tell you, another thing that I've been involved with that kind of speaks to this—I had a student in the 1990s, Doris Tsao. Doris was a Caltech undergraduate. She's very capable. I suggested that she go and work with David Hubel and Marg Livingstone at Harvard, which she did. She did some nice research with that group. In the process, I had suggested that one thing that is really special about primate vision is the perception of faces, so that facial identity is a very important part of social interaction, so it might be worthwhile to study that. At that time, there was some work that had been done a few years earlier by a neurophysiologist at Princeton named Charlie Gross, who was a good friend of mine. Charlie had seen a small number of cells in a part of the higher-order cortex called inferotemporal cortex. These cells were responsive to specific faces. A lot of people in Charlie's lab were bearded, including Charlie, and not surprisingly [laughs], they responded to bearded faces. But they' were rare, but well documented enough to convince me that they are probably real.

This was pretty controversial. There are some people that were dismissing it, but I think it's important to pay attention to unexpected stuff like that. They knew roughly where they are, but they couldn't reliably find them

At one point or another, I suggested to Doris that she might do some MRI experiments to see if she could identify where they were in macaque monkeys, and that would help her to place the electrodes, and the way that you would optimize the chances of seeing things at the single-neuron level. Which she did, eventually. At that time, there was kind of this revolution in neuroimaging, and it was typically associated with big labs with tens of millions of dollars of expenditure, rafts of people doing stuff. Very expensive!

Doris went to a place in Belgium with a colleague of mine named Guy Orban, and she learned how to do MRI in monkeys. She figured out a good way to do it in a monkey, how to put them in a scanner appropriately, et cetera. She's a person who has a real knack for experimentation. There are people like that. There are people that just have, as some people say, good hands, but of course it isn't good hands; it's a good conceptual grasp of how to do experiments, which she has, remarkably well.

She was able then to present faces to these monkeys in the scanner, and she got a clear area in the temporal lobe, several of them in fact, that were activated by the faces. Very straightforward experiment, and she did it on a shoestring, with hardly any expenditure of money, whereas these other places are spending millions, big elaborate operations. But it worked for her. It didn't work for the other guys. She then got a research position in Germany, and she pursued this. She was able to identify a whole series of very specific face patches that were reproducible from animal to animal, in the infero-temporal cortex in monkeys. Then she used the MRI imaging as a guide to put microelectrodes in those locations, and indeed, what she saw, instead of having an occasional face cell, virtually all the cells within the identified face patches were responsive to faces. That's a big difference. So she made it a reliable, straightforward, thing to do.

She was further able to show eventually that there was sort of regular progression in the analysis of features of faces in these different face areas, at about six of them. They were analyzing different aspects of facial features, and more general kinds of analysis that—in other words, low-level ones, you'd have to have the face in a particular place, and very specific triggers, whereas in the higher areas, it was much more general. You could see a logical progression in the analysis of the facial features in terms of feature analysis.

Eventually she came to Caltech and became a professor, and actually just left. [laughs] She wanted to have a job for her husband, who's a chemist, and Caltech wasn't able to provide that, so she got a job at UC Berkeley, where they could both have faculty positions, so she just moved. The work is really remarkable. It has been very widely recognized. She probably is a serious candidate for a Nobel Prize, because in a sense, it's the culmination of the work that Hubel and Wiesel began in the early 1960s. One of the key outputs of that is the ability to analyze facial features at a mechanistic level. She has answered a key part of the question of how we see complex objects.

ZIERLER: On that point, it's clear that you're operating largely in a basic science environment, but where have you seen opportunity for applications of your research?

ALLMAN: Well, I don't know, to be honest with you. I have some trepidation about it, What I'm describing now and what I'll describe with respect to fronto-insular cortex on the basis of the analysis that we've done in humans could be misused. I'm driven by the desire to understand these things, but they're also very powerful insights.

ZIERLER: You're saying that there are ethical dimensions at play here.

ALLMAN: There are certainly ethical dimensions about how the information might be used.

ZIERLER: You're concerned primarily with what? Invasions of privacy, things of that nature?

ALLMAN: Social control. But an understanding of who we are and what are the mechanisms responsible for that are a whole lot better than mysticism. But it also is powerful and could be misused.

ZIERLER: Just as a snapshot in time, what are you currently working on these days?

ALLMAN: What I'm doing now is the work on Alzheimer's disease that I mentioned with Long Cai and Barbara Wold, where we're looking at the spatial expression of genes comparing people with Alzheimer's disease with elderly controls, with an effort to try to find out what specifically is going wrong in Alzheimer's disease as people become demented.

The work that I'm doing with Ryan Cabeen—Ryan is now an assistant professor at USC, and he's an expert on imaging. We have been working with a big dataset that was built primarily by David Van Essen and his associates at Washington University. David was another colleague of mine here at Caltech at one time, but he went to Wash U in the early 1990s. David has always been one of these people that is interested in large datasets. One of the things that he did was to supervise the collection of comparable sets of data for imaging and for behavioral data from about 3,000 people. We have been working primarily with the data from young adults between 20 and 35, but there is data available for the whole span from infancy to extreme old age, and we're beginning to work with that as well. It's an extremely rich trove of data. What's important is it is high quality and done to common standards, so it's comparable.

What we were interested in, and what we began with, was a very simple thing. There were these different types of imaging that were done. Ryan and I were really intrigued by information that you could extract from the MR signal that reflected the microstructure of the cortex. These are based on a type of magnetic resonance imaging which is called diffusion imaging. The basic principle behind that is that water molecules of naturally diffuse, the Brownian motion. In brain tissue, that Brownian motion is constrained by neural membranes, so that when a water molecule goes in one direction, it will collide with a membrane and stop or bounce, and if it goes in another direction, say along the lumen of an axon or within an apical dendrite, it can go for quite considerable distances before it's impeded by the membrane.

It turns out that magnetic resonance imaging is extremely sensitive to the movement of water molecules. There's a powerful signal associated with this, so it's pretty easy to measure. In addition to that, there is this technique, which is called high angular resolution diffusion imaging, H-A-R-D-I, or HARDI. What that does is it measures your water molecule migration with respect to different directions in space. You can then measure that directionality, and actually there are several different methods that will express that tendency to move in a particular direction. One is called fractional anisotropy, which is the tendency for water molecules to move in one direction versus other directions. There's the complement to that, which is called the dispersion. It turns out that these methods, which were used initially to trace connections in the brain, and which we've used for this purpose as well, turn out also to reflect the microstructure of the cortex. Another way of thinking about this phenomenon is to imagine what one would get with HARDI if one used a completely uniform sample; the results would be isotropic, that is they would be no differences in the signal for any direction of movement of the water molecules. But if there are aligned membranes in the sample that impede the movement of the water molecules in one direction more than others, the sample is anisotropic and reflective of the microstructure present in the sample.

The remarkable thing is that while magnetic resonance imaging has, say, a resolution of a millimeter, the angular resolution of the directions of movement reflects differences in microstructure that are much smaller than the 2 point resolution. So we can actually get information about brain microstructure that's beyond the simple two-point resolution of the technique. That's because you can see the aggregate tendency for water to move in particular directions that is good enough to be able to see the microstructure based on the spatial orientation of impeding cell membranes. In a sense we're doing is a kind of physics or more specifically using physics to infer cortical microstructure.

ZIERLER: Why do you call it physics, ultimately?

ALLMAN: It's because there is a theoretical physical basis for it. Brownian motion is something that physicists analyzed in the 19th century, and its application to MRI has been very extensively and theoretically done. That's one case in which there's a nice intersection with theory. We're using physics to study cortical structure. It's really just physics. By that I mean the distinction between fronto-insular cortex and surrounding cortex is based on a purely physical measurement with no additional input from the experimenter – no pattern recognition or knowledge. It is just as though the difference was based on the wavelength of light, a purely physical difference. In this case the physical measurement is the movement of water molecules in one direction more than others within each voxel. This purely physical measure also reveals that the direction of the movement of the water molecules is perpendicular to the cortical surface, which turns out to be consistent with the known columnar microanatomy of this area. We applied this measure to the area that I've long been interested in, fronto-insular cortex, which contains these interesting cells, the von Economo neurons or VENs, for which we think there's a lot of evidence that it is involved in self-control, empathy, theory of mind, things of that nature, and is specifically vulnerable in this disease called the behavioral variant of fronto-temporal dementia (bvFtD).

We started out in the first papers that we published on this, in which I delineated, on the basis of my experience from looking at a lot of autopsy brains sections, which I did with the Yakoklev Brain Collection at the National Museum of Health and Medicine. Over a 10 year period, I had looked at thousands of brain sections through fronto-insular cortex in more than 50 brains , and had a pretty good sense of where this area was in the brain. I plotted the fronto-insular area in the MR sections. Then we asked, within that area in this thousand or so brains of young adults, is there anything that stands out as having a high degree of microstructure, or things that have an impact on the microstructure? There were several things that did stand out, which was due to the disordering of microstructure. It breaks down membrane coherence. One of them is the use of marijuana. In this study, we didn't actually have to depend on self-reports, because there was data in the Human Connectome Project for the chemical urine test for marijuana. What stood out right away was that people who tested positive for marijuana, for THC in their urine, had less orderly microstructure in fronto-insular cortex. A definite, very clear physically based effect.

ZIERLER: Which would tell us what behaviorally, or psychologically?

ALLMAN: I think that it would probably mainly impact as reduced self-control and increased impulsivity. There are a lot of ways to measure that, some of which are pretty well documented, and are in the Human Connectome database. So yes, I can go into that in more detail, but it basically has to do with self-control and the regulation of impulsivity.

ZIERLER: I'm curious if there have been any advances in genomics that have been relevant for your research.

ALLMAN: I want to not stop this here, but the answer is yes. But I think I probably should come back to that in a minute, rather than right now, because that's a long riff, and it is relevant. We were able to show that a condition that's called intrusive thinking—the inability to control your own thoughts, which is prodromal for a variety of neuropsychiatric disorders. It turned out that people who had this tendency for intrusive, self-destructive thinking also impacted negatively on microstructure and this effect was independent from the THC effect. That is to say that those individuals also had a less ordered, less coherent structure in fronto-insular cortex. We saw that, and it's quite clear. You can see where the ethical problems there are, though, because this is something that is prodromal for psychiatric disorders.

Anyway, those things were negative, but what was positive was basically most of the measures of cognition, like working memory, IQ, et cetera. What was strikingly positive, one of the most robust things we've seen, is a measure called life satisfaction. If you ask a series of questions to people about how they feel about their lives, it turns out that that is very positively associated with microstructure and in FI. There's a whole interesting story about that, but the bottom line is that what societies need to do is enhance life satisfaction. It's much more important than average income, as the USC economist Richard Easterlin has documented very clearly in many studies. According to Easterlin, long term happiness or life satisfaction is the product of reasonable job security, good family and personal relationships and good health and is independent of average income when measured long term in the same populations. I'd go beyond that and add that life satisfaction also depends on doing meaningful and engaging work. The fact that life satisfaction is related to cortical microstructure and the volume of fronto-insular cortex has interesting policy implications as I'll discuss later.

It turned out that we could use diffusion imaging to define the fronto-insular cortex, because it has very distinctive parameters that could be objectively identified with those two parameters, fractional anisotropy (FA) and neurite dispersion (ODI). Again, it's just physics, measuring how cellular membrane impede the diffusion of water molecules. We've been able to map the area purely objectively in each individual. It turns out to align pretty well with the map that I provided based on my experience looking at a lot of brains, but I can only provide an estimate for the population, whereas now we can map the area in each individual in that large population based on purely physical parameters. The most useful of the measure derived from the physical mapping turned out to be the volume of fronto-insular cortex.

When we do that, we discovered several interesting things. One is it's bigger on the left side than the right side. In terms of the percentage of the total cortical volume FI is also larger in women than it is in men on average. All the things that we saw with the measures of microstructure have been replicated. THC use is related to a smaller fronto-insular cortex, and that's also true for smoking and for alcohol use (more than 1 drink per day). It is reduced in people with negative intrusive thinking. Fronto-insular cortex scales positively with life satisfaction and theory of mind. It also is very clearly related to things like conduct disorder, so that people who report a lot of rule-breaking have a smaller FI. That is consistent with a large number of studies that have shown that people who are sociopaths have a smaller fronto-insular cortex. You can see why there are ethical concerns here. We see a strong signal associated with self-control and impulsivity. One classic measure of impulsivity is a task that's called delay discounting. On delay discounting, you have like a choice between, if you wait a year, you get 100 dollars. If you need the money now, how much of a reduction in that amount are you willing to accept? That's the discount for not having the delay, for getting the money now. That turns out to be a very robust measure of impulsivity, so that people who want the money now, they're more impulsive, rather than the people who willing wait. I think you can see interactions with savings vs spending in financial behavior, for example. There are many, many serious issues here.

ZIERLER: I can see advertisers being interested in this research.

ALLMAN: Yes, because advertisers want people buy impulsively and then become quickly dissatisfied with their purchases so that they will buy more. Capitalism is based on savings, the opposite behavior. What we're seeing across many measures of delay discounting is that the greater the discounting, the smaller the FI. In other words, addiction, impatience, impulsivity, rule breaking. It's relevant to many, many practical real-world issues. I think it's important to do. As I said, it's better than mysticism, because it's based on something real, but it still has its implications and could be misused, and we're very, very conscious of that. It's the scientist's dilemma, really.

ALLMAN: Genomics of course has its own serous ethical issues too. People who work with genomics are worried about similar kinds of problems, because the tools are powerful and could be misused. In the case of genomics, the thing that tends to be very important is gene expression. It's one thing to have the sequence information, and we can do something called a GWAS (genome wide association study) that will allow you to look at little variations in the sequence and relate that to some defect. A lot of work of that sort is done. But if you really want to understand mechanisms, you've got to understand gene expression. That is what we're attempting to do with this analysis of Alzheimer's brains.

My colleague, Barbara Wold, was one of the co-inventors of a technique called RNA-Seq. Now, RNA-Seq allows you to get all the genes which are expressed within some sample, all 20-some-thousand of them, and also their variants too, and it does so in a rigorous quantitative way. It's a very important breakthrough in biology. It's at least as important as the whole imaging technology. It's now possible to look at single cells, to do the RNA sequence on single calls and look at specific classes of cells and gene expression within that specific class. That has actually been done for the von Economo neurons (VENs), and fronto-insular cortex. That single cell RNA-Seq method has been applied to fronto-insular cortex and the von Economo neurons to map gene expression by the Allen Brain Institute. I'll describe this in more detail later. We are hoping to collect these kinds of data for fronto-insular cortex in Alzheimer's and elderly controls since it would provide a useful complement to the spatial genomics that I'm about to describe.

Anyway, we have that genomic information for the particular cell type we're interested in normal middle-aged people. The further advance, which is from Long Cai's work, is that he devised a very elegant way of doing spatial genomics, that is to say, be able to look at gene expression within the spatial context of tissue, so that you can look at thousands of different genes in their spatial context, even down to the subcellular—to the level of resolution of the light microscope, so you can see where in the tissue and where within the particular cells the genes are expressed. That is revolutionary.

In the typical histopathological study—say if you take a sample of tissue, say a biopsy of a tumor or brain tissue—there are just a very small number of stains that have been used to look at that tissue and they give you a very limited picture of what was wrong. Pathologists learned to interpret these stained histological sections by looking at them a lot, which is pretty subjective. That has been the state of the field. So if you had somebody takes a biopsy or you want to know whether the tumor is an aggressive cancer or benign, that's how it's done. But it's done primarily with very limited number of stains, and the skills and years of experience of the pathologist looking at them.

What Long's spatial genomics method makes it possible to do is to look quantitatively at a gene expression for thousands of different genes in that same tissue and gets a whole lot better of a picture of what's going on. That's what we're attempting to do with Alzheimer's disease. The overwhelming emphasis in Alzheimer's disease has been on beta-amyloid and the so-called amyloid cascade hypothesis. The idea that what's going wrong in the pathogenesis of Alzheimer's disease is the deposition of this amyloid, in the form of plaques. Big Pharma has invested many billions in this hypothesis, and produced various drugs that would remove the amyloid, including one that was recently approved by the FDA, and none of them worked.

For the one that was recently approved, the data for one of the two big studies that had been done showed a very slight slowing of the deterioration of cognitive functioning in people who have MCI, mild cognitive impairment. The other big study showed no benefit of the medication. This is not surprising because the rate of progression in MCI to Alzheimer's is extremely variable and thus it is very hard to demonstrate the effectiveness of any therapy using this criterion. This drug got approved over the strong objections of the expert review panel; 3 members of the panel review resigned in protest. The drug company will change 56K a year, which will be paid for mostly by Medicare. Medicare is structured in such a way that because virtually all the people who will be taking the drug are on Medicare, that means that what the drug company gets to charge. You can see the implications of that. Potentially very lucrative for the drug company. That got approved on the basis of a faulty hypothesis and weak data. Moreover, it exploits the hopes for an effective treatment by a very vulnerable elderly population and their families and caregivers. As it turns out, by the way, the initial indications are that doctors on not prescribing this medication, probably for the reasons discussed.

Now, we think that part of the pathogenesis of Alzheimer's is probably related to another protein called phosphorylated tau. Just recently, in Lancet Neurology, some colleagues developed a blood test for Alzheimer's disease that is predictive, and it's based on phosphorylated tau. That's something to keep in mind. Braak, who is probably the leading histopathologist who has studied Alzheimer's disease, has long identified phosphorylated tau as probably the primary factor in the disease. Nevertheless, the amyloid hypothesis continues to struggle along, and people spend many billions researching it.

ZIERLER: Given all of the interest in RNA research with regard to vaccines of course with the pandemic, I wonder if you see vaccines as relevant among the therapies for Alzheimer's.

ALLMAN: Of course, many folks have proposed that. The attempts to do it have been directed towards amyloid and have not been successful. But it's conceivable, if one did actually identify a real causative agent. Thus far, it has not been successful, but I'm openminded about it. Could be.

ZIERLER: What have been some of the advances in microscopy that allow this research at even the subcellular level?

ALLMAN: There is an ability to push the resolution of a microscope beyond the nominal limits, which is about three tenths of a micron. Some work of that sort has been done. There's a lot of reason to think that the basic mechanisms in memory formation are occurring in synaptic spines. Synaptic spines are projections from dendrites that are on the order of five tenths of a micron, so they're down close to the resolution of light microscope, and the spines—most excitatroy cortical neuron will have many thousands of them. Most synapses in the cortex are on dendritic spines. The best explanation I think for memory processes has to do with changes that are occurring within the spines. Synaptic spines might even be considered the organ of memory. Some people are attempting to use the super-resolution microscopy to look at them in living tissue, and intact animals, even. It's possible to do. I think that shows promise.

The spines are incredibly dynamic. They're changing in a sub-second, even millisecond speeds, so they're very dynamic. The spines have actin and myosin in them, and they're contractable like they are in muscle. The spines can change their shape, and that capacity to change shape is probably part of the memory process. It's kind of incredible to think of. People think of memory as stable, but it's a very dynamic system,

ZIERLER: Last question for today for our first session. The things that you're working on now, what would be an example of an issue that you come up against where the primitive basis of our knowledge is really front and center, where you're really operating at the frontier of what could be known in the long term? What stands out in your mind in that regard?

ALLMAN: Well, I'm skeptical that limits to our understanding exist. I don't have any sense that there's a limitation to our knowledge. Part of that of course emerges from my experience and more broadly from the history of science going back to Galileo. The things that were deemed unimaginable when I started out are done readily now, and at levels of understanding that seemed unimaginable at that time. The limitations we have are ethical and societal, I think, and not in terms of the ability to discover. That I think is pretty much at this point without bounds.

There was a guy who wrote a book some years ago—who went around and talked to a bunch of famous old scientists. The old scientists would typically say, "All the important stuff is already known. [laughs] and we did it." It was really silly, but he managed to get a book out of it. Anyway, no, at this point I don't have any sense that there's a real limit, but there are ethical and societal limits . Those are more important. We've got a large portion of the population who refuses to get vaccinated. That's crazy! [laughs] And not only is it crazy, but it is killing tens of housands of people and providing the opportunity for the virus to mutate further into more virulent variants. But that's where we are. That is a societal limitation; unfortunately there are many more.

ZIERLER: I wonder if you've ever considered the philosophical implications of the notion that our knowledge is limitless.

ALLMAN: The only thing that I think really can save us is deeper understanding, because a deeper understanding is better than myth or magical thinking, which are basically false understandings. I see the limitations as societal and ethical, but I'm hoping that a deeper understanding will help people to develop better ethical and societal systems. I think an awful lot of what we're seeing in the world today is the struggle between those views, between essentially long-standing myth and probably the immaturity of our ability to deal with the knowledge that we are acquiring. Because we're not there yet. We don't fully understand what to make of it ethically or societally.

ZIERLER: I wonder what role you might see in achieving deeper understanding, as you call it, with artificial intelligence or deep learning.

ALLMAN: It has its role. I use it. I would not like to see us become slaves to it. I have a colleague who was one of the pioneers in that area and has a very rosy, optimistic view of it. I don't share that rosy, optimistic view. It's another powerful technology that has its ups and its downs. We have to be mindful of that, I think we should not become over-reliant on it. AI mostly provides new ways of doing statistics and looking for structure within large data sets. That's useful but is it "intelligent"? AI provides useful tools, but ultimately intelligence comes down to moral thinking and empathy and I don't think AI can provide substitutes for that.

ZIERLER: That's a perfect place to pick up for next time. We've engaged in a very current discussion. For our next session together, I'll look forward to developing your personal narrative going all the way back to your family origins.

[End of Recording]

ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Wednesday, September 15th, 2021. I'm delighted to be back with Professor John Allman. John, it's good to see you again.

ALLMAN: Thank you. Good to see you, too.

ZIERLER: Today, what we're going to do is pick up from our last discussion, where we engaged in a wonderful tour d'horizon that covered your overall approach to your science. Today what I'd like to do is take the narrative all the way back to the beginning. Let's start first with your parents. Tell me about them.

ZIERLER: What happened?

ALLMAN: Canton, Ohio, at that time was a heavily industrialized city, and it was terribly polluted. Still was when I was a boy. Terrible coal smoke. Terrible particulate matter, sulfur dioxide. My grandfather was vulnerable to sinus problems, and he developed a serious chronic sinus infection. At that time, in 1914, there was no good treatment for this condition. There was a newly developed surgical approach to clear the sinus passages. That surgery was done at a medical school in Philadelphia. As a result, the infection entered his brain and killed him. He died as a consequence immediately of the new surgical procedure, but ultimately from the severe environmental pollution from the heavy industrial and residential coal emissions in Canton,

The family was left somewhat impoverished after my grandfather's death, that branch of the family anyway, so my dad, when he was 15, as was not uncommon in those days, quit school and went to work for the Ohio Power Company where he worked for 50 years, and he was the only source of continuous stable income for that family for many years. He supported his mother until he was 35, and other members of the family. He was a very responsible man, rock solid, generous and kind, and a very wonderful human being. From my father I learned honesty, fairness and personal responsibility for one's actions. When my father died at the age of 90, his younger brother, Walter, told me "we owe a lot to Morgan, he kept the family together". At my father's funeral, even though he had been retired for 25 years, many of his still surviving co-workers came out of respect and affection for him.

There were several things that guided me toward a scientific career. One was the sense that this aspiration that my grandfather had and which he developed up to a certain degree to follow a career in science, was frustrated. And second, that my dad's own life in a sense was compromised by the difficult circumstances that followed from his father's premature death. Those things impact over generations.

Another curious thing that happened in my family—my grandmother's father (John Morgan) was a Welsh mining engineer, and he had emigrated from Wales in 1866 and had come to America and managed coal mines in various places, first in Iowa and subsequently in Ohio, and was a very bright man. His kids were very accomplished, one of whom, Victor Morgan, became a diplomat (Ameican vice consul in Marseille, France) and then editor-in-chief of the Cleveland Press and eventually the chief of the Scripps-Howard newspaper chain. Another, Rowena Morgan Wade, together with her husband, founded a substantial corporation. My grandmother (Margaret Morgan Allman) was very involved in politics. She grew up in mining camps, where her father was superintendent of the mines. She became very active in politics, and cut her teeth, so to speak, in politics by speaking at union meetings among the miner, a pretty rough-and-tumble activity. Subsequently, she became very active in the suffragette movement. You may have seen Ken Burns's Not for Ourselves Alone, on the women's suffrage movement. In the VHS version of Not for Ourselves Alone, there is a film clip at the beginning of a woman giving a impassioned speech at a suffragette meeting. That woman was my grandmother.

ZIERLER: Oh, wow.

ALLMAN: And I have her speech, which was really [laughs] powerful. She was a radical. It's still very interesting and relevant today. This was World War I era, before the passage of the Constitutional amendment on women's suffrage. Her political activity was quite remarkable, and the family, I don't think, has ever quite understood how she was able to do this. My grandfather had died, 1914, and my father went to work shortly thereafter, so he was the only stable income in the family. He had three brothers; all of them went to college, entered various professions, the law and finance. Nonetheless, my grandmother was able to pursue this quite remarkable political career and travel extensively in the US and Europe, and we never quite understood how they made ends meet [laughs]. Because at first, my father didn't make very much money, but nevertheless, he was the sole reliable source of income for many years. My grandmother also had, in addition an older brother, Tom Morgan, who had worked at the mines and had been injured in an industrial accident. He was an invalid, and she took care of him as well. So she was a widow at the age of 35 with four kids, and an invalid brother, and somehow they made it, and made it pretty well. I think that they were really organized. What grew out of this was a very strong sense of self-discipline and mutual responsibility within the family.

In any event, she became very active as a civic leader, was one of the founders of the League of Women Voters and many other organizations and made some money from lecturing because she was a brilliant speaker. In 1923, she became the first woman to serve at the national level in either of the major parties in America. She served on the National Finance Committee of the Democratic Party, which was a full-time job without pay. At that time she gave more than 100 speeches in different places around America. A few years later, there was a tight gubernatorial race. My grandmother was quite influential politically, and she supported one particular candidate—his name was Martin Davey—and Davey was elected governor. So my grandmother was the first woman to be appointed to the Governor's Cabinet in the state; she became welfare director. She was in charge of all the state welfare systems, of the state prisons, of the state psychiatric hospitals, and the state pension fund, altogether 25 state agencies. It was the first time a woman had taken on a job of this magnitude, at least in my state, and one of the earliest in America. She had an enormous staff, thousands of people working for her. She said one of the reasons that she did it was she wanted to prove that women could handle major administrative responsibility. She took 80 women into government with her at that time. One particular aspect of my grandmother's service in government has stuck with me. In her role as head of the state prison system she signed the death warrants for people to be executed and her staff performed the executions in the electric chair. We used to have a pen and ink sketch of Gov. Davey made by a man on death row seeking clemency that struck me as inexpressibly sad, and because of my family's direct involvement with executions, I have been a life-long opponent of capital punishment. In 1940 it was widely assumed that FDR would step down, and my grandmother tried to position Gov. Davey as the presidential candidate to succeed him, but of course FDR ultimately decided to run for an unprecedented third term. She also unsuccessfully ran for Congress in 1940. People who knew my grandmother in her prime—said she was basically a general. [laughs] Sort of difficult having a grandmother who's a general, I can tell you!

ZIERLER: [laughs] How well did you know her? Are these stories secondhand or—?

ALLMAN: I knew her quite well. I spent quite a bit of time with her. [laughs] One little anecdote is that my grandmother lived in this old Victorian house. In those days and heat was generated from burning coal. It was just terrible because it really polluted everything. Coal smoke and grime everywhere, and the various pollutants that are in old-fashioned combustion of coal. [laughs] I can still smell the coal smoke! She had a coal furnace, like everybody else did, but she had had a small innovation, in that the coal was fed into the furnace by a thing called the iron fireman. The iron fireman was about the size of a washing machine and needed to be filled with coal periodically, and it had a worm drive that would take the coal from this big hopper into the combustion chamber of the furnace. Thus one did not need to stoke the furnace throughout winter days and nights to maintain heat. By this time my grandmother was disabled and someone needed to shovel the coal into the iron fireman if there was going to be any heat in the winter. My youthful duty was to go down to the basement, into the coal cellar, and fill up the iron fireman! [laughs]

ZIERLER: [laughs]

ALLMAN: That's how we kept the house warm! Somebody had to fill that iron fireman frequently but that was better than having to stoke the furnace directly. Because she was disabled, the iron fireman did make it possible for her to continue to live in her home with some help from my dad and me. My grandmother was of the school of thought that kids should work. I did a lot of things for her—I painted the floors in the rental apartment she had on the second floor. My grandmother was a person who inspired respect more than affection.

ZIERLER: Where did you grow up? Where did you spend your childhood years?

ALLMAN: I grew up in Canton, Ohio, which as I mentioned—you might even be familiar with it—is an old industrial city. It's not a great place to live. At that time, it was very polluted. Canton was about making money. There were a lot of industries, there. They're nearly all gone today. Many people lost their jobs or their pensions. Comparisons of the quality of life in modern American cities puts Canton close to the bottom nationally.

ZIERLER: Socioeconomically, how would you describe your family's status when you were growing up?

ALLMAN: It's somewhat anomalous, hard to characterize. As I say, several parts of my family were very involved in civic affairs and politics, in a serious way at the state and national levels. My father's grandparents (Carrell Baines Allman and Alice Putman Allman) had been quite wealthy; they owned a department store, the Beehive, and a number of other properties. My great grandfather, who had been wounded twice at Gettysburg but recovered, died in 1903 and my great grandmother ran Beehive department store from then on. She had a very strong sense of social responsibility. My great grandmother lost the Beehive in 1926 in an unsuccessful effort to preserve the jobs of her 50+ employees, some of whom had devoted much of their lives to the Beehive. I know this from family stories but more vividly from an extraordinary account of my great grandmother's efforts to save her employees jobs told directly to me by a former employee, Marian Novak, more 70 years after the event. Marian still felt close to my family and had made contact so that she could give me her account of them. Her family had been in desperate straits, and my family literally saved them in this era before social welfare. Marian had done well in life and now, still in good health in her 90's, she wanted to express her thanks to the family who had helped her. My great grandmother also provided homes on her farm for several of her long-term employees after the collapse of the Beehive. I remember some of them from my visits when I was a boy. That sense of responsibility to their employees is something that was shared by many employers in my community at that time and for many years thereafter; unfortunately, that benevolent attitude has been supplanted by the neoliberal ideology that insists the employer's only responsibility is their shareholders and not to the employees or to the community.

That branch of the family did manage to hang onto some resources; they moved to a farm that they owned and lived there for many years. I remember vividly my great grandmother's home built in 1843 in the Federal architectural style, the creamery where a flowing spring kept perishable food cool, and how the rooms were laid out from a center hall and some of the furnishing, I remember sitting in that central hall on the second story while my great aunt Bessie lay dying. Shortly after Bessie's death that wonderful old home was struck by lightning in 1949, and I remember scrambling through the ruins shortly after the fire. They were very interesting people. My great grandmother was a world traveler, artist and ceramicist. I inherited some of her paintings, ceramics and furniture. My great aunt Bessie (Allman Simonetta) had lived in Paris for many years during the Belle Epoch. I just came across an obituary photo of my great aunt Grace (Grace Allman Snyder). She is holding her pet duck; she lived in a sprawling tree house with her inventor husband, the ducks, countless dogs, a pony and Uncle Mel's inventions (he worked for Burroughs inventing very early automated office machines). They were generous and delightful people and great fun to visit. I think my affection for animals must have come from that branch of my family.

I would say most of my extended family were upper middle class or upper class with the exception of my father. My father started as an office boy, gradually worked his way up. During World War II, he led a team of men that established industrial-level connectivity for the power company, for the war industries. After the war, he was offered a senior executive position in management in the company, which he turned down. My father didn't like that sort of thing—he wanted to be independent. My mother never forgave him for that. [laughs] It's not easy to classify.

A big factor in my life was when my father and my mother moved around the state, for World War II, helping to build the war industries. At the end of World War II, my mother, who had been as a social worker during the Great Depression prior to the War, decided that she was not very interested in being a mother, and would much prefer to go back to work, which she did. In those days, there wasn't much day care. I was born in 1943. So there I was. [laughs] My mother went back to social work. My earliest memories of my mother were visiting her in her office at Aid for Dependent Children in the Stark County Welfare department, which may seem ironic.

So it's not so easy to classify my family, because —my father, by choice, had a working-class job, but it was by choice since he explicitly turned down a major promotion. Many members of my family were quite prominent, and some still are. So, it's not easy to answer that question, but I think the basic thing is that we were well connected, as Jane Austen would say. The other thing, just as a minor thing, my aunt Kitty was a really keen gardener and weaver. [laughs] Some of my early memories are sitting with her, with her working at her loom, because she loved to weave. That imparted to me a love of textiles, [laughs] which I enjoy collecting especially those from Peru and Central Asia. Some of those early experiences were a strong emphasis on history and the sense that we were participants in history. From my grandfather and his background, a strong interest in science and in education. My grandmother was very interested in education and public policy. Those were big influences and started giving me some direction as to where I wanted to go in my life.

ZIERLER: Would you say your family was more religious or secular?

ALLMAN: Oh, my grandfather (Charles Wesley Danford) on my mother's side was a Methodist minister. So were my great grandfather and two uncles. But they were men who had a practical social service emphasis in religion. I would say that my family's approach to religion was pragmatic. My grandfather stressed having empathy for those less fortunate and that message has stuck with me throughout my life! I thought a lot about the broad issues of life and existence as a young person, and I concluded that science gave the best approach to understanding the basic questions of life, and that's where I've held to this day.

ZIERLER: What kind of schools did you go to growing up?

ALLMAN: I went to regular public schools. I feel that the teachers that I had were remarkably dedicated. I think I got a pretty decent education from them. I loved to read, and my family were great readers. My grandmother had a large personal library which I read when I wasn't shoveling coal or painting floors. I first encountered Galileo that way. My family would talk about serious subjects in a fairly rigorous way. Even as a kid, I was expected to know history and current events and to be able to hold up my end of those conversations. It was intellectually disciplined, and skepticism was encouraged. That was the way we lived. So yes, the kids were expected to be responsible and knowledgeable and to be able to defend ideas and to know history. That seemed to me to be different from the way other kids I knew grew up. In reflecting on my childhood, I am struck by how much more independence and autonomy I had as child than do children today. From the first grade at age 6, I got myself to school, back for lunch and home again in the afternoon, rain, snow or shine for some distance through a graveyard and an old urban neighborhood; we never thought that was unusual. The long lines of cars delivering and picking up kids at schools today would have been unimaginable then, and the risks to children weren't any less then than today. I got myself about after school and weekends too and did things with much less parental supervision than is the case for many children today. I even walked to visit my Aunt Grace in the country; a distance of 18 miles. This autonomy provided valuable learning experiences and preparation for adult life that many children today do not get. The prevalent sedentary lifestyle of many kids today from infancy, focused heavily on electronically mediated entertainment driven algorithmically to grab and capture viewer interest for profit, is causing increasing obesity and vulnerability to many diseases that will afflict them later in life with immense personal and social costs to their health and well-being. These include type 2 diabetes, hypertension, arthritis, and greatly increased risk of infectious diseases, which is is serious consequence of this condition.

The linkage between obesity and risk of death from COVID has been evident during the pandemic, but had been well established in large scale epidemiological studies long before pandemic. This is an example of how the pandemic has accentuated serious long-standing problems in our society. Obesity was rare when I was a boy and now it is very common, and it is extremely difficult for most of these people to overcome this problem. I am also saddened when see young people sitting together perhaps on a date, each totally absorbed in interacting with their cell phone rather than the person or persons they are with. Ultimately the obsessive grasp of this technology isolates individuals from other people, from life and from the natural world and all that they can and must learn from those experiences to become fully functional human beings. The current fascination with virtual reality carries this obsession to an even further extreme.

When I was 14, an opportunity presented itself to work at the public library, for pay, and I did that, working 20 hours a week during the school year and full time during the summers, so it was a significant job. It was sometimes very hard work and long hours. On one occasion when a new library building had been constructed, six of us moved the entire book collection, half a million volumes between buildings between closing time (6 PM) on Saturday evening and opening time (9 AM) the following Monday morning and kept all the books in proper Dewy-decimal order, thus permitting to library to maintain normal hours for the public during this big move. I worked at the library all throughout high school. I think I learned as much from that as I did from school. It was a big public library, one of those old Andrew Carnegie libraries. Something rubbed off. I came to the world of knowledge by that experience; and it was quite helpful to me later on. I think I learned as much from that experience as I did from formal schooling.

Another thing that I did in that period was to restore an antique car. I had a 1915 Model-T Ford [laughs]—my dad and I did a lot of things together. He loved to drive around the back country roads of Ohio. We saw this old car when I was 14, and he said, "Well, maybe we should try to get that." [laughs] I remember the guy who owned it was named Peewee. He operated a pool hall, and there was this little old Ford sitting out in front of the pool hall. It turned out Peewee was interested in coins. I had a little coin collection at the time. [laughs] I remember bringing my coin collection and laying it out on this pool table. There's my coin collection, and various and sundry somewhat unsavory types hanging around [laughs]. I laid out the collection, and he had an adding machine, and we took the book value on the coins, and he gave me I think two thirds of the book value, which was generous. Anyway, it was enough to pay for the car, so I got this antique car [laughs]. Which wasn't running. [laughs]

But I liked fixing stuff. It was a challenge, and I figured out enough about it that I was able to get it to run pretty well, and I restored it. It was something that was a rewarding thing to do because it called on problem-solving and getting resources to do stuff, and finding people who could do this or that thing to help me. I had a neighbor, for example, who had worked on Model-T Fords back in World War I, and he understood the bizarre planetary transmission that the Model-Ts had, which was very peculiar and did not involve a clutch but instead a series of revolving gears and cylinders, the planets and orbits, that is entirely different from the transmission in modern cars. It was learning how to ask people for help, and how to get unusual things done, but it was a good experience for me. The experience of restoring an antique car later served as a bridge to anthropology. In the summer of 1962, I worked for pay as a regular GSA employee in the Laboratory of Anthropology at the Smithsonian Institution under Joseph Andrews, who was a restoration expert and artist who taught me a lot. There I restored ancient Japanese pottery from the Jomon period, some of the oldest pottery known. I started with a pile of about 150 shards and completely restored an entire large Jomon pot, which was a complex process that required being able to conceive of the whole irregularly shaped vessel from the shards and also to fill in the spaces for the many missing pieces. It was good training for the scientific work I did later.

ZIERLER: Obviously you would have been very young, but do you have any early memories of World War II?

ALLMAN: Not really, no. Just little fragments but no, I don't have an explicit memory. [laughs] I do remember a lot of events just shortly thereafter, including in some vivid detail the events leading to the Korean War and of the early period of the Cold War. For example, I can remember that there was an idea advocated by General MacArthur that the U.S. should use atomic bombs against China during the early stages of the Korean conflict. We had a very contentious family discussion about bombing China at that time. I understood that was a very serious step to take, and that we should not do it. That was something that I thought about when I was six, seven years old. Later, President Truman fired General MacArthur, which I remember vividly and MacArthur's rather maudlin departing remarks to Congress, "Old soldiers never die; they just fade away". I also remember very clearly the CIA overthrow of the democratically elected Iranian Prime Minister, Mosaddegh in 1953, which had ominous implications for the future in the mid-East. The repercussions from that event are still felt today. At the time in the early 1950's, I was concerned about both the potential conflict with China and the Iranian situation, which are still important issues today.

ZIERLER: What about Sputnik? Did that register for you, as a boy?

ALLMAN: Well not so much as a geopolitical issue. I was certainly aware of it. Let's see, Sputnik was 1957, wasn't it?

ZIERLER: Yes.

ALLMAN: I was quite aware of Sputnik in connection with the issues associated with getting a satellite into orbit, for example powerful booster rockets, things of that sort, that we were, or at least thought we were, behind the Russians. I've always been interested in acquiring knowledge and to the extent that space exploration contributed to new knowledge that I found it exciting.

ZIERLER: When did you start to get interested in science?

ALLMAN: I was interested in it, I don't know, probably—

ZIERLER: As early as you can remember?

ALLMAN: Yes, probably very early. You'll notice in my book that I dedicated it to my father. One of the things that was really great about him was his encouraging intellectual curiosity, and encouraged me to ask questions about things. That of course began very early in my life, as far back as I can remember. I can't identify a specific point when that happened, but quite early. The basic thing is the importance of curiosity and of pursuing that in a rigorous way.

ZIERLER: When it was time to think about university education, was it science specifically that you wanted to pursue?

ALLMAN: No. As I said, I've had a strong interest in history my whole life. Still do have, for some of the reasons I mentioned. I had visited the campus of the University of Virginia when I was a teenager, and I was taken by the architecture and ideas of Jefferson, so I went there as an undergraduate, at UVA, partially because of the sort of political ideals and so on, and their strength in history. That's why I made the choice to do undergraduate work at the University of Virginia. But at that period, my interests took a reductionist bent and gravitated first toward the social sciences, and then strongly towards biology, somewhere roughly in the latter part of my undergraduate years. I had a growing interest in evolution, which was sparked in part by an excellent course in Geology and Paleontology. I got an NSF graduate fellowship, and I took that to the University of Chicago, initially in social anthropology, but I quickly realized that my real interests were in the biological basis of behavior. I pursued that, as I have continued to do so, throughout my life. I think I may have spoken about that, but the idea of understanding the way information is transformed at different levels in the nervous system, and accessing that through microelectrode recording, which at that time was just in its infancy.

ALLMAN: In those days—and I think this is very concerning—education was very much less expensive than it is today in real terms, so that the entire cost of an undergraduate education at the University of Virginia, as an out-of-state student, was about $2,000 a year, at that time. I contributed part of the expenses from my own earnings, part of it from the sale of my antique car, part of it from scholarships, and part of it from my parents' support. My parents paid for, I would think, about 5/8th of my undergraduate education, about$5,000 out of a total of $8,000 at that time. You can inflate that total according to the standard inflation procedures; you might come up with$40,000 in modern money. Anyway, it's less than a single year of schooling at that same university today. College education has become outrageously expensive, and I think that there are serious social consequences from that, including burdening of people with mountains of student debt that can take a lifetime to repay, which I think is wrong. I believe that education is a powerful social good and that better educated and informed people tend to make better citizens; develop better critical thinking skills; make better life decisions and as a consequence tend to be healthier; make better parents for their children and make better lives for their families. Learning a profession to earn a living is only part of it.

Education is also a life-long learning process and not necessarily just formal schooling. Because of these considerations, which transcend the individual and impact positively on the broader society and future generations, I think there is a strong case for the public support for education at every level. This view is consistent with the policies advocated by the great educational reformers such as Horace Mann that led the United States to become the most highly educated and productive population in the world until about 1980 when attitudes supporting public support for education began to wane, another negative contribution of neoliberal economic ideology.

To answer your question, we were able to do it, although I needed to be pretty frugal. It would be very difficult to do it today. It would certainly have involved taking on large debt, when we did not have to take on any debt. Then I was fortunate to get excellent graduate support to pay for everything. Again, that was probably better then than it is today because I had more independence and could chose were to work because I had my own support throughout graduate school from NSF. I think that we lived in an environment when I was getting my schooling, almost 60 years ago that was much easier and better than it is today. The people who are coming up now, I think face much more serious burdens than I did.

ZIERLER: When you went to the University of Virginia, was it integrated at that point? Were there Black students?

ALLMAN: I had a direct experience with that, actually! [laughs] When I was at UVA [laughs], I had a friend, who was a direct descendent of the first colonial governor of Virginia. He was an FFV, First Families of Virginia, which meant a lot there. Anyway, my friend said, "Let's go over to the Jefferson Society and interview for it." I said, "Oh sure, okay, I'll come along." [laughs] So we show up for the interviews. He was politically conservative, and [laughs] one of the interviewers asked whether he thought that American school children should listen to Russian music. [laughs] And he said, "No, no, they shouldn't be exposed to Russian music." [laughs] The interviewer said, "Well, how about Peter and the Wolf?" [laughs] And that ended his interview. And they interviewed me, and I said the right things, whatever they were, [laughs] and they invited me. It was kind of ironic, because it's something I probably wouldn't have done otherwise, another chance occurrence. I got full membership eventually in the Jefferson Society. It was very interesting. We got good speakers. There were thought-provoking discussions. There was a Black medical student who applied for membership in the Society, and of course it had been all white and privileged. I remember he went through the whole process. I'm pleased to say that when he was considered for membership, in spite of the fact that there were some rabid racists members who said the sort of things you'd expect them to say, we voted against the racists. We admitted him, and he was the first Black member of a significant social organization at the University of Virginia, ever.

ZIERLER: Wow. How did you come to focus on anthropology? What was the intellectual trajectory that landed you in this area?

ALLMAN: I was interested in behavior. I was probably influenced to some extent by my mother, who was a social worker, and had some of those sorts of interests. It soon became clear to me that the explanatory power of social science as it was practiced at that time was not very satisfying. That led me, through reading and so on, to decide to pursue the biological approach, which I've done. Why was I particularly interested in the scientific study of behavior? I really can't tell you! [laughs] That ancient Greek thing of "know yourself," try to understand the world around you, basic curiosity?

ZIERLER: Given the intersection of behavior with biological considerations, did you consider anthropology to be the connecting point between psychology and biology? Was that the idea?

ALLMAN: To some extent. There's a long tradition in anthropology of what was then called physical anthropology, or today is called biological anthropology, which is human evolution, archaeology, hominid paleontology, primatology, and also descriptions of natural variations in existing human populations. Those were interesting to me, particularly paleoanthropology and human evolution interested me then and is an area in which there has been enormous progress made in recent years resulting from the ability to analyze ancient DNA, that has made it possible to understand ancient populations in much greater detail than we ever thought would be possible. That has been done. But the option that I took, which was slightly different, was a burgeoning interest in non-human primates. My entry point was in the study of non-human primates.

ZIERLER: What were some of the big issues in physical anthropology when you were an undergraduate? What were some of the big ideas?

ALLMAN: One was the domestication of plants and animals, and their impact on human societies. That's something that again I have retained some interest in, particularly domestication of dogs. More broadly, when I teach my course in this, I devote a part of the course to the interaction between humans and the animal/plant worlds via domestication. Domestication has had an enormous impact on human life. It's hard to imagine modern life could exist without it. That was one that really struck my interest quite early on, and again one that the analysis of ancient DNA and genomics has had a very important role in. There's a deep set of questions with respect to the origins of human behavior, and how much can we infer from the behavior of non-human primates. That is also something that has intrigued me quite a lot. However, many of my interests were beyond the field of Anthropology as it then existed,

My own particular approach to that was to try to understand the organization of cerebral cortex in non-human primates, and more recently, when it has become possible to do, in humans as well. I'd say it was clear to me that that was a very important area of potential investigation, and one in which there had been some work in. But we really pioneered in that and did a lot of the original work in it, particularly with respect to the organization of the different cortical visual areas. So I'd say that the recognition that you wanted to see what was distinctive about the brains of non-human primates and of humans was something that people recognized even then was pretty important, but for which at that time they didn't have good methodologies for doing it. That has changed radically.

ZIERLER: In terms of your curriculum as an undergraduate, how much of it was in biology? How much of it was learning the anatomy and the physiology?

ALLMAN: As an undergraduate, practically none. As a graduate student, a fair amount. I would say that I learned, as a special graduate student and later as a postdoc, in the Laboratory of Neurophysiology at the University of Wisconsin, a lot of it through direct, hands-on work, actually doing, rather than learning from a textbook. I was fortunate. It was a very conducive environment for exploring the brain.

ZIERLER: What kinds of graduate programs were you thinking about, and did you know specifically that you wanted to remain in anthropology?

ALLMAN: There weren't a lot of choices in terms of good programs in anthropology. At that time, and perhaps it's still true, that the premiere one was at the University of Chicago. I got in. I would say it was a more conventional graduate program in the sense that you took courses, and then you would do like a thesis proposal and go off and study some exotic people somewhere in the world, and you'd get a thesis and then you would get a faculty job somewhere. That was kind of the standard model. As I mentioned, that was not really all that compatible with the study of biological basis of behavior, but I was fortunate to have an advisor who was very supportive of that, Clark Howell, so I was able to pursue quite a different route, which ultimately took me to the Laboratory of Neurophysiology at the University of Wisconsin.

I'd say that I ended up at certainly a very good place, Chicago, and that I was very fortunate to have someone who I could interact with and was supportive of my peculiar interests, and who himself of course was a biological anthropologist. [laughs] And that through his direction and my own good luck, I ended up at the Laboratory of Neurophysiology, which at the particular time that I was there, was a very fertile place. There was great stuff going on, and a lot of really interesting collaborations and interactions and exciting discussions, and so on, and a good learning environment, and a great environment for doing research on the brain.

Clinton Woolsey, who was the principal investigator and lab director, had built a very strong, supportive staff of very highly skilled technicians. You could go with those people and do really great cutting-edge stuff, at that time, because of the infrastructure that he had built. I have to say that I was fortunate to get into that environment, and I was also fortunate to have the NSF fellowship that gave me the freedom to do it. There are times in life when you have to look back and say, "I was really lucky!" [laughs]

ZIERLER: How did you go about narrowing the wide world of things to study for what ultimately would become your thesis research?

ALLMAN: It was pretty explicit. I had this vision that you could understand cortical evolution by understanding the way information was handled at different levels in the cortex, and that one would look at that in non-human primates physiologically. That's what we did. I again was fortunate that I had John Kaas as a collaborator, who was at that time beginning assistant professor. He had been a postdoc there, but the microelectrode recording we did was new to him as well. Actually, this was a really remarkable thing. There was a recently vacated lab that was about 10 by 20 feet. It had a rack of electronic gear and an oscilloscope and stuff like that. Woolsey said to me, "Go to it. Just do it!" [laughs] And I did it! It had a lot of vacuum tubes! It was, by our contemporary view, extremely primitive, but it did work. It was simple enough that I could make it work pretty well. I learned how to make platinum-iridium microelectrodes and that sort of thing. I pretty much did what I had in mind doing at the outset.

ALLMAN: Woolsey and Clark Howell were my thesis advisors. They said, "We'll let this guy do what he wants to do." [laughs] That was that.

ZIERLER: On the social and political side, what was it like being in Chicago in the late 1960s?

ALLMAN: I left Chicago in 1968. There was massive rioting on the west side of Chicago following the assassination of Martin Luther King. I attended a service for King at the University chapel and outside there were perhaps 5000 Blackstone Rangers, the southside gang, congregated outside. Their leaders had pledged to honor King's belief in non-violence, but a spark could have set them off as had already happened on the West side; and there we were, very vulnerable. However, I would say that the University of Chicago wasn't that much of a hotbed among the students at that time. But going up to Wisconsin, Wisconsin was. I was there at the time in which the New Year's Gang blew up the Army Math Research Center. I don't know if you know about this? You might. The New Year's Gang were a group of political radicals, and in the peculiarities of that time, they wanted to blow up something symbolic. [laughs] They actually went to the state authorities in Wisconsin and applied for a blasting permit! [laughs] Which was an unusual thing for political radicals planning to blow something up to do. [laughs] Anyway, they rented a truck and filled it with petroleum and ammonium nitrate fertilizer, which makes a powerful explosive when mixed together, and they got a couple tons of the stuff, and drove over and parked it next to the Army Math Research Center, which was an easy target. Then they called the campus security late at night and said, "We're going to blow up the building, clear it out." Unfortunately, security apparently didn't take them seriously, and there was a physics researcher working in that building, and he was killed and 3 were injured when they detonated this thing. A ton of high explosives completely destroyed a six-story structure. I came by it the next day, and all there was a 20-foot-deep hole in the ground. Blew out all the windows nearby, including some in our lab.

The New Year's Gang left the vicinity and were driving up to a place called Devil's Lake, and they were stopped by the Highway Patrol. The Patrolman said, "Do you know anything about this explosion?" They said, "Oh no, we don't know anything. We're going camping!" in spite of the absence of camping equipment in their car [laughs] "Not a problem." So they let them go. Later, some of them went to Cuba. Eventually one of them, came back, served 7 years in prison, and then the last I heard of him, he was a city council member in Madison. [laughs] It's a strange story.

Anyway, that was a pretty concrete political action. I was disturbed at that time about how accepting people were of political violence. It became an everyday occurrence. There was a lot of that kind of activity at a lower level—breaking of windows, rioting, and stuff like that—that was a fairly frequent occurrence in the 1969-1970 period. Anyway, yes, it was definitely turbulent, and it made me aware of how accepting people can be of acts that are very harmful and dangerous.

ZIERLER: Before we get too far afield, what were some of the central conclusions of your dissertation, your graduate research?

ALLMAN: We did the microelectrode mapping. This was very straightforward. The monkeys were anesthetized. We exposed the relevant area of cortex, and we inserted with a Microdrive— very tiny, microscopic electrodes into the cortex and were able to elicit activity either in single neurons or in very small populations of neurons, which we could see by the action potentials of the firing of the cells on the oscilloscope. We fed that to an audio amplifier so we could listen to it as well. We had a plastic hemisphere in front of the monkey, centered on one eyeball, and literally with little spots of light and shadow, we'd map out the receptive fields of the neurons in the cortex with this very simple but effective method. We would do that by listening to the activity and then moving a little spot of light or shadow, and then marking the receptive field with crayon. [laughs] Basically you needed a microelectrode, which I made from platinum-iridium wire etched with cyanide and coated with molten glass; a low noise amplifier of the action potentials (based on vacuum tubes); an audio amplifier and loudspeaker so you could listen to the action potentials firing, and the hemisphere, and away you go.

We did that, and we were able to relate the locations of the receptive fields—it was quite clear that they formed a map of the visual field. It was also quite clear that there were many maps of the visual field cortex. So each of these maps comprised a distinctive cortical area with the presumption that those different cortical areas did different types of analysis of the visual input. What was my original thesis—the 2 publications arising from my thesis have been referred to about 1,000 times—and still referred to a good deal, now 50 years later. The basic substance of the thesis was the retinotopic maps of primary visual cortex and of a couple of higher-order visual areas, particularly the area we called MT. We were really the first to see MT, and maybe several of the other areas. Subsequently, there have been thousands of papers done on MT, because it has such clear physiological function with respect to the analysis of visual motion. It has been a favorite thing for people to do because it's so straightforward. [laughs] My thesis was the mapping of primary visual cortex, MT, and some parts of other cortical areas. It's work that still stands.

ZIERLER: Tell me about the Laboratory for Neurophysiology at the University of Wisconsin.

ALLMAN: Woolsey was the director and principal investigator of the program project grant that supported it. He had another colleague, another senior person, whose name was Jerzy Rose. They made kind of an interesting pair. Rose had quite an important impact on my thinking as well. Rose was trained as a psychiatrist, but he got very interested in auditory physiology. Rose and his colleagues did microelectrode recording at the more peripheral parts of the auditory system, the cochlear nerve and the cochlear nucleus, first and second order parts of the system. They carefully quantified the responses to sound input so that they were able to show quantitative relationships between the auditory input and the activity of single neurons. It was clear to me that that was the way to proceed, and it should be done in vision. (As it turned out, Jerzy's uncle, Maximillian Rose, also had an important impact on my research but much later in my career when I used his massive comparative study of the microstructure of insular cortex publshed in 1928 in my work on fronto-insular cortex; it's a small world.)

ZIERLER: Why was it clear to you?

ALLMAN: Because it was real science. You had the ability to quantify the stimuli, and the output of the system, the firing of the action potentials, was essentially digital, and again was readily quantifiable. So you could look at these input/output relationships in a rigorous quantitative way. That's something that I saw as an important thing to do in vision as well. Which we did, beginning there at Wisconsin. This is technically a difficult thing to set up, but we pursued that, in some of my papers where we followed that paradigm but at higher levels in the visual system, particularly MT.

I have to give credit to Rose and his colleagues. They were really the pioneers in quantitative single neuron recording. They were also pioneers in the sense that they probably were the first scientists outside of some areas of physics to utilize the potential of computing in conducting experiments. We had some of the very early computers, these LINC (Laboratory Instrument Computers), with 8K of memory that filled a room, and were very difficult to program. They were some of the very earliest users of computer technology in the biological sciences, possibly the first. They had begun this in the early 1960s, so they were way ahead of the curve. You needed to have electrical engineers and machine-language programmers to do this stuff at that time. I was fortunate that there was an electrical engineering student, Fran Miezen, and he and I worked together for 16 years, first at Wisconsin and then subsequently here at Caltech, where he did all the engineering and computer aspects of the research we were doing. Fran was a very positive factor in the success of our research during that period. He eventually joined my former student, Steve Petersen, and became a tenured professor at Washington University working in brain imaging and retired recently. It's amazing to me that so many of the people that I worked with— people who were my students, too, are all [laughs] retiring, or are retired. I'm still around and working. It's one thing to see your colleagues retire, but it's another thing to see your students retire!

ZIERLER: When you became an NIH Fellow in 1970, did that substantively change your work, or that was an administrative change?

ALLMAN: It was very helpful. That was Woolsey's doing. Woolsey was very supportive. I couldn't have done it without it, just to be blunt. I wrote a competitive fellowship in which I outlined these ideas about doing a quantitative study of visual processing with single neuron microelectrode recording and precise control of optical stimuli, which was turned down [laughs]. That's where the field went, of course, but it was a little bit too early for people to accept it, circa 1970. I've had that happen several times in my career-a bit too early!

ZIERLER: Besides the funding, was the connection to NIH specifically useful from a research perspective?

ALLMAN: No, no role at all.

ZIERLER: What were you working on, at that point? How had the field and your own research changed from your graduate school days?

ALLMAN: I did the work that I described in the owl monkey visual cortex when I was a visiting graduate student at the Laboratory of Neurophysiology. This was the extent of my official connection, but I did the work, and it was a supportive environment, although I was nominally only a visitor. I then stayed on as an official postdoc at the same place, and I pretty much did the same thing. The reason for that was there was still a great deal to do, with the particular paradigm that John Kaas and I were doing. So it was a direct continuation of what I had done as a graduate student. Then moving into this more quantitative approach is something that I was able to do at that time as well.

ZIERLER: Were there advances in observation, in instrumentation, even in the literature? What were the new developments at the vanguard of the field at this point?

ALLMAN: Well, the great thing of course was David Hubel and Torsten Wiesel's studies of visual cortex for which they won a Nobel Prize.

ZIERLER: What was specifically relevant about that work to what you were doing?

ALLMAN: They had been interested in the way in which the activity of single neurons is reflecting in processing in several cortical areas, first in cats and then in monkeys. They also found the thing for which they won the Nobel Prize, which is the columnar organization of cortex, which is the observation that when you're in any one particular point in the cortex, that cells in the cortex are organized into a column perpendicular to the surface, and they all share similar features of processing as you go down through the different layers in the cortex. It's a fundamental organizing principle of cortex, and that work stands.

They particularly got the prize with for what's called orientation selectivity. That is to say that they're activated visual cortical neurons by an edge or light or shadow in one orientation versus another orientations. They famously discovered orientation selectivity by accident, but it proved to be a powerful organizing principle for columnar organization since the neurons in a column shared the same orientation preference.

Now, it became clear to me that something that was really potentially interesting was to carry this forward and to see how information would be processed in this variety of higher-order cortical areas that we had uncovered. As I mentioned, MT turned out to be very specialized for the analysis of the direction of motion of objects in space. I did a lot of the early work on that. Throughout that period of my career, I had a close relationship with David and Torsten. Eventually, Torsten went to Rockefeller University in the 1980s. I gave a talk at Rockefeller in the mid 1980's and Torsten in his introduction described me as the "scientist's scientist", which was finest complement I've ever received. In the late 1980's David offered me Torsten's position at Harvard, and I seriously considered going to Harvard.

That was essentially the message that I gave to Doris Tsao when she worked in my lab in the mid-1990s, and then encouraged her to go and work with David at Harvard, which she did. Later, she pursued this higher-order aspect of visual processing with respect to analysis of the facial features. That was extremely successful. As I say, she may well win a Nobel Prize for that work, because it really brings this all together, in terms of a really detailed analysis of how we see complex objects. That's a little thumbnail sketch of it. So that was something that was going on at that time, and it has evolved over a period of 50 years.

ZIERLER: What was the job market like when you first went on it?

ALLMAN: It was pretty good. Woolsey suggested to me that I apply to this position at Caltech, which I did. Caltech was at that time building in neurobiology, and they had this new building, Beckman Behavioral Biology, and they were populating it.

ZIERLER: What was your sense at Caltech—who were driving these developments in neurobiology?

ALLMAN: That's an interesting question. Caltech had had several very distinguished neurobiologists, Cornelius Wiersma, Antonie Van Harreveld and Roger Sperry. Van Harraveld did some of the early work on myosin in dendritic spines that suggested that the were motile, which I discussed earlier. Roger was particularly interested in the higher-order aspects of neural processing and cognition. When I interviewed, Roger was very supportive, and I was very fortunate in my interactions with him. He subsequently became a good friend. But I would not say that they were necessarily driving it.

My impression is that Jim Olds, who was another senior professor interested in learning and motivation—and Bob Sinsheimer, who was then chair of biology, were probably the driving force for it. Then of course they were able to get very substantial support for this from Arnold Beckman. So I would say that Jim Olds, Bob Sinsheimer and Arnold Beckman were the drivers of it.

ZIERLER: What were some of the major research questions at the time at Caltech when you joined?

ALLMAN: There was a lot of interest in visual processing or sensory processing in general. For example, they also at that time hired David Van Essen, who had similar interests in visual cortex. David subsequently has gone to Washington University and has done wonderful things with what's called the Human Connectome Project, which is a tremendous contribution to the infrastructure of knowledge, and one which we use a lot, and is an enormous positive resource.

Jim Hudspeth was another person that was hired at that time who was deeply interested in the biophysics of auditory processing. He subsequently moved on, I believe to Texas and eventually to Rockefeller. And Jack Pettigrew, who was interested in binocular vision, stereopsis, who returned to Australia. And Ron Konopka, who had done very important early work on the genetic basis of circadian rhythms. Ron died—but that was later. The work that grew out of his early work won a Nobel Prize for people who pursued it. Sensory processing was most of it at that time.

ZIERLER: Did you get the sense when you came to Caltech that Caltech's approach to so many scientific issues was multidisciplinary, that the walls between academic departments were quite porous? Did you get that sense? Was that useful for your research agenda from the beginning?

ALLMAN: I'd have to say yes. Caltech is a pretty interdisciplinary place. I think that the relatively simple organizational structure of Caltech and its relatively small size have helped with that. Of course, I feel that Caltech professors have been treated very well by administration. It has been generally very supportive.

ZIERLER: What illustrates that point in terms of the kinds of colleagues that you interacted with?

ALLMAN: I think that the classic thing is the emergence of the CNS program. I don't know if you're familiar with that.

ZIERLER: I'm not.

ALLMAN: Carver Mead, whom you know, Richard Feynman, and John Hopfield taught a course together on the physics of collective computation, which excited students. I knew Carver in particular pretty well, and it was also clear that the students often coming out of physics or electrical engineering wanted to have a program that would link these areas to the nervous system. The students in effect demanded a PhD program in these sorts of quantitative and modeling approaches to understanding the nervous system, hence CNS. Carver and I and a number of other people talked a lot about this at that time. And it happened. We hired people, brought in a lot of students, and it has been a real success story.

ZIERLER: Where did you see your areas of expertise and Carver's intersect? How did that work together so productively?

ALLMAN: Carver had a graduate student named Misha Mahowald. Misha was interested in creating an artificial retina, on a chip. Misha and Toby Delbruck, who has pursued this up to present—the idea of creating an electronic analog of sensory processing on a chip. Misha was doing it for an artificial retina, and Carver also had people who were doing it for auditory processing as well. So that became a major focus of his lab—we talked a lot. It resulted in all sorts of good things happening.

ZIERLER: What was your impression of the undergraduates when you arrived at Caltech?

ALLMAN: At that time, the typical undergraduate, say 80% of them, were inspired by Richard Feynman, and they all wanted to become physicists. [laughs] That has changed, as you probably are aware.

ZIERLER: In a big way. Certainly.

ALLMAN: If you talk to a typical Caltech student these days, they all want to do CS. Honestly, I think the interest in becoming physicists was basic curiosity about the physical world and understanding it. I hate to say this, but a lot of the interest in CS is in making money and of course having a BS from Caltech in CS can be very lucrative.

ZIERLER: Was biology in growth mode at that point, when you joined?

ALLMAN: Yes, but not as much as later. Biology was working in a very limited number of model systems, like drosophila, for example. I had the feeling it was quite constrained. There was also very much the sense that the only people that can do that stuff were members of that particular community, so I felt a little closed. That has changed a lot. For example, Joe Parker, whom we recently hired, is a person explicitly interested in evolution, and is studying as his model organism a type of beetle. Now, there was no infrastructure of molecular genetic knowledge with respect to that beetle or members of that family of beetles, which are parasites on ants, the rove beetles. That would have been something that people would have said, "Well, you just can't do that," a few years ago. Because we haven't mapped the genome. We haven't cloned genes, et cetera. All sorts of basic technical issues that would have been in the way. Anyway, Joe was able to solve those in a matter of a year or two and has brought the rove beetles up to being at least as good as the standard model systems. That's now possible to do. That's a tremendously liberating thing, to not be confined to a few model systems. That has allowed for an expansion of the kinds of experiments that you can do and also expansion of how you think about things. I think that has been very positive.

ALLMAN: Oh, yes. I had a fair number of students, and interacted, particularly in the early years, with a number of graduate students in genetics, and because of my interest in some of the developments in that area.

ZIERLER: Did you see particular relevance in the rise in genetics for what you were doing?

ALLMAN: One of the puzzles about the way the cortex is organized is that there's an enormous apparent redundancy in cortical areas, so that there are, say, a dozen or so cortical visual maps, and a number auditory and somatosensory maps. If you put down electrodes on those different maps for each sensory modality, you'll see a lot of commonalities in the responses to stimuli. What is the meaning of having these multiple structures that seem to be doing similar things? A built-in redundancy. That occurs in genetic systems as well.

It goes back actually to ideas that were developed by Calvin Bridges first at Columbia University and then subsequently at Caltech, in the World War I era and into the 1930s. What Bridges was interested in doing was mapping the giant chromosomes of flies and relating the specific sites within those chromosomes to specific mutation sites controlling development. That line of investigation was pursued by Ed Lewis and led to the discovery of the homeotic genes. Ed won the Nobel Prize for how the homeotic genes control the formation of the different parts of the body. It is a very great discovery and is a major organizing principle in development and evolution (EvoDevo). Bridges original 1935 map of the chromosomes in Drosophilia is on display on the 3rd floor of Alles near where Ed's lab was located. Bridge's map is the father of all genetic maps.

The point, though, was that there's this apparent redundancy in genes, just as there's a huge apparent redundancy in cortical areas. Bridges' contribution was that he recognized that a major factor in the evolution of genomic systems was duplication of genes, which he developed in 1918. After the initial production of the duplicates the copies were similar to the functions of the first one, except that the copies could undergo mutations that would have compromised the functioning of the original gene, and thus the copies could develop new functions while of the original gene continued to perform its vital functions. Evolution by gene duplication is an absolutely fundamental mechanism in biology.

I thought, "Well, that has some explanatory power with respect to thinking about multiple cortical maps." That is to say that these extra areas—and we now know something about how those areas arise, and how they are encoded—that the principle would apply that you could have the basic functions performed, and then have extra maps that could be modified by evolution to perform new functions as well. This seems to be a powerful organizing principle in biology, and helps to understand why there is this apparent huge redundancy in biological systems.

But an important corollary is that these ideas come in conflict with ideas of efficiency, so that there is a notion, which I think is actually incorrect, that biological systems prize efficiency, in other words getting the most done with the least expenditure of energy would be one way of defining that. I think that the real principle is one of resilience. That we are all the descendants of organisms that survived and reproduced, for millions of generations. They were not necessarily the most efficient, in fact almost certainly not the most efficient. They're carrying a lot of baggage with them, a lot of extra cortical areas, a lot of extra genes, that are basically kind of similar to one another. Indeed, in gene knockout studies, it's often the case that you don't really get much of an effect at all, knocking out a particular gene. You might have to knock out all the paralogs of the gene as well, to actually start to see an effect. The replicas are called paralogs.

So the real thing about biology is that you survive and reproduce. [laughs] That requires resilience. Resilience means that you can deal with abnormal situations that would otherwise kill a hyper-efficient organism. I think that that has deep principles that apply across biology and across social organization, political organization. That if you strive for efficiency, you're always going to compromise resilience. Because resilience is expensive.

We have developed an economic system that prizes efficiency at the cost of resilience. That means we're extremely vulnerable to anything that's outside of a narrow range of very specific conditions. Biology doesn't have that luxury. We have to deal with the world as it is, and the world is constantly in flux and doing weird stuff. It's unpredictable. This would kill a hyper-efficient specialized organism.

ZIERLER: A broad political or even sociological question—at what point in your research career did concerns and even protests with testing on animals really come to a crescendo? When was that really front and center?

ALLMAN: I was chairman of the Animal Use Committee from the mid 1970s for about 20 years, so I've had a lot of exposure to this. I think that it's clear that it became somewhat politicized. People were concerned about it. Congress got a lot of mail about it. There are serious ethical issues associated with it. It was something that we attempted to deal with as best we could. In my own case, I decided to slowly get out of animal research. In the mid 1990s, I gradually transitioned out of it, and I've been able to sustain my career by working on humans. Quite a lot of that I did using the Yakovlev brain collection at National Museum of Health and Medicine in Washington, and through the advent of imaging technologies. I've been able to do quite a bit with that, and still quite active in it.

I think the answer is it had a huge impact. I think that procedures did improve, and I think we've been able to live with it. The downside of that has been that certain types of research have been greatly limited. For example, the monkey research is really now limited to a very small number of institutions that do it, Caltech being one of them, with Doris when she was here and Richard Andersen. On the whole, I think the community has responded to pretty well. You're not going to please everybody, but that's where it is. I believe that it's done pretty ethically, too.

ZIERLER: Where did these limitations constrain your research? I'm intrigued by the idea that these discussions actually enhanced the research in certain regards. I wonder if you can expound on both of those.

ALLMAN: It's certainly stuff that we had to deal with, but I wouldn't say that it hugely constrained us, no. We were able to work with it. It's just my own feeling with respect to my own work, that is partly of course as my interests were gravitating towards understanding human behavior. I could have continued to do the non-human primates if I had chosen to.

ZIERLER: Why the owl monkey? Why is that so central to your research?

ALLMAN: First of all, there were owl monkeys that were available. Owl monkeys have been used quite extensively in research on malaria, which was a particular concern to the military. It has a long history, as you know, of malaria being a serious problem—in other words, historically, there have been more casualties from disease than from combat. There was a big program to develop new chemotherapy agents for malaria, because there was this constant evolution of the parasite that resisted drugs like chloroquine, for example. They were just keeping ahead of evolution by trying to develop new treatments, and also for treatment of several of the other malarial parasites like plasmodium vivax. That involved the use of quite a large number of owl monkeys.

Woolsey became aware of this, that these animals had been used in the malaria experiments, and that they were available, and said, "Do you want to do that?" Well, the owl monkey had also some important technical advantages to us in that the cortex was lissencephalic, that is to say it was relatively free of fissures, so it was easier to map. Subsequently, I've had a long collaboration with Pat Wright, who was the first primatologist to study the natural behavior of owl monkeys, which is also quite interesting. I can come back to that in a minute, because that is another sort of facet of the owl monkey research that we did. In any event, there were a number of practical advantages to doing owl monkeys, and that's how we made that decision.

ZIERLER: What were some of the advances in imaging that might have been relevant for the work you were doing with owl monkeys?

ALLMAN: Well, it hadn't happened yet. I remember talking to a colleague of mine about it might eventually be possible to do some sort of a recording without electrodes, and they thought I was crazy. [laughs] At that time.

ZIERLER: What was lacking? What did you need?

ALLMAN: We simply didn't have the technology to do it. That changed when Paul Lauterbur developed NMR-based imaging and then it was subsequently discovered that the NMR had a signal associated with it that reflected neural activity, and that led to this huge burst of brain mapping studies done in humans of which I have done some. Then there was also what's called optical imaging with a sensitive CCD camera, you can actually see neural activity. That also had some usefulness as done particularly by a former postdoc at Caltech, Gary Blasdel. NMR and its many variants is an enormously powerful technology, and truly has revolutionized neurobiology, certainly human neurobiology. But that was years in the future—I'm talking now about late 1960s—and that stuff didn't come on for 20 years later, even the very earliest manifestations of it.

ZIERLER: In terms of the broader questions, where are you learning simply about the owl monkey and its visual perception, and where can you extrapolate that to other mammals and of course even to humans?

ALLMAN: We now know that the basic organization of primate cortex is pretty similar in most non-human primates. The owl monkey doesn't have vision that's quite as acute as a macaque monkey or a human, so there's a differential enlargement of the central vision, and there may be some differences at the organization of cortex. But the thing that one is struck by is the similarity of organization.

One of my postdocs, Marty Sereno, did quite a bit of the owl monkey mapping, and we published a modern version of that just a couple of years ago. I was amazed, actually—it pretty much matched with what we had done back in the 1970s. But he had done it with strictly quantitative methods and modern analytical procedures, whereas I had just done it with my eyeballs. [laughs] We published that paper about four or five years ago. Marty went on and did it in humans, with MRI, so we now know a good deal about the organization of human visual cortex as a consequence of his work and that of others. There's quite a bit of similarity, within a resolution of what we're able to do. It proved to be a pretty good bet. It could have been quite different, but that is not how it turned out. Again, it was lucky! [laughs]

ZIERLER: An academic politics question—when you joined Caltech, did you have the sense that the culture of promotion was one where the Institute supported junior faculty and the impetus was to give you the resources with the expectation that you would achieve tenure?

ALLMAN: Yes. It was very positive, and I'm again very fortunate to have been the beneficiary of that. There was very much the feeling that they carefully selected people at the entry level, and then they did everything possible to help us to succeed. That's a wonderful model. It's in direct contrast to the model applied by some of the eastern universities, in which they hire lots of people at the assistant professor level, let them compete, and then maybe not hire any of them at the tenure level. It's totally the opposite model. I'm fortunate to have been in the one we have here.

ZIERLER: Last question for today, and next time we'll pick up for the 1980s. You mentioned earlier that the culture, the undergraduate interests, were dominated by physics, of course. When did that start to change? When did more students become interested in biology, or maybe even think about cross-disciplinary opportunities at the interface of disciplines like biology and physics? When roughly did that happen in the chronology?

ALLMAN: I'd say in the mid-1980s. Part of that was certainly Carver's initiative. There were other things that were happening. I'm not sure that there has been such a huge move into biology as you might have expected. There has been some, but perhaps not quite as much as I would have thought given the tremendous development of fantastic tools like RNA-Seq, and spatial genomics. They offer tremendous opportunity for investigation. And they have been exploited, for sure. But given the power of these technologies, I somehow think there might even be more interest than there is. Part of it, I think, is that biology requires a different way of thinking about things. Part of it is those issues that I was alluding to with respect to efficiency and resilience. That it's very hard for people to think about things that way, because the tendency is to want to think about things as being efficient and always striving for efficiency. The thing about biology is it's basically about maximizing resilience and survival, or at least to the point of reproducing.

ZIERLER: Good. We'll pick up on that for next time.

[End of Recording]

ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It's Wednesday, September 22nd, 2021. Once again, it's my great pleasure to be back with Professor John Allman. John, good to see you again.

ALLMAN: Good to see you!

ZIERLER: Today I want to continue on our discussion about owl monkeys, and in particular ask you about what you learned in their parenting behavior. First, what does that mean, parenting behavior, in your field?

ALLMAN: Let me give a little background about this. As I mentioned to you in our last chat, it was just a set of factors of convenience that happened to direct us into the study of owl monkey cortex. I believe it was in 1980, I attended a symposium in Niagara Falls, New York. At that symposium, another one of the attendees was Pat Wright. Pat had done the first study of owl monkey behavior in nature. I immediately recognized her because I had read her paper. It literally was the only one. I was eager to find out what the natural behavior of the species that we were studying was. She was the best resource for that. So we got to know each other and became good friends, continuing down to this day. I had a long discussion with her yesterday.

One of the things that emerged from her study of owl monkey behavior was that fathers had a very large role in parenting. We could see that too. We made a big commitment to breeding owl monkeys in captivity so that we wouldn't be taking them from nature, which was successful. So we observed the behavior of owl monkeys and owl monkey fathers in particular, in captivity as well. Indeed, it was very striking that the male behavior was very important in caring for the offspring. Pat quantified this in very careful studies in the Peruvian Amazon and wrote a book about it, High Moon Over the Amazon. What she found was that essentially from day one, the owl monkey baby goes onto the father and spends nearly all of its time on the father, and that is pretty much true until they're independent. They just return for brief bouts of nursing, but apart from that, they're just about always on the father. One of the things about living in the very complex rainforest environment is that you have to learn what to eat and what not to eat, because many things are toxic. Dad teaches the baby how to do that. The baby will learn from his father's foraging what is suitable to eat and what to avoid as toxic.

It was quite striking that in owl monkeys and in titi monkeys, another group of New World monkeys that turn out to not be closely related, as molecular studies have now shown. The owl monkeys are nocturnal, and another money called the titi monkey or Callicebus are diurnal and live in the same forest. Pat observed them as well, and they also exhibit male parenting. So it emerged independently in these two lines of monkeys. The fathers do virtually all of the care and they form long-term pair bonds. Very territorial, like many birds.

Other groups of New World monkeys, the marmosets and the tamarins, live in extended families where the fathers do quite a bit of care. I had marmosets too, and it was really striking how much the fathers were attracted to the infants, and actually will try to steal them. They love those babies.

In the case of the owl monkeys and the titi monkeys, the care falls entirely on the father because they live in monogamous families, and not the extended families like the marmosets, so if the care is going to be done, it's really going to have to be done by owl and titi monkey fathers. We actually saw that in a case where we had to foster a baby owl monkey. The babies really depend on the owl monkey dad. Mom is just not interested in carrying the baby. In contrast, in the marmosets, although the males are very interested in the babies, there are multiple males in the group and they share in the care. Sometimes other younger members of the family will also help out, so it's not really dependent on a single individual, is the way it is for owl and titi monkey fathers.

I was thinking about this, and the hypothesis that I developed was that in situations where the survival of the infant is skewed in terms of parental care by one sex or the other—so in owl monkeys, it's skewed towards males—so if something happens to dad, that's a disaster for the offspring. In the case of marmosets, if something happens to dad, there were other caregivers that can help out. In the case of most other monkeys, the mother is doing the care, and in most types of monkeys this is really pretty much only mom. It follows from that, if there's a skew in the parenting behavior, then you would expect that natural selection would favor the survival of the sex that does the bulk of the care, because if something happens to the parent of the sex that's doing the bulk of the care, the chances of the offspring surviving are reduced. That is to say, they are less likely to reach maturity and reproduce themselves. In the cases where there's male care, it will be skewed toward male survival, and cases where there's female care, it will tend to be skewed toward female survival. Female survival is by far the more common case, of course. In humans, for example, where there's certainly a skew towards females in parenting behavior—it's not absolute, but across all modern nations, there is about a 7% female survival advantage over males. It's clearly biology.

ZIERLER: What does this tell you overall for your research, the fact that the fathers play this role?

ALLMAN: We got a hold of studbook data from zoos, and we looked at the mortality rate for thousands of animals in captivity, and it turned out that this was born out quantitatively. That is to say, owl monkey males do live longer than females by a quite substantial advantage, about 20% on average. So did titi monkey males. In marmosets, it was equivalent, as the thesis would predict. And in all the other eight or ten primate species for which we could get good quality studbook data—studbooks are databases accumulated by zoos, of the births and deaths of animals in their collections—and for the other ones for which we could get good data, in every case where there was a female survival advantage, and it was associated with a skew towards female care. It is also consistent with longevity data for natural populations of chimpanzees where females do virtually all the care and have a large survival advantage over males. That led me into a whole different sort of area of biology, which I continue to do down to the present, of thinking about the relationship between what are called life history adaptations, different ways of passing through life as an individual, and their impact on survival, the impact on health, their impact on brain functioning and brain structure. There are impacts on all these areas, and they have thus far only been recognized in medicine fairly recently. But as I say there's a very striking differential in patterns of mortality and morbidity between males and females in humans.

Andrea Hasenstaub, a Caltech undergraduate in applied math, and I were able to show, for example, in another paper, where we looked at World Health Organization data that men have much higher mortality rates for violent death and for risk-taking behavior, between the ages of 15 and 40. Obviously you're going to have a bias against risk-taking behavior if that risk-taking behavior also puts your offspring in peril, and so you see for men versus women there's a differential there, and it predicts a lot about human behavior. It also predicts that there might be differences in the brain that one could see. In most causes of death that are later in life, females also have a survival advantage from ischemic heart disease, cancer and stroke. There is a good deal of evidence that females contribute to the survival of their grandchildren as well that could contribute to this selective effect. Experiments on parental care by Hopi Hoekstra and her colleagues in hybrid voles indicates that parenting behavior is under separate genetic control in each sex and thus could be selected for on the basis of sex.

You asked how this relates to my research. Well, it does, remarkably. I've done quite a number of papers with Ryan Cabeen, who I've introduced before. This is an ongoing collaboration. We're now in our fourth paper in a series on this, and there are many more to come based on the Human Connectome data. As I discussed earlier, we have been able to measure the volume of fronto-nsular cortex, the area that contains the VENs, with diffusion MRI in individual subjects from the Human Connectome Data. When we did that, what we found that fraction of total cortical volume of fronto-insular cortex is larger in women than it is in men on average. I had mentioned that in the behavioral variant of frontotemporal dementia (bvFTD), Bill Seeley and I found that the von Economo neurons (VENs) degenerate, so there is a clear linkage between fronto-insular cortex and bvFTD. My collaboration with Bill began when I give a talk about the VENs to the Neuropathology group at UCSF back in 2004. Bill came to me after my talk and told me that he thought the VENs might be involved in bvFTD and we arranged to meet at the Yakovlev brain collection in Washington the next week where there were histologically sectioned brains and detailed clinical records of people who had suffered from bvFTD. It immediately became clear that the VENs were indeed degenerated in this condition as Bill had hypothesized, which we followed up with more cases; this has become a major focus of Bill's research at UCSF.

During that period our collaboration on the VENs and fronto-insular cortex, which included Bill, Kebreten Manaye, Chet Sherwoood, Bud Craig and Patrick Hof gained substantial long term support from the James S. McDonnell Foundation, which was extremely helpful. The big McDonnell collaborative investigator grant to the support the VEN research was another instance where I have been very fortunate. Bill showed that degeneration of the VENs occurs early in the course of the disease and is particularly related to the loss of empathy in these patients. Very recently Bill and his colleagues found that women have less severe bvFTD compared to men, who have the same genetic mutations that cause the disease. Thus, the impact of bvFTD is less in women than it is in men. The symptoms of bvFTD are obvious, like lack of empathy or very impulsive or self-destructive behaviors, things of that nature. Things that really wreak havoc and are just an utter tragedy when they happen to a family member. In any event, for comparable degrees of pathology, women are less affected than men. My guess is that its because fronto-insular cortex occupies a larger fraction of total cortical volume in women than in men women tend to have more reserve and thus resilience in bvFTD.. Fronto-insular cortex is also involved in autonomic regulation (heart rate, blood pressure etc.), and the larger size of FI in women may relate to better autonomic regulation and thus possibly their lower risk of heart disease and stroke in women.

ZIERLER: What are some of the health outcomes as a result of this finding?

ALLMAN: We don't know how to treat bvFTD yet, but it probably is important to know that there is a significant sex differential and a possible brain correlate. The smaller the area, the more impulsive subjects are. You may be more prone to become addicted because you're impulsive, and as you become addicted, you become more impulsive still. This has serious implications.

ZIERLER: It's a vicious spiral, it sounds like.

ALLMAN: It's a vicious downward spiral. That's right. And that has clear clinical implications,

ZIERLER: Is the best line of attack drug delivery, surgery, psychological applications? How do we come at this problem?

ALLMAN: There is a group who has looked at bariatric surgery, so people who were very obese and had surgery to reduce the absorption of food from their stomach. They did brain imaging on these folks before the surgery and three and six months afterwards, and amazingly, fronto-insular cortex got bigger after the surgery, implying that there's a feedback from the body that is impacting on the size of the area in the brain. That does suggest that interventions might help.

I'm loath to say give drug X and it will fix the problem I would much prefer behavioral, non-drug approaches to this problem. We've got too many drugs, including prescription drugs. So, I would be loath to give the impression that is the solution this is what I see. I think that it has got to be in the form of behavior. Actually, just today, there's a remarkable piece in The New York Times by Tom Edsall, on how boys are very sensitive to poor parenting behavior, and that poor parenting behavior results in what is called externalizing behavior in boys, basically aggressive behavior. That's very problematic for those boys because people don't like aggression. The title of that piece is remarkable, that boys are getting a message, "We don't value you." That's a pretty serious thing when you talk about a significant portion of the male population. I think it calls for behavioral management of the problem, and doing things that will improve parenting behavior, which may have to do with poverty and lack of job security I'm loath to see drug approaches taken to this, as for example, amphetamine-related drugs, which of course has been done for attention-deficit hyperactivity disorder. I do not think drugs are the answer to what is probably mainly a socio-economic problem.

ZIERLER: These findings have public policy implications as well.

ALLMAN: Yes.

ZIERLER: For you, what are the forums or modes of communication where you might have an opportunity to present your findings to people, legislators, people in government that have the resources and administrative capacity to deal with these issues?

ALLMAN: My feeling is first of all, you've got to get the science right and publish the findings in peer-reviewed journals. I see that as my responsibility is get the facts down. In particular, we're in the process of getting access to a lot of data from children. Not just the Human Connectome data, but another even larger database. There are some other databases from other nations and cultures as well that we may be able to get into. We want to put this on a firm empirical foundation.

So the first thing is to find out what the facts are. In particular, for the children, we have another measure. There's a group at Yale that's very interested in food addiction, and they developed a behavioral test, for food addiction. That food addiction scale has been included in the databases for children because childhood obesity is a very serious problem. Incidentally, you may have seen that the CDC found that the rate of increase of obesity in children accelerated during Covid. That's not just a problem because kids are fat, but it may also a problem because the kids may function poorly physically, intellectually, cognitively, behaviorally. What we want to do when we finish the adult study is to go and dig into the data for children, and particularly to look at the biggest addiction, which is food addiction. I want to get the facts right on it, and get the facts from several databases, and hopefully from several nations and cultures.

Eventually it is incumbent on us to try to reach out to people who actually make policy on these matters. I'm an old guy, and I probably won't see all that happen, but I have some students who I think could carry this on. I maybe still have another ten years or so if I'm lucky. We'll eventually say something. We're putting it in peer-reviewed journals, of course, and that's the first thing to do.

ZIERLER: Switching topics a little bit, tell me about how you got involved with the Helmholtz Club.

ALLMAN: That's a good point to [discuss this]. First of all, there is a professional historian of science named Christine Aicardi who actually did write, in part on the basis of my input, a history of the Helmholtz Club, because it is quite a remarkable thing.

ZIERLER: I know it well.

ALLMAN: Oh, you know it? Excellent. Carver and I had a long dinner with her discussing the Helmholtz Club back about 2012, I think. That was the beginning of an exchange that we had with her.

ZIERLER: The fact that it was you and Carver suggested how interdisciplinary the Helmholtz Club was created to be.

ALLMAN: Yes, that's true. To go back to the beginning of it, sometime in the late 1970s, Francis Crick got interested in my work on owl monkey cortex. He came to see me, which I was kind of blown away by. He was a wonderful man.

ZIERLER: About how old was Crick at that point when he came to see you?

ALLMAN: That would have been about 1978. He died in the early 2000s, when he was in his late eighties, so he was born about 1920 or a little earlier. You could check that, but approximately right. So I guess then he would have been—

ALLMAN: Yes.

ZIERLER: He was still active at that point?

ALLMAN: He remained active really right to the very end. His widow, Odile, told me that he was correcting page proofs on his death bed. He was a great intellectual gadfly. He asked a lot of questions, was very probing, mind like a sponge. He wrote a piece for the Scientific American, in which he put my owl monkey visual cortex map. So that's how the connection began. We many discussions. Ramachandran—do you know Rama?

ZIERLER: Sure.

ALLMAN: Rama is an interesting guy. Rama was briefly a postdoc in my lab in the late 1970s. That happened because he had been a postdoc with Jack Pettigrew, and Jack went back to Australia, and Rama needed a sponsor, so I provided him an academic home at Caltech for a little while before he got a job down at UC Irvine. I knew Rama, and at that time Rama was very interested in perception of motion, which I was too, MT of course, being involved with that. Rama had this idea of forming a club. There was an earlier club, I think, that Christine talks about, a particular club at Cambridge, I believe, that was the inspiration for Helmholtz Club. This idea germinated amongst different folks—Rama, me, Francis, and Gordon Shaw, who was a physicist who had gotten interested in neurobiology at UCI. I think that that was the core group at the beginning.

We began having meetings. They were at UCI, at the Faculty Club, beginning in 1982. We'd have two speakers, and there was lots of discussion so that each talk would typically be on the order of two hours with a lunch and a dinner. It ate up a lot of time! [laughs] Basically it was a whole day affair. I gave one of the early talks there, and it was a good experience. It was an unusual opportunity to present things in more depth and with more feedback than one does typically at a scientific meeting.

ZIERLER: Is that because, by definition, you were talking with peers who were in different disciplines?

ALLMAN: Well, it was certainly true. Gordon Shaw was a physicist, for example. Carver became involved later on, of course. Obviously, he was a physicist. So yes, there was a diversity of disciplines represented. It was built around visual cortex, basically, although occasionally it would stray into other areas. We would have like one local speaker, and we eventually drew going all the way up to UC Santa Barbara, and down to UC San Diego, five or six institutions. UCLA, Caltech, UCI, et cetera. Then we would get an outside speaker. Francis had gotten this open-ended grant from the Systems Development Foundation—it was for a million dollars—and he said, "What do we do with this money?" [laughs] Rama had a solution to that problem. The grant paid for the thing in the early years. It went on from 1982—we were still having some meetings probably as late as 2006, maybe? Roughly 25 years.

ZIERLER: Was the goal to have publications come out of these meetings?

ALLMAN: No.

ZIERLER: Just an exchange of ideas?

ALLMAN: Purely exchange of ideas.

ZIERLER: What was the value, as a two-way street? What did you bring to these meetings, and what did you get out of them?

ALLMAN: I think that the idea was to have really good discussions of things and to go home with new ideas to actually test. That did happen. And to have an intellectual ferment. But no, there was never any talk of publications coming out of it, or much in the way of rules, either. It was pretty open-ended, but it was still nevertheless a remarkably polite discourse. I can remember very little friction.

Francis was a joy to be with. He was really full of ideas. I think he really was thoroughly enjoying himself, too. When Francis died, I sent his widow a note, and I said, "Francis is one of the few people I've known who was a truly happy person!" There's this passage from Walt Whitman— "singing chants of pleasant exploration"— that represented Francis' joyful scientific quest. They found my note in her papers after she died. I really did think he was truly a remarkable person in terms of the sheer joy of intellectual thought and discovery. That's what Francis was about. If I reflect back on it, that's perhaps the greatest gift that I received from from knowing Francis. Having known someone like that is just a remarkable thing.

Then Carver got involved in it a few years later. Part of that was I thought it was important to have another scientific heavyweight, and Carver definitely was a world-class scientist, so it was good to have a couple such people there. That was certainly part of the motivation of it. Carver became very involved, contributed a great deal to it, of course enlarged the scope too, more towards the computational. That was healthy. It was also important that we continued to introduce new people, so as to keep the thing fresh. That's how it was able to go for such a long period of time, I think.

ZIERLER: Is it still active?

ALLMAN: No, Carver retired, moved up north, and of course Francis died. They had been very crucial to the health of the organization. We really weren't able to sustain it after their departure, to be honest with you. But it had also kind of served its purpose. That period of the 1980s was a period of great interest in visual cortex. The world had kind of moved on from that too. Actually, I'm pleased that one direction it culminated was in Doris Tsao's work on the perception of faces, the neural mechanisms of that. In a sense her work represents where that line of thinking ultimately led. In a sense, we did what we set out to do.

ZIERLER: What is the legacy of the Helmholtz Club, would you say?

ALLMAN: Some understanding of the computations and the cell types and the processing that goes on when you perceive something. That is something we didn't know before. It's fodder for modelers, of course, and fodder of course for people who are trying to make artificial systems. But that's not why I did it. I did it because—just the great dictum of "know yourself." It's just a very interesting question.

ZIERLER: When you say that the world has moved on to some degree from visual cortex research, why? Is that because most of the main research questions have been answered, or they have been subsumed into larger questions?

ALLMAN: I think that some of the questions have been answered, yes. When we mapped visual cortex in owl monkeys, we found a whole bunch of cortical areas, of course, and we only have a sort of preliminary understanding of a few of them. There's still a number of them out there that we really don't have a clue about yet. So, there's plenty more to do there. I'm reasonably confident that eventually it will happen. I think a lot of it is the great focus in neurobiology moved molecular. Indeed, I moved in that direction myself. Also, moved forward (anterior) in the brain [laughs], in my case to fronto insular cortex. I feel that those are really challenging questions of behavior, as we just discussed, and questions that do have profound implications for how we organize society and enhance human well-being. Which I don't think visual cortex has that potential, in the sense that the frontal systems do. That would be my particular odyssey. I hope I've answered your question.

ZIERLER: Absolutely. Another topic that I want to engage you on, entirely different, is that of electric cars. What is your interface with electric cars, and how far back does that go?

ALLMAN: It goes pretty far back, to the origin, really, of modern electric cars. I had a very unusual graduate student, Dave Sivertsen, who came to me as an undergraduate from electrical engineering in the 1970s. We did a project together on motor cortex. He applied to graduate school, and lo and behold, I had Dave Sivertsen as a graduate student. I was a bit shocked by that. I think it's probably better if people go someplace else for graduate school, but there's Dave. Dave got interested in owl monkeys and went to Peru, and worked with in the Peruvian Amazon observing owl monkeys with Pat Wright. He did a project on owl monkey vocalizations during different phases of the moon. Pat describes that in her memoirs. She wrote two books of her life story, and the first one has to do with the Amazon. She has an amusing account of Dave as a graduate student in the early 1980s in her High Moon over the Amazon. Another one of their exploits was to track a dispersing owl monkey through the rain forest at night. When an owl monkey reaches maturity and leave its parents, he/she moves quickly through the forest in a more-or less straight line, making special vocalizations as he/she passes through the territories of other owl monkey families until he/she finds a mate. Dave and Pat followed the disperser for many miles through the forest at night until they reached a stream to deep to wade across and the owl monkey crossed in the canopy over the stream at which point the realized they were lost!

Anyway, Dave came back from the Amazon [laughs], and had a little side interest in spiders. There's these highly visual spiders, the jumping spiders. Dave wanted to record from the optic glomeruli in the brain of jumping spiders. Not much was known about spiders. He used our setup and actually was successful in recording from neurons in the spider optic glomeruli, which itself was something of a feat. Got a PhD thesis out of it.

I told you he was an unusual guy; I discovered that he was actually spending quite a bit of his time when he was in graduate school becoming an expert on bamboo [laughs]. He was working over at the Huntington Gardens part-time while he was my graduate student, and he had become their bamboo expert. They have a lot of bamboo there. Huntington hired him on the curatorial staff, once he finished with me, and he still works at the Huntington now. He's still a curator there, doing scientific exhibits and botany.

This seems like an unusual preparation for a career as an inventor in the car industry, but he was an electrical engineering student as an undergraduate. Another thing that he was doing together with his friends from electrical engineering was that they got interested in Paul MacCready's project on human-powered flight. Paul MacCready had—it was the Gossamer Challenger, I think, sort of a bicycle with wings on it. They actually did get this thing into the air and flew some distances with it. That was in the early 1990s. So, David did unusual things. [laughs]

It turned out that a friend of his, Alan Cocconi, came up with the idea that you could use lithium batteries, computer batteries, to power a car. At that time, of course, they were very expensive, so it didn't seem like it was even remotely economically feasible to do, but they formed a little company called AC Propulsion in 1992. Dave was one of the early people who were part of the company out in San Dimas. They started trying to make a practical vehicle powered by computer lithium batteries. I maintained contact with Dave, and actually rode in some of these vehicles. One of them was a modified Scion.

ZIERLER: Toyota?

ALLMAN: Yes. They took out the engine and put in an electric motor. But the electric motor wasn't the great innovation; the innovation had to do with managing the batteries, part of which is maintaining the appropriate temperatures for the battery and distributed the load and optimizing the recharging so that the batteries have a longer lifetime and a much larger number of recharges. As you know, in computers, the batteries fail on you, so a key was understanding what it took to get many, many recharges, and how to do that. Also, they needed to know how the vehicle would behave under actual driving conditions.

His personal vehicle was one of these craft. As I say, I was amazed by it. He lives up in La Cañada, and there's a pretty steep climb from La Cañada up the Angeles Crest Highway. I remember zooming up the steep Angeles Crest highway in this electric Scion at top speed. It was pretty impressive because we weren't struggling along; it was really moving. It was clear that his electric car had real performance.

Anyway, they made a number of trial vehicles of this sort, and they went around to the various car companies and tried to interest them in this vehicle. I'm sure they nearly all said, "That's nuts! The batteries are way too expensive to put in an electric car in the number that they would need." But they did actually get a positive response from BMW, which is run by engineers, and not accountants, who can be serious obstacles to innovation. (Ed., see, Hayes and Abernathy, Managing Our Way to Economic Decline, Harvard Business Review and Clayton Christensen, The Innovator's Dilemma). BMW liked the idea. And Elon Musk liked the idea.

ZIERLER: I was going to ask about Elon Musk. I assumed he was part of the mix.

ALLMAN: Made specific contact. The two nibbles that they got were from those two sources. For Musk, they built a prototype, a roadster. They actually designed and physically built it. It was their stuff, their patents and everything. Dave got patents on some aspects of the regime for charging. So they designed and built the original technology which is the basis of the Tesla. At that time, the cost of lithium batteries was on the order of 1,000 per kilowatt of storage capacity, so that meant necessarily that they were going to be very expensive cars. In the case of the BMW, they went a little bit further. Eventually they built at least 1,000 of them for BMW, and they were reconfigured Minis, that they stripped out the engine and put in their engine, their batteries. Dave told me one time that he had bought up a fifth of the entire world supply of lithium batteries for computers, just to fill this order. To scale up, they had to take on other investors. Then they got into various cash problems characteristic of such startups, and they lost the company. Dave went back to the Huntington, so he's fine. In the course of this he spent quite a bit of time in Germany, working with the BMW engineers. It's curious that BMW have produced a pretty decent electric car, but they haven't marketed it very effectively, and don't seem to have been all that interested doing do, although there has been, I understand, considerable demand. I considered getting the BMW electric myself. Eventually I did get an electric car, a Mercedes Smart 42. Dave said that he didn't work on the Smart car. Mercedes came along a little later, in 2006, and I suspect somehow Dave's technology leaked into their electric car as well. I think Musk eventually got a hold of the patents and put them into public domain, but I'm not sure of the details of that. In any event, it was their technology in both BMW and in Tesla. It's a testimony to where important innovation comes from, and the interesting characters that actually do it. That's the story. I had the opportunity to see much of it as it happened. It's a world-beating technology with far superior performance, and I can say a much better experience that driving an internal combustion vehicle. It's clear that electric cars will eventually take over the whole market. It probably will be as important as computer technology in terms of its global impact and is absolutely essential for reducing carbon emissions and other pollutants. They are also much quieter, thus reducing noise pollution as well. It is also spreading to other modes of transportation. For example, in British Columbia they are building electric ferries and small aircraft for service to the Gulf islands. When future historians look back, it will be one of the great events of this era in our history. (Parenthetically, I have another curious connection with electric cars in that my great grandmother, Alice Putman Allman, had a Detroit Electric car arround 1915 that she drove to the Beehive each day. Most people don't know that there was an earlier electric car industry in America. Edison focused the later part of his career as an inventor to developing high-capacity batteries with the objective that they would be used in cars; his batteries were used to power vehicles in mines where emissions were crucial but unfortunately not in cars.) ZIERLER: Moving to relatively more recent areas of research focus for you, when did you first start to collaborate with Barbara Wold? ALLMAN: That goes back to about 2007. I had known Barbara for a long time, of course, because we were colleagues at Caltech for 25 years before. Barbara had developed this technique called RNA-Seq. It was the first of these variants sometimes called "the Seqs"—there will be something, and then a "Seq" after it. They're all based on this massive parallel sequencing, and totally different sequencing strategy from Sanger sequencing. That innovation has made it possible to do an awful lot of new things in molecular biology What we did initially was look at gene expression in fronto-insular cortex and in the cerebellum, in people with autism, compared with normally developing children. That was not a brilliant success, in part because of the scarcity of the tissue so that we couldn't get an adequate number of samples to do statistics. Along about 2012, I began to have an interaction with David Bennett and his group at Rush University in Chicago. David and his group have done an enormous study of aging that was initially based on members of Catholic religious orders, priests and nuns, but this eventually included regular folks. These people that might enter the study in their seventies or eighties, and would be studied for the rest of their lives, so there was extensive cognitive studies of them, imaging, and genomics. It occurred to me that because the subjects had agreed to go to autopsy, and because they had banked their brains, that I would be able to dissect fronto-insular cortex, and we could look at the RNA-Seq from FI and see if there were any differences between the cognitively normal and the demented. That was kind a shot in the dark, honestly. So we pursued that for a bit, and we're still doing that, as we speak. Along the line in this, Barbara has a really excellent IT person, Henry Amrhein. Henry and I did a lot together looking at these data, but also looking at data from Mount Sinai College of Medicine in New York. Mount Sinai had done on the order of a 1,000 brain samples, doing RNA-Seq on four different cortical areas in a range of people ranging from elderly people who were cognitively normal to severe dementia. They had done the sequencing pretty well, and they had some good diagnostic information. We analyzed that, so we had data from perhaps 250 individuals or so, for each of these four cortical areas. Two were in the frontal cortex, two were in the temporal lobe. But not fronto-insular cortex. What became clear from that was that area 36, which lies closest to entorhinal cortex where the disease originates according to the studies by Heiko Braak. In these samples the effects related to Alzheimer's versus controls were stronger in women than in men. ZIERLER: If I can just interject on a technical question, area 36, what is the schema for mapping the areas of the brain? How does that work? Is it an XY axis? ALLMAN: No. This is a parcellation of cortical areas that was done by Brodmann back in 1909, but it has stood the test of time quite well, and it is pretty much universally used now. I should have said "Brodmann Area 36." That is something that has a distinct boundary to it. You need a common geography. Fortunately, Brodmann has provided that for us. That's the basis of it. But it's not based on coordinates. There are schemes based on coordinates, of course, but that's not what we did. What emerged from that was that we saw quite a lot of evidence for decreased expression of a big set of genes that are involved in synaptic function. That was clear. That says that as the disease progresses, you get reduced synaptic function. I think pretty much everyone would agree with that. But it's probably not causative. We know that Alzheimer's disease kills neurons, and it destroys synapses. So, it's not surprising that you see the reduction of gene expression for those functions, because in a sense, that's the disease, but that isn't necessarily what causes the disease. It's a consequence of the disease. That's one effect, and that's quite clear. The second effect that we saw was increased expression of a big set of genes that are associated with a cell type in the brain called the microglia. The microglia are the immune cells of the brain, and they come from outside of the brain. They have a separate embryologic origin which comes out of the yolk sac and colonizes the brain during fetal development. They migrate into it. The original immune cells in the blood can't get into the brain, because they're separated from it by the blood-brain barrier. The blood-brain barrier is a physical barrier, so the brain has to have its own way of protecting itself from infection, and that's one of the things that the microglia do, attack viral and bacterial infections. The microglia are very active. They're constantly surveilling the brain and locating infectious agents and gobbling them up, phagocytosing them. That's a type of innate immune response. That is the way we protect ourselves from brain infection. But it also has these other functions that are more recently emerging, including the control of the connections and activity of neurons, so it impacts directly on neural processing, too, to our surprise. Anyway, the genes that are associated with the microglia are upregulated. That was also quite clear, an increase in the expression of genes in these immune cells, the microglia, implying an increased level of activity of that system. Then the third thing that we saw, which was really surprising, is that there's a distinct set of genes that are normally engaged in regulating brain development. Many of these are members of a class of genes that are identified in fruit flies called the Hippo genes, because they control organ size, the sizes of different body parts. They do this in part by controlling cell replication cycles to provide the right number of cells for a particular organ. Amazingly, they're turned back on as people become demented. One of the Hippo genes, YAP1, seems to be central to this process. One of the deep puzzles is what does it mean to be reengaging genes that are normally engaged early in development, and now they're reengaged in pathological change. That's the most puzzling and most bizarre thing that we've seen, but there's quite a few of these developmental regulatory genes, and they're very strongly up, as cognition declines. That's something that I'm particularly intrigued by, is this very curious reengagement of the genes involved in brain development. That's where we are now. Along the line, another important technology was developed that is closely aligned with Barbara's work on RNA-Seq and comes from Long Cai and his development of what he has called spatial genomics. It's a technique that allows you to do in situ hybridization, that is to say to look at gene expression at a cellular and subcellular level within intact sections of tissue. You can have a histological section, and you can see the gene expression within that section and not just for one gene, but for very large numbers of genes. What we're currently doing is about 1,500 different genes. Long developed this incredibly clever strategy to make that possible to do this with many genes at the same time. ZIERLER: What's the big breakthrough in Alzheimer's research for you from your vantage point, where you're coming from? ALLMAN: If it turns out to be the case that there is a reengagement of development genes, that is probably something where you actually can intervene. That probably would have to be a drug-based thing. ZIERLER: What's the problem? What do you see as the issue? ALLMAN: If you look at a brain with a conventional staining technique, thioflavin for example, you'll see the amyloid plaques. They're very obvious. It's a short leap from that—"Well, these obvious things must be causing the disease." But like the loss of synapses or the loss of neurons, which are also obvious, maybe it's a consequence of disease. What's really causing it is some other processes, that occurred at earlier stages, that you really can't see so easily. When a pathologist looks at this, it's all at the end-stage of the disease, not the processes that caused it. I think it's sort of tumbling to the obvious. There's a peril to that, to thinking, "Oh, it's so obvious that there are amyloid plaques there. It must be the cause of the disease." Rather than, "Sick brains produce amyloid plaque." It isn't just Alzheimer's disease; amyloid plaque comes up in lots of situations, including just getting old. It doesn't actually turn out to be a particularly powerful discriminator between the demented and the non-demented. There are other things that are better. Also, a problem was that there's an early onset form of the disease, and a late onset form of the disease. The early onset of the disease is rare, maybe less than 5% of the incidence of Alzheimer's disease. Then there's a late onset disease. ZIERLER: What does early onset qualify as? What's the limiting factor there? ALLMAN: Classically below the age of 65. The late onset disease is typically in the eighties. It turned out that the genes that are implicated in the early onset form of the disease and the late onset form of the disease are entirely different. The early onset are genes that are in fact directly related to amyloid, and you can make a mouse model, by inducing those mutations, like in presenilin. Whether that really is a good model or not, that's a different matter, but it's easy to do, and it's easy to write a grant, and get Big Pharma involved, and get these mice, and do stuff with them. They get drugs approved, et cetera. It's just they don't seem to help the patients much! The late onset form of the disease they say has an entirely different set of genes, and those are not particularly related to amyloid. The strongest one is related to the transport of cholesterol. Cholesterol has to be made entirely within the brain because doesn't get through the blood-brain barrier, so even if you eat a ton of eggs, it won't help [laughs], because it doesn't get into the brain. It turns out the neurons don't do a very good job of making cholesterol, and they need lots and lots of cholesterol to make and maintain synapses. It's an important constituent of synaptic membranes and vesicles. It has to be made by another type of cell, which are the astrocytes. Then it's exported from the astrocytes to neurons. That export process is controlled by a transporter protein, APOE, and variations in the gene for that cholesterol transport are strongly related to the late-onset form of the disease. This is entirely different from the early onset form of Alzheimer's. In the early onset, the rare form, there's a clear implication for amyloid, but in the common form of the disease, the relationship is not strong. There are now known to be roughly a dozen genes that are related to the late onset form of the disease, the most important of which is APOE-variant 4 (APOE4). But none of them are directly related to amyloid in the way that the genes that cause the early onset are. ZIERLER: Your perspective is coming from the genetics side of things. What about lifestyle factors? To what extent do we understand lifestyle factors in the way that this happens? ALLMAN: David Bennett's group have worked on this quite a bit. They have been very interested in lifestyle factors and how they might impact on the risk of dementia. They have some real data, because they've been doing this study for more than 20 years and have a wealth of information. The thing that is clearly positive in reducing the risk of Alzheimer's is physical exercise. That is pretty well documented. Getting a good night's sleep also seems to be important. There are interesting mechanisms that may be involved with that. In terms of behavior, I think the one that is most striking is purpose in life. They have good evidence that people who have a strong purpose in life seem to be protected. There is the suspicion, of course, that cognitive engagement, which is going to be related to purpose in life, is important. But I wouldn't say go out and do lots of crossword puzzles. There are people who seriously do advocate that, but I would say not proven. To reduce the risk of Alzheimer's, be physically active every day, get a good nights sleep and avoid napping during the day, and have something you want to achieve! ZIERLER: I wonder, from an evolutionary perspective, what some of the takeaways might be of this? ALLMAN: I actually wrote a tiny piece about this years ago. I suggested at that time that before the advent of writing, the only store of memory was in people's brains. It's important to have that sort of wisdom, and that having cognitively functioning elderly people who have some long-term information might be beneficial and influence natural selection so as to favor genes that enhance the maintenance of cognitive functioning in the elderly. They are past the age of reproduction but can by the knowledge they possess enhance the reproductive success of their offspring. Maybe you read it? I speculated on this a long time ago. [laughs] It may be why in hunter-gatherer populations, that elderly people are respected, because they are a repository of information about things such as variations in the environment that might be severe enough to overwhelm those younger and less experienced or less knowledgeable. In other words, how to deal with very unusual occurrences. In the paper I cited an elderly Australian aborigine who was able to lead his tribe to resources in the remote locality that sustained them during a servere drought, because he had observed these resources many years earlier as a young man. ZIERLER: Tell me about your collaboration with Peter Williamson, leading to the book The Human Illnesses. What's the origin story of that collaboration? ALLMAN: Peter is a psychiatrist at Western Ontario. I visited there, and he said he was really interested in doing a book on this. I must say that my overall experience from this was realizing how little we know about psychiatric disorders and their treatment. [laughs] It was a humbling experience. It's kind of painful to try to write about things where you know we just don't know much. [laughs] We tried to say something that wasn't too ill-founded. That's how that came about. ZIERLER: And why the title, The Human Illnesses? Obviously, you're focusing on the brain, but your title suggests something more expansive. ALLMAN: The point was that many of these chronic neurodegenerative and psychiatric illnesses seem not to have any natural counterpart outside of humans. Schizophrenia is an example. ZIERLER: Which suggests that these are illnesses of culture, of modernity? How do you understand it? ALLMAN: There certainly are diseases of modernity such as the various addictions and especially obesity and food addiction, but that's not the subject of the book. The human brain evolved pretty rapidly in the last couple million years, and so did our capacity for upright posture. We've got lots of problems with our spine. One of the leading reasons people go to doctors is because of pain associated with upright posture. The implication of that is that we haven't quite got all the kinks worked out with respect to bipedal posture. It's kind of humbling when you see how fast a four-footed creature can move, relative to us. The fastest human can maybe do a mile in four minutes, and a dog can do that easily twice as fast, or more, and can do it for many miles, too. Bipedal posture is kind of a crappy [laughs] adaptation. People have argued that it's for manual dexterity but in fact capuchin monkeys are quadrupedal, and they have excellent control of their hands, are very manipulative, and it is now very well documented that they make stone tools in nature. They can do it with considerable proficiency and skill and have been doing it for a very long time using the same anvil rocks for hundreds of years. So can chimpanzees. So, it isn't tool use. It's actually hard to understand why we're bipedal. Anyway, there are costs to being bipedal, in terms of being clumsy and slow. There probably are costs to having an exceptionally large brain, particularly in terms of very slow development and slower processing speed because it seems to be related to that. So the general idea that I've had is that some of these neurodegenerative illnesses that humans are prone to may be that. like the disorders of the spine, that they're things that have costs associated with that rapid evolution. I think that was the origin of The Human Illnesses title. ZIERLER: To what extent do you see this work as a sequence in what you were doing with Evolving Brains, a decade earlier? ALLMAN: Actually, Evolving Brains has proved to be a pretty good foundation. It has stood the test of time, pretty well. It's now 25 years [old], and most of it's still right. [laughs] ZIERLER: Did you ever consider a second edition? ALLMAN: Yes, many times. I actually had someone come to me and say that they wanted to rewrite it for me! [laughs] I didn't want to do that. I've actually had a number of publishers approach me, too, about it. Sadly, Scientific American Library went out of business, which I think was very unfortunate, because they produced very useful books for public information about science. They did a good job, and they were great to work with. But no, I continued to work with some of those paradigms that we developed there, particularly related to the issues of brain development that I think are useful. I was fortunate that I had a really wonderful editor, Nancy Brooks, for Evolving Brains. Nancy had 3,000 queries for me on my manuscript. It took me a year to respond to all of them. It was always, "Make it clearer." You probably know this, but one of the great difficulties in writing something for a popular audience is trying to understand what they don't know. It's a "theory of other minds" kind of problem, because they often do not know things that seem obvious. But they're not obvious to them, and you have to make them clear, and you have to approach the writing from that perspective. That's I think one of the biggest things I learned from writing the book. ZIERLER: Bringing our conversation right close to the present, tell me about the ideas that you had that ultimately ended with bringing Charlie Gross and Joyce Carol Oates to campus for a wide-ranging discussion on science and art. ALLMAN: That's a good point. I knew Charlie for a long time, going back to the early 1970s from his recordings of neurons specifically responsive to faces in macaque monkey infero-temporal cortex that I described earlier. He directly inspired perhaps through me Doris to do what she did, which is to make that whole story have a firm scientific foundation to it, by coupling MR imaging with micro-electro recording. She was eventually able to show was that nearly all of the cells within the face areas or "face patches" were responsive to faces. Also along the line, Charlie married Joyce Carol Oates. It was a late life romance. Doris and I were having sushi together. We were talking about ways to liven up intellectual life at Caltech, and the idea came up. I don't know whether it was her idea or my idea—it just came up—of inviting Charlie and Joyce to give a public talk about science and art—they're the ideal couple for this! [laughs] We floated that idea with them, and they were enthusiastic about it. We floated the idea to the powers that be at Caltech, and I think they saw it as an opportunity to do things that were positive. And it happened. I don't know if you've watched any of it, but it's interesting. It was a fun thing to do. ZIERLER: Overall, for you, what is the importance of that artistic perspective, the visualization, for the research areas that are most interesting and important to you? ALLMAN: Some things, of course, are the consequence—in science, as in art—of just sort of playful inspiration. Actually, Charlie represents that pretty well. People often commented that his lab looked like a toy store. Indeed, I sat in on some of those experiments, and there's a lot of free experimentation. What Doris did was to systematize that in a rigorous way, in a way that even the hardest-nosed scientist had to accept as being correct. That took a while, but that eventually happened. It's that sort of playful exploration, which actually I think Francis Crick represents really well, together with hard empiricism, which Francis also was very concerned about. You need both. ZIERLER: Now that we've worked right up to the present, just about, I think we're ready to go to the last part of our discussion today. I'd like to ask you some broadly retrospective questions about your career, and then we'll end looking to the future. First, very broadly, on the subject of brain evolution, if you can think back to when you first started thinking about these things, even in graduate school, to where we are now, where have been the real breakthroughs in the field, things that were just not understood or we didn't even have the tools to ask the right questions 30, 40, 50 years ago, where today you can say, "We've really pushed the needle forward on this"? And then where are those areas where essentially, we're still in the wilderness? We're still as unsure about these things as we were when you first started thinking about these questions. ALLMAN: For example, in the study of cortex, the attitude was, circa 1960, that most of the cortex is this sort of amorphous structure that was called association cortex, and somehow associations happened there. [laughs] That was thinking. It was actually pretty much like saying, "A miracle happens." We just didn't know. So all this mapping and the more targeted type of functional studies have achieved a great deal in that area. That has been a revolutionary change. I should also say that an important development in that was accomplished actually by a friend of mine from UCSF (now retired), Mike Merzenich, who demonstrated that in spite of the topographic organization, that there was considerable plasticity even in adults in the cortical organization. That was quite important to understand as well. There is a framework of brain organization, and then there's plasticity within that framework, and it's experience dependent. That's one big thing that I think was accomplished. There are issues with respect to free will that people often raise with me. The top-down determination of behavior. It's a very interesting philosophical question of how free will emerges, creativity, things of that nature. I think our work with fronto-insular cortex and self-control may be relevant to this question, ZIERLER: Are you content that some of these are simply not answerable in a scientific realm? ALLMAN: No, I don't agree with that. I have actually had colleagues who have argued that there are many aspects of emotional behavior that could not be studied scientifically. I have a colleague who wrote a whole book about that, in fact. I don't believe that at all. I believe that these sort of things can be studied scientifically. I think that all these things are things that we don't necessarily have a necessary foundation to go after, but that's not to say it can't be done. ZIERLER: Terrific. That's a great place to end for today. [End of Recording] ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It's Friday, September 24th, 2021. Once again, it's my great pleasure to be back with Professor John Allman. John, thanks again for being with me. ALLMAN: It's great to be with you. This is the fourth one? ZIERLER: That's right. We've covered a lot of ground. We ended last session talking about some of the frontiers in thinking about consciousness, as it relates to the things that are most important to you. That gets us to another area of research for you, and that is the way your research touches upon psychology and economic decision-making and rational thought. I wonder if you could reflect a little bit about how your work has touched on these areas. ALLMAN: I'm really glad that you brought this up. I've had this conversation with Charlie Plott. There really is quite an interesting story there. I'd say probably about 1990, roughly 30 years ago, I began to have an interaction with the behavioral economists at Caltech, and that would be specifically Charlie Plott, David Grether, and Colin Camerer. A number of interesting things grew out of that. ZIERLER: How did that happen? Did they approach you? Did you approach them? Were you just finding yourselves asking the same kinds of questions? ALLMAN: I think it was a commonality of interests. Certainly, what happened very early on in this interaction was that we had invited Tony Damasio to give a talk at Caltech. Tony had just written a very famous book, Descartes' Error. Tony presented the impact of lesions in orbital frontal cortex on decision-making. He had this classic case of an individual who had been very successful and had a resection, I think, for a tumor, of orbital frontal cortex, and his life just totally fell apart after that. He had been a corporation executive. He went bankrupt. That was one of the manifestations of this dysfunction that occurred. Obviously numerous examples of very poor decision-making that he made after the lesion. It was clear to all of us, I think, that it had disastrously impacted his economic decision-making. There are other instances of that. Not to digress too far, but similar phenomena occur in people who have the behavioral variant of frontal temporal dementia (bvFTD). They often make poor economic decisions. Indeed, those are often the earliest manifestations of the disease, bad financial decisions. Those have to do with impulsiveness and cost-benefit, risk kinds of calculations that become quite skewed. So, we recognized that this was really quite a moment of insight. Tony is a person with quite a few stories to tell and a lot of patients to report on. As I recall, he began a lecture at 11:00 in the morning. we took a break for lunch, but I think he continued on until about 5:00 in the afternoon. He had more stuff to say! A lot of it was very relevant. That I think had kind of a galvanizing effect on—one important part of that—maybe this is even the late 1980s—is that Ralph Adolphs eventually worked with Tony, did his celebrated work on the amygdala with Tony, beginning it with Tony. Eventually he joined us as a faculty member at Caltech. He had been a graduate student studying the owl auditory system with Mark Konishi earlier. That was one very concrete consequence of that. What emerged from was a social decision-making program at Caltech. It eventually was associated with the development of our brain imaging facility, MR facility. I'll just say a little bit more about that. I began talking with Charlie, David and Colin quite a bit. That led to a paper with Stephanie Kovalchik, Charlie, David and Colin that has actually been pretty widely cited, in which we looked at a number of standard measures of economic decision-making in an elderly population and compared them with young adults. This was a population of high-functioning elderly people who were a control group for a big Alzheimer's study at USC, so we had this good study population of elderly subjects. Then we did young adults. I believe it's initially undergraduates at Caltech. What emerged from that study is that by most measures, there wasn't a decline in decision-making in the healthy elderly, although notoriously, that does happen in the prodromal state, in Alzheimer's disease. So for Alzheimer's, that's often an indication of deteriorating cognition. That has been studied by David Bennett's group in Chicago, where they have looked at this explicitly in what they call financial literacy. They found that deterioration of financial literacy was indeed a sign of incipient dementia. At any rate, the people who were healthy elderlies in their 80's, no problem. But we did find interesting that the healthy elderly actually did have an advantage, and that advantage turned out to be that what is sometimes called meta-knowledge, that the healthy/elderly were much better at gauging the quality of their own decisions. Whereas younger subjects were inclined to be impulsive on these tasks, the elderly were much better calibrated. That is to say in a question where there's a high degree of uncertainty associated with it, they were able to gauge whether their response is accurate or whether they were just guessing, whereas younger people tended to be overconfident when they were really just guessing. It was really quite a striking effect, which Stephanie Kovalchik and I then followed up with a subsequent study. Stephanie was the first author of both studies. She was a Caltech undergraduate, very bright and capable. In essence, the healthy elderly knew their own minds better. They were better calibrated, presumably by a lifetime of experience, as to what they knew and what they didn't know or in other words they were wiser. That was quite a remarkable finding. That's probably why this study has been quite well cited. That was one very concrete result of this collaboration. Another was that we all had the intuition that what economics could bring to functional imaging was a set of hypotheses to test. We tested some lines of economic thinking about decision-making in the scanner. Caltech did not at that time yet have a scanner, but we worked at UCSD with a scanner down there, and we did the responses that subjects made in a particular type of auction bidding, which was of theoretical importance to the economists. We have a collaboration that was published in the Journal of Experimental Economics, which is one of the very early studies of economic decision-making in functional imaging experiments. There of course now have been a great many of those done, thousands I suppose. ZIERLER: What did this scanner allow you to see that wasn't possible previously? ALLMAN: We could see a sequence of activity in different parts of the brain associated with making a more or less optimal auction bids. That explicitly seemed to involve the frontal pole (Brodman Area 10, which we have also studied in the context of Alzheimer's disease).. That has also been confirmed later by other imaging studies. The frontal pole seems to be very much involved in probing uncertainty and set-shifting and to some extent quantitative reasoning. We also saw it in the basal forebrain in areas that are associated with reward. We also saw it in the amygdala. Those are the primary sites of activity. Of course, none of that was known, it was totally frontier stuff at that time. We even coined a term, as kind of as a joke, of calling what we were doing "neuro-economics." That actually stuck! This research became an important argument for Caltech acquiring a functional imaging facility. Gordon Moore gave substantial sum to Caltech, and about25 million out of that went for that facility. That facility has been a great success, and many, many studies have been done in that facility, one of which I did with Karli Watson, in which we looked at humor, and were able to show that social humor as depicted in cartoons, like from The Far Side, was a powerful driver of activity in the fronto-insular cortex. The degree of the funniness of the cartoons is associated with increased activity in fronto-insular cortex, which is also involved in many other aspects of social decision-making. We believe that humor serves as a means of resolving conflict both between people and in the decision-making process itself. Humor has a powerful biological utility as a way of recalibrating information and resolving conflicts.

Ralph Adolph now runs the MRI facility. There have been thousands of studies done in it. It also interacted, of course, with our bringing Doris Tsao to Caltech, because she needed to have the imaging facility to do her monkey experiments, although that involved acquisition of a second magnet. All that stuff followed from that original impetus. We made some faculty hires as a consequence, developed a new academic program at Caltech. Graduate students came in. A number of them have gone on to have distinguished careers. It was something that had not been happening really anywhere, 30 years ago. So, we were kind of on the forefront on that.

ZIERLER: It's a uniquely Caltech story to think of economists and neurobiologists getting together and thinking about these things.

ALLMAN: That's right, yes. It is also an integration between quantitative social sciences on the one hand, and physics. After all, MRI is physics. I continue to do that to this day. These physical techniques are enormously helpful in understanding brain function.

ZIERLER: You mentioned graduate students. That's another area of your career we haven't yet touched on. The graduate students, the postdocs who have really done significant work and have gone on to very distinguished careers, first and foremost I want to ask about Pat Wright. When did you first meet Pat?

ZIERLER: I first met Pat in 1980. The only serious study of owl monkey behavior in nature had been her study. I was eager to learn about how owl monkeys actually behaved, given that we had made this huge investment in trying to understand their brains. A few years later, Pat was interested in going to a site in Madagascar at a place called Ranomafana, which means "hot water," to see whether an animal that had been reported many years before still existed. This was a type of lemur that was specialized for eating bamboo, very distinctive dental specializations, and other than that was only known from museum specimens.

She went out there, and she was at that time my postdoc in my lab. The details of the discovery of the Golden Bamboo lemur I described earlier, but not some of the background and consequences. She had managed to persuade the government of Madagascar to set aside a 42,000-hectare reserve at Ranomafana, for preservation of this new species, which is quite a commitment. Pat recognized that the conventional models for conservation were inadequate, and that it was not sufficient to have reserves, but what you absolutely had to have for them to be successful is really substantial engagement and cooperation with the local populations. Because if that doesn't happen, they'll go into the reserve and kill the animals, or they'll harvest resources in the reserve, and it will defeat the purpose. That is typically what has happened in many reserves around the world. I have actually visited some reserves where the forest was devastated. Because you can't just create a reserve. That had been how people thought about conservation 30 years or so ago—buy land or acquire control of land, try to keep the people out. That doesn't work!

What Pat understood this, which is one of her great contributions to conservation—and she received a MacArthur Award and the Indianapolis Prize for her work in conservation; she's become one of the world's foremost conservation biologists. She introduced education and healthcare; she employed a lot of the local people. Now about 150 people are employed by the Centre ValBio. Many of those people have been with her since the 1980s, people whom I met back in 1986 when I was there the first time. The healthcare role has gone on to a new organization called PIVOT, which provides healthcare for about a quarter of a million people in that part of Madagascar. They make a huge difference for those people. There is now a very extensive eco-tourism busines, but it has been interrupted by COVID.

The research part of this is supported to a significant degree by fees paid by visiting researchers, and by students from other nations coming in and doing like a semester abroad in Madagascar, actually doing behavioral ecology on the Reserve. Which of course has been a real problem due to COVID, because you can't do that during the COVID period. One of the things that I've been involved with is how to keep the place afloat, when the main sources of revenue are cut off.

Anyway, this model began with the creation of the park and the founding of the Centre ValBio, the research institute within the park that I'm connected with, which are central to this model of conservation that actually works. Also, a number of other implications of that. One is the long-term monitoring of plants and animals over time is absolutely crucial. If you just look at plants or animals in a narrow segment of time, you don't understand the real story. You have to look at it over time. Having a sustained research institute that's monitoring continuously is crucial for really understanding what's happening, particularly in the context of climate change.

Another area is that many new drugs emerge from plants and other organisms, living in the rainforest. They created an organization to cultivate different plant species that had been recognized by the locals as having a therapeutic benefit, with the idea that those might become the basis for the development of new medications. The famous example of that is the drug vincristine, for the treatment of leukemia, that is derived from the Madagascar periwinkle, Vinca. Most drugs actually come, as their foundation, from some natural substance. The idea would be to facilitate that. That's another one of the enterprises there. You can't just set off a piece of land and say, "That's it." That's just the beginning.

ZIERLER: A broad question as it relates to your graduate students and your postdocs over the years—coming back to the fascinating intellectual academic trajectory that you had from anthropology into neurobiology, into neurophysiology, what have been some of the most common degrees that you've taken graduate students on with? Have they come also from anthropology, or does that suggest a certain maturity in the field of neurobiology that a lot of these students did study this as undergraduates?

ALLMAN: I have had 2 postdocs who came out of anthropology, Pat and Emmanuel Gilissen, who was a co-author of our original paper of the VENs and is now curator of mammals at the Royal Museum of Central Africa in Belgium. I've had students coming out of different areas of biology, mostly, and electrical engineering, and also the computers and neural systems, or CS. I've had interactions with people, say, in computer graphics and things like that, over the years. Those have been the kinds of preparations that people typically have had. Biology and different forms of engineering and CS.

ZIERLER: On the whole, are most of the postdocs and graduate students you've had, were they pursuing an academic track? Were some of them more applied in their thinking, and they're working at, for example, pharmaceutical companies, things like that?

ALLMAN: I don't believe I have any students who are now working in pharma. Most of them have been able to get academic positions. Bill Newsome at Stanford; Steve Petersen and Fran Miezin at Wash U. who recently retired; Jim Baker at Northwestern; Marty Sereno at UCSD and Calstate San Diego; Elliot Bush at Harvey Mudd; Allan Dobbins at the University of Alabama, Birmingham; Karli Watson at the University of Colorado. Emmanuel Gilissen at the Central African Museum; Pat Wright at SUNY Stony Brook; Dave Siversten, as I mentioned earlier is a curator of botany at the Huntington Museum and Gardens. One, Richard Jeo, is senior vice president of Conservation International. Several Caltech undergraduates whom I worked with closely have also gone on to successful careers: Doris Tsao as a professor at Caltech and now at UC Berkeley as related earlier; Paul Manis as a neurophysiology professor at the University of North Carolina; Andrea Hasenstaub, as a neurobiology professor at UCSF; Gisela Sandoval as a psychiatrist at Stanford; and Stephanie Kovalchik at Victoria University in Melbourne, Australia.

ZIERLER: This gets me back to the thrust of where we ended in our last conversation, about the broad retrospective questions as they relate to your career. Given your longstanding interest in brain evolution, what does that tell us more broadly about human evolution anthropologically, culturally, across the board? What do you see as the particular focus of brain evolution and what it tells us more broadly about how humans have evolved?

ALLMAN: Speaking broadly, I think that expanded brain and expanded cognitive capacity has to do with living over a broader time span, that is to say, integrating information over decades or much longer periods of time, and incorporating that experience as a guide for your behavior. So that capacity to integrate over time and probably over space, too.

You could see one of the great differentiating factors of the way we're living now is between very local thinking and global thinking, and between self and perhaps one's immediate acquaintances and family, versus the broader community. If you take that narrow perspective of things which are extremely local and living extremely "in the moment," that's not very adaptive in the context in which we're living. We live in a global environment filled with a diversity of people of different cultures and races and of different life experiences, and we have to be mindful of that diversity and of the historical past and the future. We also have to develop further our capacity to see things from the perspective of other intelligences, both human and animal. We need to develop our theory of other minds to transcend the limitations of self. I see that as very important aspects of the cognitive evolution and the brain evolution that differentiate the smaller nervous systems from larger nervous systems, is that capacity to integrate over successively larger space, time and differences in perspective, self vs other.

I've argued for example, in my book, that what having a big brain (or at least cerebral cortex) may help not so much with the day-to-day routine events, but dealing with the things that are really unusual, that enable you to have sufficient reserve to be able to develop a way of dealing with those unexpected events that might kill you and thus to thrive.

ZIERLER: Do you see the growth of the brain evolutionarily more as a response to the relative weakness of our physicality—not having fur, not having claws? Or does it go the other way around? That we shed those traits because we didn't need them, because of the large brains that we had?

ALLMAN: The brains of the apes and the new world of cebus monkeys and spider monkeys, are pretty big, and they live a long time, too, so that capuchins amongst new world monkeys and apes have a maximum life span in excess of 50 years. They're very much longer-lived than most mammals are, and they have an extraordinary range of foraging capabilities. They can eat lots and lots of different things, make tools and colonize different habitats as well, to a remarkable degree. But they've got plenty of fur, and they've got pretty big teeth for their size. Curiously, the reverse argument (the expensive tissue hypothesis) has made that having a big brain requires energy, particularly during development, that might otherwise go for muscles and digestion. I discuss that in some detail in Evolving Brains.

ZIERLER: So there's not as much correlation there as meets the eye, perhaps.

ALLMAN: I don't know. It's a possibility. I would be perhaps a little reserved about jumping to conclusions about it. The thing that I'm really struck by in addition to the capacity to deal with the broader spatial and temporal domains and the capacity to use the cognitive reserve to be able to exploit new resources or to be able to deal with situations which are so unexpected and so traumatic that they would kill a less well-prepared organism. In addition to that, I think there are several things that are crucial. One is basically self-control, which we're seeing in fronto-insular cortex. That capacity to resist impulsivity is central to almost everything that we do that requires any sort of focused effort. Basically civilization and complex social life require self-control.

Correlated with that, or probably part of the same story I should say, is cooperation with other individuals. Cooperation is really a hallmark of being human. Another way of putting it is from some very nice work by Hilly Kaplan and his colleagues that has been done comparing chimpanzees and humans living in hunter-gatherer groups. Young apes after they are weaned eat only what they can forage. In humans, they are part of an extended family in which there is substantial provisioning of reproductive females and of youngsters, so that children really don't become fully self-sufficient until way past sexual maturity, and that their efficiency or effectiveness as foragers may not reach a full maximum until they're in their forties, as observed in contemporary hunter-gatherer populations. Because to be an effective hunter or forager—and that goes for women and for men—requires a lot of knowledge and a lot of cooperation.

That to my mind is central to being human. It's basically taking care of other members of your group in these broad extended families. Not nuclear families, mind you, but more broadly than that. I see that as sort of the basic human social organization. It involves provisioning reproductive women who have a very high metabolic requirement because they're constantly pregnant or nursing. The energetic cost of lactation is far greater than the energetic cost of gestation. They typically need some help calorically, as do the children. There are older women, grandmothers, and men who do that. Inherent in that is a system of sharing resources and cooperation.

The same applies to the very old. And it's significant. One of the great mistakes that people make in thinking about this is the idea that there are no old people in hunter-gather populations. In fact as has been shown in demographic studies of hunter-gathers, if you manage to survive to sexual maturity, your chances of making it to age 60 in hunter-gatherer populations is about 50%. The great infant mortality gives the false impression of a short life expectancy. The first few years of life are very, very risky, and that will bring the life expectancy numbers down. But in fact, there are plenty of old people and particularly old women in hunter-gatherer populations.

ZIERLER: Because their wisdom is valued?

ALLMAN: They will obviously have a value in terms of their aggregate knowledge, and they're the only way that knowledge is stored, of course. There's no technical way of preserving it—no writing, no recordings, et cetera. So, I think they do have a survival-enhancing value for their offspring in their kin group. That's the way I see it, in terms of evolution.

There are other animals that have gone down the same route, I think. Very highly social birds, for example, are extremely long-lived, like crows or parrots. Parrots have life spans that may exceed humans. You also see it in other social mammals, for example elephants, that are also intensely cooperative. We also even have some neurobiological evidence with respect to VENs in fronto-insular cortex in elephants. And there is certainly strong evidence for respect for elders in elephants and awareness of death, and even evidence for the beneficial effects of grandmothers. I see that as some of the important developments in the relationship between brain evolution and basically a capacity to live in a broader spatial-temporal context.

I wanted to say just a little bit on a couple of other issues that were related to this, that you raised. There's the issue of consciousness, for example. Now I personally think the quest for consciousness is overblown. [laughs] There are people that believe that the great question of neurobiology is consciousness. I think that that's because consciousness has become heavily encrusted with meta issues that may have a religious context. But if you study consciousness operationally, it's quite study-able and understandable. In that context, it should be remembered that a great deal of behavior is not conscious. That is to say that many things that we do as we go about our daily existence are things that we're not consciously aware of.

There's a good reason for that—because consciousness can get in the way. The point is that anything that you do that you're really good at, you're not generally consciously aware of it. Writing, any sort of skilled act, for example, it's best to offloaded it to the cerebellum that can take on these complex routine behaviors and do them effortlessly without conscious intervention. In fact, conscious intervention csn degrade performance—for example, if you think about riding a bicycle, you're likely to fall off.

ZIERLER: [laughs]

ALLMAN: It's better if that is an unconscious skill. For many other things, when you get good at it, you don't have to think about it step by step. You just do it. That's the function of the cerebellum. The cerebellum has also undergone great evolutionary expansion, and it is surprisingly connected with the frontal cortex, with the evolutionary expansion of frontal cortex. So much of what the cerebellum is doing is routine thinking, in a sense. Linguistic functions, things of that sort, that you don't have to think about, you just do them. Those are all things where consciousness gets in the way. [laughs]

Consciousness is a reflective mode that has some importance in guiding some aspects of behavior, but even in decision-making, a lot of that will not be conscious, and indeed with things we're good at. For example, once you become skilled at it, as for example, in auction bidding, which can be very fast paced. I suspect that auction bidding once well-learned in these situations is probably a cerebellar function.

In any event, I think that decision-making and capacity to cooperate, to overcome impulsiveness, those are the more interesting phenomena. This may sound like a digression, but I'd like to reflect on a couple things, one of which is in my book. Back about 30 years ago, I was visiting my cousin Steve Allman, who was at that time running an electrical generation facility, a power plant, down in Chula Vista, south of San Diego.

I got an insider's tour of that power plant and how it worked. We went into one room, and it was full of little, tiny pneumatic tubes and valves. I asked, "What are all these little tubes doing?" He said, "They're running the plant." Went into another room, and I saw some rather primitive looking computers and asked what they're doing. He said, "Well, they're running the plant, too." And another room had more modern computers. "What are they doing?" "They're running the plant, too." It was clear that there was an overlay of control systems that were operating the plant. I said, "This doesn't seem very efficient." And what he said was, "Well, this plant is so important to the generating capacity of Southern California that we can't shut it down. We have to keep it going all the time. We can't retrofit the plant because they need the power all the time."

Now, what occurred to me, "Biology is like that." You can never shut it down. That's lethal. That's the end of evolution when you shut it down. You have to keep it operating all the time. So we are the descendants, each and every one of us, of a continuous line for billions of years. It's just inherent in biology. A lot of people have trouble thinking about that because they worship efficiency.

What actually happened a few years later is that the legislature in California decided to deregulate the power market inspired by neoliberal economic ideology. As a consequence of this deregulation, they started shutting plants down. Then we got a wave of power shortages and outages, because of the reduced production of electricity. That resulted, in turn, in the large increase in the rates we were paying for electricity, when began about 2000. So it was an example of the massive failure of deregulation, because our policy-makers didn't understand a fundamental principle: you can't shut it down without very severe consequences.

Now, another thing that's related to that—Put it this way, in biology, that's extinction. [laughs] Related to this is a tremendous redundancy that we see in brain organization. That is to say, why do we have a dozen or so cortical visual areas that are distinctive? The idea that I derived from these earlier studies, particularly by Bridges back in 1918, with respect to genes, as discussed earlier. Now that is an expensive way of doing things, because you have to support all the replicas. But it provides something that is a very robust system, because you have essentially a backup system too, that available if necessary for survival. This redundancy enables innovation on the one hand, and it provides resilience on the other. That is to say it reduces the vulnerability.

The broader implication of that is that biological systems have two things that are quite different from artificial systems, or at least many artificial systems. One is that they have a lot of redundancy in them, and that they are quite resilient to perturbation. That perturbation could come in the form of a mutation or of damage to the circuitry or starvation, say. But the point is that it's not maximally efficient. We have developed a culture that arises from a particular school of economic thinking that worships efficiency. But that efficiency only comes at the cost of resilience.

Another point that needs to be made about this is that biological systems are mainly about regulation. If you look at the actual functions of genes and proteins, they're heavily involved in regulation. So if you look at any system, you'll see that there are many genes for which their primary role is to serve as buffers between too much or too little, that serve to center the function of activity so it doesn't go off the rails in either direction. So there's a huge amount—most of biology is basically regulation. That is an inevitable attribute of complex systems. We have to have regulation, but if we deny that by political and economic philosophies that are anti-regulatory, or if we do regulation poorly, as I think America tends to do by emphasizing strict adherence to arbitrary rules or by ignoring them or by deliberately violating them. In this context I think of the advice given during the COVID pandemic by Dr. Bonnie Henry, the highly effective chief health officer for the Province of British Columbia: "Be kind, be calm, be safe". This deficiency in regulation means that our capacity for resilience, our capacity to withstand perturbations, shortages, all of those sorts of things, is greatly reduced, and our chances of becoming extinct are increased.

My colleagues, Jim Bonner and Harrison Brown, back in the 1950s and for quite a number of years thereafter, had a series of symposia at Caltech "The Next 100 Years" and then they had "The Next 90 Years," "The Next 80 Years," and so on. I attended the last of these. Harrison Brown and Jim Bonner published a book in the late 1950s that was called The Next Hundred Years. They talked about technical innovations and things like that, as you might expect. But the deep insight, and the thing which they really emphasized in the book, is that the real long-term peril has to do with vulnerabilities inherent in mutual interdependencies. That by creating more and more complex systems, essentially systems that are poorly regulated, that you have a situation in which you become extremely vulnerable. They recognized that before the internet, or before much of the communication revolution that occurred after the 1950s. But they were dead right! You can see it all the time, in everything you look at.

The current supply chain shortages are an example. It was painfully obvious, for example, in a recent account of why it has been so difficult to vaccinate the world, and the production of vaccines from COVID. It's a classic interdependency problem. But it's just a very concrete example of what is a massive problem for us. If there is a failure at any node within a very complex system, the system fails, if it has inadequate regulation. That's what biology is about. Biology is about surviving and helping one's offspring to survive and thrive so that they can reproduce.. Climate change, for example, is another horribly relevant example of this. Everywhere you look, this is what you see. So Jim was exactly right when he wrote this in 1957.

ZIERLER: We've talked a lot about biology. On the technical side, if you can think over the course of your long career, what have been the biggest game-changers in terms of instrumentation or computation, that have allowed you to make these scientific insights?

ALLMAN: One thing to remember is that much of what I did early on was with micro electrodes and an audio amplifier, which was pretty simple technology. What we did was that no one had really had the wit to do what we did, before in part I think because they didn't imagine that there was even something to be learned from it. But we saw the potential of visual cortex mapping and we systematically went about that, relating the receptive fields to the formation of the cortical map, and that proved to be very powerful in discriminating functional organization of cortex. My point is that that was a very simple technology; someone had to have the imagination to do it, and the grit to get it done. That in a sense is true of a lot of things, that a systematic application of something, with the right question, can change the world.

Now, in terms of the technologies, it's quite clear that those are basically the magnetic resonance imaging, derived from NMR. Paul Lauterbur invented it specifically to look at cancerous tissue, but it turned out to have what might be called a pleiotropic effect in revolutionizing the mapping of the brain. When the MRI technology was developed to be able to look at the movement of water molecules in three dimensions, the HARDI technology and the various modifications of that, that has proven to be revolutionary.

The similar story pertains for gene mapping, so that you could initially map genes working your way across the DNA molecule systematically over and over again. But that's really slow. The real revolution came, and it was related to the development of the Illumina platform for sequencing, to break up the DNA molecule into pieces that were only a couple hundred base pairs long and to sequence those little pieces massively in parallel. That in turn became the basis of the RNA-Seq technology and all the various derivatives of RNA-Seq technology that look, for example, at areas that are covered with chromatin versus not, and many things of that nature that are now possible to do. That has become an enormous revolution, but it's not restricted to the brain. It involves everything. Every biological system, you can be helped in understanding it by applying these technologies.

The key, I think, was that in their initial conception, the people that conceived of them probably had no realization of how general they would turn out to be, or how incredibly revolutionary they became. It's hard to know where these innovations will come from. As I say, with my former student Dave Sivertsen, who would think that an expert on bamboo at the Huntington Gardens would help to develop the electric car industry?

ZIERLER: [laughs] John, what about the role of simulation, computer simulation? Has that been relevant for your research?

ALLMAN: I wouldn't say that it has had a terribly big impact. People would argue with me about that. What has had an impact is something slightly different, and that is called cluster analysis So you have a big bolus of data, what to make of it?. To give you a specific example of this, up at the Allen Brain Institute in Washington. They got interested in von Economo neurons or VENs in fronto-insular cortex. They dissected out layer five from fronto-insular cortex from some human autopsy brains and then isolated the cell nuclei from that layer of cortex, which is where the VENs are located. They then proceeded to sequence the individual nuclei, using single cell RNA-Seq, to look at the gene expression in about a thousand of those nuclei.

What do you do with so much information? A very important aspect of modern science is the strong expectation that you'll share the data. So they made the data available online. Data-sharing has become kind of a moral ethic of much of modern biology. It stands in marked contrast to other kinds of science done in the past, in which the privacy of the data was often a great impediment. We got the data, and Henry Amrhein, who is quite adept at this sort of thing—I'm not—applied a number of different AI clustering algorithms to it, but the one that worked really well is an algorithm called UMAP. It's an algorithm that has arisen out of AI to look at complex data sets and find hidden structure within them, the clusters, in this case genes that are expressed in different types of cells, such as the VENs. What UMAP will do is break down that data sets into things that have close relationships with one another. So, you're looking at that. Lo and behold, when he applied the UMAP in a two-dimensional format, that it beautifully separated the VENs out, or the genes that we think are related to the VENs, from other the other type of excitatory neurons, the pyramidal cells as separate clusters.. You could see a separate cluster of genes expressed in the inhibitory neurons. You could see a cluster expressed in oligodendrocytes that make myelin. You can see cell clusters of genes expressed in the astrocytes and microglia. The combinatorial space is pretty big. But UMAP is able to boil it down into a very straightforward two-dimensional space, and that two-dimensional space makes sense genomically and functionally. That's a real contribution. We know that the VENs are also located in another area, anterior cingulate cortex, so we applied UMAP to the comparable data from anterior cingulate cortex, and it gave us approximately the same set! That's an example of where AI has helped us and has become really pretty much part of the standard toolkit of genomics. However, not all AI algorithms work well and some can be extremely misleading; its crucial to have empirical validations to test their validity.

ZIERLER: I'm curious, broadly conceived, either as a direct result of your research or inspired by your research, what do you see as some of your greatest contributions in the translational realm?

ZIERLER: Yet you work on things like Alzheimer's, which are crying for translational solutions.

ALLMAN: First, we can't offer a cure to Alzheimer's at this point in time because of the immense complexity of this disease. And second, I'm not a physician or a lawyer or a businessman; I'll leave that to others who have those skills and resources if that time comes.

ZIERLER: [laughs] The last thing that I wanted to ask you, before we look to the future, to go back to something very interesting you said last time—obviously this will get us into perhaps a more philosophical realm, is your insistence that despite the large gaps in our knowledge currently, that all the things that you study ultimately do have a scientific explanation, and if not today, at some point in the future. Does that then crowd out the possibility in your mind that there's such a thing as a soul that might exist somewhere in our consciousness?

ALLMAN: I don't believe in extra-corporeal existence, i.e. souls. . I feel that the really important thing is the continuity of our existence, the fact that we are the product of billions of years of evolution, and we're part of this great continuity in which the cycle of life and death is natural and necessary part of that continuity.

ZIERLER: The question I was asking, though, was more scientifically based, in the sense that the things that we ascribe to be uniquely human—our emotions, our fears, charity, love—my question is more on the basis of, do you think that these what we might consider metaphysical concepts ultimately do boil down to atoms and molecules at the end of the day?

ALLMAN: First of all, I do not believe our emotions are uniquely human. My view is based on a lifetime of close observation and interactions with animals and is also in the long tradition in evolutionary biology with respect to emotions. Darwin addressed this issue in his Expressions of Emotions in Man and Animals. This issue has also been very thoughtfully addressed by Frans de Waal with particular reference to empathy in animals. I do not think that emotions are any more difficult to study objectively and rationally than many other natural phenomena or that there is anything magical or metaphysical that sets emotions apart from other phenomena. I see them as essential parts of life and fully study-able and understandable at a mechanistic level. I do see emotions as boiling down to atoms and molecules like everything else in our existence. Among many other things, my collaboration with Bill Seeley on behavioral variant fronto-temporal dementia and subsequent studies by Bill and others on the neuropathological mechanisms in this terrible disease that involves deficits in the most profound and intimate emotions, such as empathy, reinforces this view. This view is also supported by the powerful effects of drugs of abuse on emotional states, where the roles of specific molecules and their receptors in the brain are well known.

ZIERLER: Last question, looking to the future, for you personally, for the field, what do you want to accomplish for however long you want to remain active? Then an even broader timeline than that, where do you see the field going, if you could use your powers of extrapolation?

ALLMAN: It is clear that we now have the power to do much larger-scale studies than were hitherto possible, to get at some of the kinds of questions you were raising. I think that that will be done in such a way as to provide satisfying answers for those kinds of deeply philosophical kinds of questions. What is happiness and how is it best achieved and sustained?

I do think that central to all this is the notion of achieving a reasonable degree of life satisfaction, within bounds of course. I think that should be one of our central goals in life, to provide a decent level of life satisfaction and health where possible. I see that as a moral imperative, as best we can do it. That arises from very different kinds of considerations, from other kinds of optimizations currently in vogue with many such as maximizing wealth, GNP growth or efficiency, which do not necessarily support life satisfaction, health or resilience.

That would be the paradigm that I hope people will eventually follow, and which many nations do follow today, the ones which have high indices of transparency and life satisfaction. They're the Scandinavian countries, Germany, Canada, New Zealand, Costa Rica, and a few others; all stable, well-functioning, capitalist democracies. Significantly, life expectancies in these countries have continued to improve while it has begun to decline in the US driven by obesity, addictions, sedentary living and poor access to health care. These countries are not paradises but are achievable reality. The citizens of these countries are well aware of their many problems, but objective studies of well-being find that the countries with the high levels of life satisfaction have a strong attribute in common, which is a high degree of social trust. We don't have a high degree of social trust.

ZIERLER: Here in the U.S., you mean?

ALLMAN: In the U.S. That's really what having a good society boils down to. If you want to have a happy and healthy society, you basically have to have people trusting one another because co-operation is the core of our social existence. I think the lack of trust that we are seeing now throughout our society is a consequence of severe homeostatic dis-regulation, some of which may be exacerbated by the social media and AI algorithms that tend to drive polarization and are profitable because they enhance advertising revenue. Achieving homeostatic balance between opposed tendencies within societies is the key to long term well-being and survival as Walter Cannon recognized many years ago. We are way out of balance.

ZIERLER: Indeed, indeed. John, on that note, this has been a great pleasure spending all of this time with you. I'm so glad we were able to engage and discuss all of your research and perspective over the years. I'd just like to thank you so much for spending this time with me.

ALLMAN: It has been a wonderful experience.

[End]