George W. Beadle Professor of Biology; Investigator, Howard Hughes Medical Institute
By David Zierler, Director of the Caltech Heritage Project
January 6 and 27, 2022
DAVID ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It's Thursday, January 6th, 2022. I am so happy to be here with Professor Elliot Meyerowitz. Elliot, it's great to see you. Thank you for joining me today. Elliot, to start would you tell me please your title and institutional affiliation here at Caltech?
ELLIOT MEYEROWITZ: I'm the George W. Beadle Professor of Biology and an Investigator of the Howard Hughes Medical Institute in the Division of Biology and Biological Engineering.
ZIERLER: Let's start with George W. Beadle. Can you talk a little bit about him and what the significance might be of being named in his honor?
MEYEROWITZ: I don't think there's any significance. I think it was just a chair that was lying around when my turn came up. I don't think it's an especially funded chair either. I don't get any benefit out of it except the title.
ZIERLER: Do you see any significance, any intellectual connection between Beadle's research and what you do?
MEYEROWITZ: Oh, yes. Certainly. There's no question. He was a giant of plant genetics before he did the one gene-one enzyme stuff. I'm a great admirer of his work, but that didn't have anything to do with my becoming the Beadle Professor. That was just happenstance, I think. Beadle was a former chairman of the Caltech Biology Division, as am I.
ZIERLER: When were you named an investigator for the Howard Hughes Medical Institute?
MEYEROWITZ: I think it was the beginning of 2013.
ZIERLER: What has that designation allowed you to do that might not otherwise have been possible?
MEYEROWITZ: Pretty much everything my lab does because it comes with a pile of money for research which isn't tied to particular projects and which has a much longer timeline than federal funding. We can take on things that are much more challenging than we could ever do with federal funding.
ZIERLER: Does HHMI have a long history of funding research in plant biology?
MEYEROWITZ: No. It was a new venture. It began in around 2011. It was an idea I think of the then president, Tom Cech, and happily followed up upon by the next president, Bob Tjian. Eventually they established a program and they selected a set of I think 15 original plant investigators who were added to the existing roster of HHMI investigators, who up to that point were largely doing medical research. I joined in 2013 because in 2011 and 2012 I was on leave from Caltech.
ZIERLER: Is there an aspect of your research that has a specific medicinal component that would make Howard Hughes a likely funder of your research?
MEYEROWITZ: No. Keep in mind that about 25% of our pharmaceuticals are plant products so that it's a contribution to the type of medicine that Howard Hughes did previously to know something about plants. Also keep in mind that there's much human mortality and human illness due to the lack of appropriate levels of food in a lot of parts of the world. The numbers of people who are dying of starvation outstrips the numbers who are dying of malaria or tuberculosis or any of the other major diseases, even probably cancer. Human nutrition is an incredibly important element of human health. The people who suffer most from lack of appropriate nutrition are children and women. Given that it's children there are a lot more years of life lost to undernutrition than there are to most of the diseases we study, maybe to all of the diseases we study. There are very important medical aspects to plant science that might justify the research to HHMI; I don't study them though.
ZIERLER: Elliot, to get a sense of your overall research and career trajectory, is it correct to say that earlier in your career, certainly during your education, you were most focused in animal biology? Then at some point you made a transition to plant biology?
ZIERLER: When did that happen and what were the circumstances of that decision?
MEYEROWITZ: [laugh] I don't know if there was ever a decision. You just do what you think; you follow your nose if you're free to choose your scientific projects, which you are in a place like Caltech if you can get appropriate funding. I came here studying development of the nervous system in flies and insects. I'd always had or had had for many years an interest in plant genetics and plant development. It seemed to me that there was a real frontier there. Shortly after I got here as an assistant professor I began some side projects in plant biology which took off in the early 1980s, eventually becoming the sole subject of our research. We finished up with the fly projects in the early 1990s and went fully onto the plant stuff because it was just so much more fun.
ZIERLER: In talking to colleagues, other people in the field, is it common to make that kind of a switch?
MEYEROWITZ: I don't think it's uncommon. A lot of the people who entered plant development and plant genetics in the 1980s and the 1990s had previously been working on other things, on animals or bacteria.
ZIERLER: The basis of your lab of course at the most elemental level is understanding how plants grow and develop. Of course this is a very old field. I know Charles Darwin thought about such questions. Today, 2022, what are the frontiers of knowledge? What are the big question marks in understanding how plants grow and develop?
MEYEROWITZ: There are a lot involving, first of all, how it is a cell knows where it is in a developing organism which is a question in plants or in any other sort of multicellular development. That is how the cells become specified to become the types appropriate for their positions. Then how do they undergo division, local expansion, directional expansion to create organs of appropriate shapes and then how do they know when to stop so that the organs are of appropriate sizes? They're questions of what a developmental biologist would call pattern formation and morphogenesis.
For plants there are very strong effects of the environment on growth and on development. Plants grow very differently in different external environments unlike humans who have their own internal temperature and are wet inside and so on. Plants can be dry or wet, they can be hot or cold, and they can be in the dark or in the light and they grow very differently in those circumstances. That adds an extra element to plant development. It isn't a major element in most of the types of animal development people study.
ZIERLER: Elliot, is there a particular plant or species that you focus on and you can extrapolate more broadly?
MEYEROWITZ: Well, that was what we really did. In plant biology my lab established a new model system, Arabidopsis thaliana, which is a mustard that had been used in a few laboratories before we started on it, but not for molecular biology research. We studied its genome and began cloning genes from it. Initially it was used because it is very easy to use in the laboratory. Most of that sort of work that was being done when I started was being done on plants that are much harder to grow. To get enough crop plants to do a good genetic experiment, you needed a lot of field space and tractors and assistants and irrigation. For example if you're doing it with maize you couldn't really do the genetics without command of a lot of field space, and the genetics of the other plants that were being used like tobacco aren't that practical because of its tetraploidy. The genetics in tetraploids is really very difficult, the sexual genetics.
What I thought was that using Arabidopsis would enable much faster research —it was known to have Mendelian genetics, is very small, and has a very rapid life cycle. You can grow a lot of it inside the laboratory. In our lab we could probably grow a million plants a year if we wanted to. It would enable people to do experiments that they generally were unable to do with the sorts of plants that were being used before that. It turned out I wasn't alone in that. There were other people with similar ideas and we all worked together to establish Arabidopsis as a new model system whose uptake was very rapid. There are a very large number of labs that use this now.
A plant's a plant to answer the other question you asked. Whether you can project from the knowledge of Arabidopsis to other plants, well, there are specific things that are different about all the other plants. Clearly they grow differently, a little bit. They have different sizes, they have differently shaped organs. But the principles seem to be the same. It hasn't proven very difficult for people interested in crop plants to take knowledge that was derived in Arabidopsis and apply it.
ZIERLER: Is the extrapolation in plant biology different than extrapolation in animal biology?
MEYEROWITZ: I don't think so. I'm not really sure how to answer that. It depends what you're extrapolating. A lot of the research of animals is research on diseases. The model animals in labs don't necessarily get the same diseases that people get. The extrapolation could be rather difficult. Plants pretty much get the same diseases. The ones we care about.
ZIERLER: Elliot, in your lab what aspects of research are devoted to simply basic science and where are you focused on translational research or even applications?
MEYEROWITZ: We don't do anything that's translational or applied. We just follow our noses into what we think are interesting fundamental questions. Some of it has led to application, but not in my hands.
ZIERLER: In what ways? What have been some applications?
MEYEROWITZ: Some of the processes we studied like flower development or genes discovered—they're used in agriculture now. We discovered genes that control the development of flowers or of fruits, and responses to ethylene, and some of it has been applied for agricultural uses by other people. Not by me.
ZIERLER: I wonder if you can talk a little bit about the Computable Plant Project and more broadly when a computational approach became a part of your research agenda.
MEYEROWITZ: Pretty early. I can't really say exactly. I can't remember when we started this. We started to do genetic experiments like many people did to work out the gene regulatory networks that were downstream of regulatory genes that are active in particular places in a plant and lead cells to develop to the types that are appropriate for those places, like a petal cell in a flower or something like that. Once you get past two or three genes if you consider that the gene activities can go up or go down in a continuous fashion, that the genes are regulating each other and their feedback is such that one gene may regulate a second one and a second gene may feed back on the activity of the first one—you can't calculate that in your head anymore. What you need is a set of equations that represent that and parameters that represent the degree of effect that the different genes have on each other and the rates at which their expression increases. Then you put that into a computer and you tune the parameters until you get the phenomenon that you see in the plant. This tells you things that you couldn't measure in the plant and also enables you to build a general model of what's going on in your system that you can send to any other lab and they put it in their computer and they'll get the exact same result.
The more traditional way was to have a diagram where there are lines between names of genes with arrows or bars at the ends and maybe a circle around it, some of them, and another circle that represents the next cell over. It's all some sort of a drawing, but if two people look at that they could come to entirely different conclusions about what the effect of limiting one of the gene's activities would be. Because you don't know the degree of feedback or the speed of the feedback. It all has to be made entirely explicit for a model to be honest. I started to work with physicists and mathematicians and engineers very early on in this business because very rapidly we had gotten to a point where our models were complicated enough that expressing them the old-fashioned way with a spaghetti diagram was just not honest.
ZIERLER: Is this to say that computers really changed the relationship between theory and experiment in your work?
MEYEROWITZ: I'm not sure. I think there are a lot of earlier examples of the sort of modeling that we did that didn't involve computers that is conceptually the same thing. It becomes easier with computers because you can write a long list of differential equations and numerically solve them really quickly. You can get the work done a lot faster with computers. Similar sorts of work where people tried to create explicit models of physical or biological phenomena and then saw to what degree those models reflected reality has been done for centuries. That is if you change some component, went and did the experiment, did your model tell you the right thing or not? And if not, continue to refine the model. That goes back possibly 2,300 years.
ZIERLER: Obviously well before computers. [laugh]
MEYEROWITZ: The particular case I'm thinking of actually did involve a computer of 2,300 years ago. The Antikythera mechanism.
MEYEROWITZ: I think there's a real question about that astronomical computer as to whether the astronomical theories of the ancients Greeks came from playing with the machine or whether they built the machine after they had the theories. I think it's a serious question. I think they were doing what we're doing. A great example of the sort of thing we're doing is Maxwell's calculations regarding Clausius's virial equation in the 1870s where he explicitly set out to find what would happen to a bunch of molecules banging off each other and whether that would give the amount of pressure that is actually measured as a gas heats up. He was able to say really a lot about the mechanism and what was going on at the atomic level long before anybody really believed there were atoms.
ZIERLER: Elliot, some technical questions. As your research statement says much of your work is directed to the—pardon if I'm pronouncing this incorrectly—shoot apical meristem. What is a shoot apical meristem?
MEYEROWITZ: It's the tip of every branch in a plant. There is a collection of stem cells that are dividing and differentiating to provide the stem so that behind the meristem it pours off cells that make the stem. The stem elongates and carries this meristem with it at the tip and then on the sides of the meristem it makes leaves during the vegetative growth of the plant and during the reproductive growth of the plant it makes flowers. If you go outside and look at a branch on any plant you see there's a long branch there which is a result of a long period of activity with some apical meristem which is sitting at the very end, a tiny microscopic structure of dividing cells. New leaves are formed and new flowers are formed at the end of the branch generally where the meristem is located.
ZIERLER: Can you call this a nanomachine? What does nanomachine mean in this context?
MEYEROWITZ: Would I call it a nanomachine? I have no idea.
ZIERLER: [laugh] Why this particular part of the plant? Why is this an area of focus?
MEYEROWITZ: It's where a lot of the development is happening. The rest is in the root meristem and in the cambium which is radial meristem that makes a tree grow wider. That's where the decisions are being made by cells about what they'll turn into.
ZIERLER: Can you talk a little bit about your focus on peptide signaling?
MEYEROWITZ: In the course of trying to understand how flowers developed we had first figured out how the radial pattern of organs in a flower was established - why sepals are on the outside and then petals and then stamens and then carpels that make up the ovary in the middle. We had a pretty good handle on that, but we didn't understand how it is a flower knew how to make the right number of organs: in the case of an Arabidopsis flower that's four sepals, four petals, six stamens, and two carpels. We started to collect mutations where those numbers were not correct. We had a series of mutations that had extra sepals, extra petals, extra stamens, and extra carpels and when we cloned the genes we found out that they revealed a peptide pathway with a transmembrane receptor kinase that senses a peptide secreted by nearby cells. This was part of a communication network that controlled the growth of the meristem. When the meristem got larger there were more organs. That told us two things. It told us, one, that organ numbers are specified by some sort of spacing mechanism and if you have a bigger field in which the spacing is occurring you get more organs. It also told us that there is very careful control of the size of something like a floral meristem or a shoot apical meristem because if it got even slightly bigger you've got the wrong number of organs - and generally you don't.
ZIERLER: To come back to an earlier comment you made about the importance of this research because of how important it is to feed the world. What aspects of this research do we need to continuously understand because the green revolution perhaps needs an update?
MEYEROWITZ: Well, sure. I think it needs an update in a lot of ways. The history of the field tells us that as soon as we fundamentally understand anything, somebody finds a way to apply it usefully to increase the yield or the sustainability of agriculture. I don't think we have to pick out particular areas that are of overwhelming importance. It turns out they're all important. There are people now using this exact peptide pathway that we discovered 25 years ago to breed new varieties of tomatoes that yield much more. This could not have been predicted when the original work was being done, and we can't predict now what areas of basic plant research will be the most important for agriculture in the future.
ZIERLER: Are some of these advances specifically geared toward adaptability in a world that's warming and desertifying?
MEYEROWITZ: The stuff we do not so much, but some of it is.
ZIERLER: In what ways? How does that work?
MEYEROWITZ: Plants respond to temperature by developing at different rates in different temperatures. We don't work on temperature responses, but we do work on environmental influences that alter growth rates. The work we've done is to look at how it is that increased nitrate nutrition at the roots leads to more rapid flower formation at the shoot so that you get more flowers and more seeds forming when the plants are properly nourished. There are a variety of interesting aspects of that. They all relate to changing environment in lots of ways. One obvious way is that in modern agriculture most of the nitrate comes from fertilizers which are made by very energy intensive and fossil fuel burning processes, and which lead to large-scale release of nitrous oxide, a potent greenhouse gas. The increased yield of our crop plants comes with a penalty of increased carbon dioxide and nitrous oxide in the atmosphere.
ZIERLER: I'm curious if you have any work that's related to the Resnick Institute and some of the things they're concerned about.
MEYEROWITZ: We started to think about the interactions of plants in the soil a little bit. I've been encouraging that area in the Resnick Institute, but we're not doing a lot of work in it yet. I'll be teaching a new course in the spring about plants in soil to see if we can get some students interested.
ZIERLER: Can you talk a little bit about gene expression in shoot apical meristems?
MEYEROWITZ: What do you want me to say? [laugh] Their genes are expressed.
ZIERLER: What does that mean? If you could explain. What does it mean for genes to be expressed?
MEYEROWITZ: Well, each of the cells in the shoot apical meristem has a collection of genes called its genome distributed between various chromosomes. They all have pretty much the same set of genes. Yet, if you look at the transcription of the genes - conversion into an RNA copy - it occurs at different rates in different parts of the meristem for different genes to the degree that there may be hundreds of different cell types in the meristem defined by the patterns of RNA expression. Anywhere you go in a meristem a particular cell has a collection of genes that it's expressing out of the full genome's worth of 25,000 genes or so. There's some subset of those that are being expressed at high levels and it's different from other cells in other parts of the shoot apical meristem. Gene expression differences characterize the cells becoming different from each other as a result of different positions and different neighbors in the meristem and different concentrations of plant hormones and everything else that's going on there. By looking at the patterns of gene expression you can establish how those cells are becoming different from each other and in what patterns.
ZIERLER: What are some of the big questions about how plants regenerate?
MEYEROWITZ: There are a bunch. There are different ways to regenerate plants. One is just to mince up a plant with a razor blade, put the resulting cells on nutrient medium and a tissue grows out of that called callus which looks like an unorganized mass of cells. If the hormone conditions are correct the callus will then make new shoot and root meristems and it'll regenerate an entire new plant. Some of the questions about that are what is callus? What is it that allows meristems to form? The whole callus doesn't turn into a meristem. It forms in little places in the meristem. What is it that specifies those places? What is it that the cells are doing that enable them to organize into a new meristem even though previous to that they didn't seem to be organized like a meristem?
We've found some surprising things in looking at callus formation. One is that when you mince up a plant like that the callus derives from only a very small subset of one specialized cell type of the plant, sort of an adult stem cell. Another is that the callus isn't unorganized at all; it's highly organized in terms of its patterns of gene expression. That organization changes very rapidly when the callus starts to regenerate in ways that we still don't quite understand. We know some things about it, but not a lot.
There are other modes of regeneration. We can break down the plant into individual cells by removing the cell walls. When you do that probably any cell type can regenerate a new plant. It's a somewhat different process. So, there are different ways that plants regenerate.
ZIERLER: Elliot, the question we've all been dealing with—what have been some of the challenges in managing a lab during the pandemic?
MEYEROWITZ: We're jumping around to a lot of different topics. The main challenge is that for a lot of the time everybody couldn't be in the lab at once. People had to work in shifts which took more organization than we're used to. It also meant that a lot of the work wasn't getting done because lab work can't be done from home.
ZIERLER: Is there an aspect of simulation or remote control of instrumentation that allowed for operations to continue or did some aspects of the lab really have to shut down?
MEYEROWITZ: It slowed down. People were able to come in, just in shifts and keeping socially distant and so on. Two of the things that were difficult were actually doing experiments. We don't have machines that do any of those automatically. Our microscopes are all computer controlled, but somebody has to be there to put the sample on the stage. That's not automatic. No matter how computer controlled the microscope is you still have to be there. The other aspect that suffered was training. If somebody new comes to the lab and somebody's going to show them how to do something they have to stay six feet away while they're doing it and wear a mask. Not so easy.
ZIERLER: Just for a snapshot in time—what are you working on currently?
MEYEROWITZ: We've got a bunch of different things going on. One is looking at the effects of particular classes of hormones on the shoot apical meristem. Another is that we're exploring a new area in development - traditionally developmental biologists think of pattern formation as resulting from diffusion or transport of chemicals from one cell to another, through which the cells signal each other, and this creates a pattern either by self-organization or by some induction from a particular point where the chemical makes a gradient and the cells respond differently to different concentrations. These moving chemicals are called morphogens. We found that scalar fields of chemicals, just concentrations of chemicals in some tissue, is only a very small part of the story.
The mechanical interactions of cells with their neighbors and with the tissue as a whole is a very large part of the story. Instead of scalar chemical fields we're now dealing with what mathematically are called tensors. They're physical fields not chemical fields. They interact with the transport of the chemicals in a lot of different ways. Without understanding the mechanical interactions of the cells the chemical interactions are incomprehensible. We're working very hard to understand the mechanisms by which cells know who's pulling on them and what direction they're being pulled on and there are multiple such mechanisms that we so far have found.
One other thing we're doing is looking at a type of alga that seems to contradict current ideas of developmental biology even worse than mechanical signaling does, because it's a giant single cell. Pretty much all of our current theories of development have to do with cells signaling each other. This thing has leaves and roots and stems - leaves of particular shapes, and roots of particular length, and everything else just like a land plant might. But it's all one cell. There isn't any cell-to-cell communication. How do they do that? We don't know.
ZIERLER: You mentioned earlier some of your work necessitated collaboration with physicists, mathematicians. Is most of the collaborative work you do outside of biology, does that take place mostly within Caltech or not necessarily?
MEYEROWITZ: None of it is within Caltech really. We've never met anybody in physics or engineering here who's been interested in the stuff we do. The initial collaborations I had where we began the Computable Plant Project were with a guy (Eric Mjolsness) at JPL, which is close to Caltech, though. He was in the machine learning group at JPL and we hit it off and started to work on the stuff together and we still are. He's a professor at University of California, Irvine now. Later there was a postdoc who worked with both of us who is now a professor at the University of Cambridge (Henrik Jönsson). He's one of my main collaborators. He started at Caltech, but he isn't there any longer. Similarly, a lot of the collaborations started with people who came to my lab, but the collaboration continues with them in their current locations. None of them were other faculty members at Caltech. I've never met anybody on the faculty here who's that interested, really. I've tried.
ZIERLER: You mentioned earlier following your nose in science and that's what got you into plant biology at Caltech. When that happened did you have a sense that you would stay in this field for as long as you have? Or was it initially just sort of an exploration and you thought you'd go back more to animal biology?
MEYEROWITZ: I don't think I ever thought about it.
ZIERLER: But you never did go back. You've been focused exclusively on plants at Caltech?
MEYEROWITZ: Since the early 1990s.
ZIERLER: What does that tell us both about your interests and about all that there is to know in plant biology?
MEYEROWITZ: I think there are still a lot of frontiers in plant biology. It's a much less populated field than animals. It's kind of fun in that respect. There was a time when I knew everybody who worked on Arabidopsis. No longer because it's thousands of people. Even so it's a very congenial community of people who share everything. That keeps it nice. What else does it say about plants? I don't know. Just that I find them more interesting than I found the animal work and so I'm working on them. [laugh] If someday the plants got boring I'd go work on something else.
ZIERLER: Is the field big enough now where it's not just that you can't know everybody in the field, but that it's not possible to keep up with the literature? Has the field grown that much?
MEYEROWITZ: I couldn't even keep up with the literature when it was smaller.
MEYEROWITZ: If you really want to read a paper carefully that takes you a day, so how many papers can you read a year?
MEYEROWITZ: And how many are published a year? The 10,000 in my field published a year, how many of them can I read? 100? So, no. I can't keep up with the literature.
ZIERLER: Elliot, switching a bit to some institutional history. When you got to Caltech one of the interesting questions always is Caltech's devotion to smallness, to being as small as it is. Going from when you arrived to now, how much growth has there been in biology generally and in plant biology specifically?
MEYEROWITZ: Those are two different questions. To take the second one first, in plant biology when I got here there was nobody working on plants. When I started to work on plants there was one person in biology and so it remains. The growth is infinite; it went from zero to one.
MEYEROWITZ: Infinite percent. After that first minute it hasn't changed at all. As far as the biology division as a whole, it's gotten bigger. There were maybe 30 faculty members in the Biology Division when I got here and there are probably 50 something now. Part of that was because the development of the Biology Division in the areas of bioengineering and computational biology was initiated by hiring in the Engineering Division and Chemistry Division and in geobiology in the Geology Division, so there was until the 2010s considerable growth of biology in Caltech, but in other divisions than Biology. There was a reorganization a few years ago where the people who'd been hired in the other divisions to work in these biological areas became biology faculty. There was a quantum leap in the size of the biology division due to reorganization more than due to hiring.
ZIERLER: The non-growth in plant biology—is that unique to Caltech among peer institutions? For example, if you went to Harvard or Stanford would there have been one plant biologist in 1980 and still one plant biologist?
MEYEROWITZ: No. At somewhere like Stanford there have been five or ten plant biologists then and there would be five or ten now. At Harvard there's the Arnold Arboretum. There have always been a few plant biologists there. As far as plant biologists in the biology department there might not be any now. There might not have been any then.
ZIERLER: What have been some of the challenges in working not with a large group of like-minded colleagues?
MEYEROWITZ: I am working with a group of like-minded colleagues. They just don't work on plants. There are plenty of developmental biologists and there used to be plenty of geneticists here. I've never suffered from lack of collegial interactions with other people at Caltech. It's just they generally have not been scientific collaborations because the materials we work on are so different.
ZIERLER: What about among your students? Has the number of graduate students that you've had fluctuated over the years? Or that's been steady?
MEYEROWITZ: It's very small and steady. I never took that many students. Maybe in my whole career 15 students. I don't have any now. It's been mostly a postdoc lab from pretty early on and it still is. The numbers have fluctuated anywhere from the dozen or so we have now to as high as 18 or so. Maybe as low as nine. I don't know, but not very much. It's about the size I want it and that's where I keep it.
ZIERLER: The unique way that Caltech organizes itself at the divisional level and not the departmental level, is that significant at all for your work or your research?
MEYEROWITZ: I don't know. You can imagine if you were organized at the departmental level there'd be an additional department chairman or chairs. There'd be deans and possibly heads of schools and everything else. There would be even more paperwork I suppose than there is now. And more drivel to put up with. In that respect I can't say I think Caltech's system has contributed in any particular way, but the other system would probably have been more detrimental.
ZIERLER: How so?
MEYEROWITZ: There'd just be more people saying what can go on, more discussions, more paperwork, more bureaucracy. Consider Berkeley.
ZIERLER: Elliot, let's take it all the way back to the beginning. Let's start first with your parents. Tell me a bit about them.
MEYEROWITZ: My father grew up in North Carolina. He was born in Washington, D.C. His father, when he was a baby, moved to North Carolina. They owned a general store in a little town in the Inner Banks on the Pamlico Sound. He went to college at the University of North Carolina. When he graduated he joined the Navy. World War II started and he spent the war in the South Pacific. Then he got married. He met my mother at the Charleston Navy Yard. They had a family and moved to Washington which is where his grandfather had lived. While he was in the Navy his parents had moved from North Carolina back to Washington where they had lived when he was born because they had other family members there. They moved to the Washington area and that's where I was born.
ZIERLER: Where is your mom from?
MEYEROWITZ: She was from Charleston, South Carolina. Born in Charleston. She didn't go to college; she went to secretarial high school. I'm not sure she even graduated from high school. She was working at the Charleston Navy Yard during the war as a civilian. That's where she met my father after he came back from the Pacific.
ZIERLER: Did your dad ever talk about his military service, his experiences during the war?
MEYEROWITZ: Reluctantly. Not much. No. He was on a bunch of different islands in the South Pacific. At one point his ship was the farthest behind Japanese lines of any ship. He thought it was a suicide mission, but they managed to survive it. He didn't have a lot to say about it.
ZIERLER: What was his profession after the war?
MEYEROWITZ: He was an accountant. He had various jobs. The time I can remember most, he was a bookkeeper at a motel in Gaithersburg, Maryland.
ZIERLER: Where did you grow up?
MEYEROWITZ: Maryland. I was born in Washington and my parents moved to Maryland just on the other side of the Washington border.
ZIERLER: Were you always interested in science? Were you always interested in biology?
MEYEROWITZ: I don't really remember. I think I was probably interested in science from a pretty early age. I'm not sure why. Biology, maybe not so much. I think that probably came when I was in college when molecular biology at that time was just developing. I found it very appealing.
ZIERLER: Did you go to public schools?
ZIERLER: Strong curriculum in math and science in middle school and high school?
MEYEROWITZ: Well, I did the best I could. I took advanced placement courses in physics and chemistry and calculus when I was in high school. Those were offered and that's all to the credit of the Montgomery County School System in Maryland. Were they really strong courses…
ZIERLER: Tell me about your decision to go to Columbia for undergrad.
MEYEROWITZ: I was just going to go to the University of Maryland like almost everybody was who was going to go to college from my high school. That minority of people from my high school who were going to go to a four-year college. But I had a chemistry teacher named Mrs. Diamond and she had a broader experience of the world than many of my teachers. She'd been from New York and she suggested that I probably should look for somewhere else to go to college and I might have a more interesting time of it, and suggested that I apply to Columbia, which I did. By the time I got in there Columbia was shut down because of political riots. I went and visited there and it seemed like a pretty lively place. I wasn't particularly political, but it seemed like it would be fun to be there and so I accepted the offer they made. I don't think I got in there because of my academic record. I think it's probably a combination of two things. One is that I was a varsity wrestler and they needed lightweight wrestlers at Columbia. The other is that I imagine their applications had probably dropped off after the riots. Probably a combination of happenstance events led me to the place.
ZIERLER: It must've been pretty wild at Columbia in 1969.
MEYEROWITZ: By the time I got there school was back in session at least temporarily. The classes went back out on strike again—I can't remember if it was the first or second half of my freshman year—because of the Cambodian invasion. Classes were out, so I had a lot of time to read in the library.
ZIERLER: Elliot, what about racial tensions and civil rights? Was that a big issue when you arrived at Columbia?
MEYEROWITZ: Not that I can remember.
ZIERLER: Was the plan to start studying biology from the beginning or did you do a more general approach to your studies?
MEYEROWITZ: I think at Columbia everybody starts with a more general approach. Your first two years are pretty much specified and it's largely humanities courses and history courses. It's what they call the core curriculum. I knew I was interested in science and so the way you did it typically then was that you took physics your first year and maybe chemistry also. Then after that organic chemistry if you're still interested in chemistry. I did that sort of thing my first couple of years. I also took an introductory biology course which was taught by a physicist, a guy named Cyrus Levinthal and by a virologist named Jim Darnell. That's what really got me excited about it, I think.
ZIERLER: What was it about Levinthal that got you excited?
MEYEROWITZ: I think it was exactly what it is now. It was a mathematical approach to biology in a way or a physical science sort of approach. Computation and deriving equations for what's going on is really a part of the whole thing.
ZIERLER: Was the term biophysics in use at that point?
MEYEROWITZ: Probably. I'm sure it was. I don't remember, but I imagine it probably was from the very beginning.
ZIERLER: What was some of the lab work you did as an undergraduate that was important for you?
MEYEROWITZ: I took a job when I was a junior and senior. I worked part-time in the laboratory during the school year and full-time in the summer in the Levinthal lab. I had some biology students I knew who were older than I and they said, "If you want to go to graduate school,"—which I thought maybe I would—"it'd be important to get some lab experience." Since I'd taken this course with Levinthal I went and asked him how one went about doing that. He offered me a job. I worked in the Levinthal lab on fish studying the development of the fish brain. Some of the methods used were rather similar to the things we do now. [laugh] That is I used the the good microscopes of the day to make three dimensional images of the disposition of various neurons in the fish brain, traced them into computers so that we could rotate them in three dimensions and measure various aspects of their shape and structure, such as the branching network of the dendrites. Although the computers were more primitive and the microscopes were more primitive, not so different from what I'm still doing.
ZIERLER: Do you remember what kind of computers they were back then?
MEYEROWITZ: PDP-11. We were using it with some sort of a graphics terminal.
ZIERLER: Was Levinthal's overall lab directed on the brains of fish or were there other things going on?
MEYEROWITZ: There were a lot of things going on. A couple of us were working on the brains of fish. There was some brain development in Daphnia and rotifers also going on. There was a lot of software development for these computational image processing approaches. There was also some work on bacteria that he was doing. A lot of different interests for people to come in and work on it.
ZIERLER: What kind of advice did you get if at all about graduate programs to apply to?
MEYEROWITZ: I think my professors there listed for me the five or six places they thought I should apply to and I did.
ZIERLER: Why Yale?
MEYEROWITZ: I applied to a bunch of places. I visited some of them. I'd applied to Yale and to Harvard on the East Coast and I had a friend who was a year older than I was who was a biology graduate student at Harvard. I visited him and he hated it, so that was out. I'd applied to Caltech and got in, but there wasn't really any opportunity to go visit the place. Again, I knew a guy when I was an undergraduate who was a year older than I was and he'd gone to Caltech. I happened to see him and I asked him what it was like. He said Pasadena was incredibly boring. At the time I was really interested in developmental biology and Yale had good faculty and a good curriculum in developmental biology.
ZIERLER: Was your interest in developmental biology related to Levinthal's work?
MEYEROWITZ: I can't remember really. Probably, but I can't remember.
ZIERLER: What else would account for your interest in developmental biology?
MEYEROWITZ: I took a class in it. [laugh] I read papers. Could've been that. I just don't remember.
ZIERLER: When you graduated was the draft something you needed to contend with or was it over by that point?
MEYEROWITZ: By the time I graduated it was over. When I went to college—and certainly it was an incentive to go to college rather than not going to college—I had good friends from high school who were in Vietnam, and they told me I didn't want to be there and I believed them. But I had intended to go to college anyway. Also my father had had a career in the military. I think he'd have killed me if I went into the military.
ZIERLER: Very different war, very different time.
MEYEROWITZ: I'm not sure he enjoyed it that much. Probably he could see that I wouldn't have done very well at it. [laugh]
ZIERLER: When you got to Yale was your idea from the beginning to focus on developmental biology?
MEYEROWITZ: No. I don't think so. Genetics and developmental biology, maybe. I had a lot of interest in genetics which wasn't much involved in the work I did in the Levinthal lab. You do rotations in labs there and I did a rotation at genetics lab first and wasn't having much fun with it. I went over to a lab of a new faculty member who'd just arrived and was doing developmental genetics and I ended up staying there.
ZIERLER: Which faculty member was that?
MEYEROWITZ: Doug Kankel.
ZIERLER: Oh, he would end up being your advisor.
ZIERLER: What was his research? What was he doing at that point?
MEYEROWITZ: He was studying the development of the nervous system in flies. That's what I did my Ph.D. on. He had come from a postdoc at Caltech in Seymour Benzer's lab.
ZIERLER: Did you talk to him about Caltech? Was it boring for him also?
MEYEROWITZ: No, no. I think he had a great time at Caltech, but he was a postdoc at Caltech not a graduate student.
ZIERLER: Very different experience. [laugh]
MEYEROWITZ: I might've had a wonderful time if I had gone to Caltech too. It was an institute of technology. I had interests outside of science. Lots of reasons I probably at that age decided to go one place and not the other. If had the decision to make over again maybe I would collect more information.
ZIERLER: What were some of the big questions in Drosophila biology at that point?
MEYEROWITZ: I don't know. [laugh] I think from the Benzer lab it was questions about function and development of the nervous system. There were other labs that were working on embryonic development, some at Yale. The same sort of developmental biology questions that we talked about before. How is it that a cell knows where it is in a developing organism and turns into the appropriate cell type? How do organs form their shapes and come out in correct numbers and so on?
ZIERLER: What specifically was your focus in your thesis research?
MEYEROWITZ: It was the development of the eye and the brain. Insect eyes are compound eyes. There is a complicated pattern of ingrowth of axons from the eye to the brain in flies. A highly organized set of optic globes just beneath a highly organized eye. What I wanted to know was whether there was communication between the developing eye and the developing brain that were necessary for the organization of both and whether there were signals being sent back and forth. What I found was that the ingrowth of neurons from the eye was necessary for the appropriate organization and growth of the brain, but not the other way. I never found any evidence that the brain mattered to the eye, but the eye mattered to the brain. It explained in part how the brain could organize itself so that the different columns of the lamina and the medulla which were parts of the fly brain corresponded one to one with the ommatidia in the eye. It's that the ommatidia formed first and then they went down to the brain and said, "Make me a column."
ZIERLER: Elliot, what were the instruments that were relevant for this research?
MEYEROWITZ: It was microscopy again—not computers—and various ways of staining the neurons and a lot of genetics which used the fly model.
ZIERLER: To go back to the question of extrapolation. The things that you found about Drosophila, can you extrapolate these findings to other animals?
MEYEROWITZ: I think there's a lot of information that is similar to other animals. There was before I did it. The different parts of developing organisms communicate with each other and control each other's activity. I don't think that this was a theoretical idea., there was plenty of evidence already. That wasn't anything new. That probably went back to the 1890s. The specifics of brain development hadn't been looked at so much.
ZIERLER: Besides Kankel who else was on your thesis committee?
MEYEROWITZ: I have to think about this. J.P. Trinkaus, who studied wound healing and things like that with live imaging which is one of our mainstays right now. Tim Goldsmith who is a neurobiologist. His wife was an eminent plant physiologist. I didn't know much about her work until afterwards. Years afterwards I talked to her about plant research. Let's see who else. Don Poulson, another Caltech product who worked for T.H. Morgan as a graduate student, had been a Caltech undergraduate in the late 1920s and early 1930s and was a Drosophila geneticist. I was a teaching assistant in his genetics class the years I was at Yale. Poulson was on my thesis committee. I'm sure there was somebody else, but I can't remember exactly.
ZIERLER: Was there an oral defense? Anything memorable from that?
MEYEROWITZ: Oh, yeah. Absolutely. I mean I can remember two things about the oral defense. One of which is completely irrelevant today which is that I remember Goldsmith wanted me to revise some things at the beginning of a chapter and I argued with him over it quite aggressively because if I had to change something at the beginning of the chapter I'd have had to retype the whole chapter.
ZIERLER: That's right. [laugh] This is a type-written dissertation, not a computer dissertation.
MEYEROWITZ: Yeah. The things that they asked me to change at the end of the chapter, no argument at all. No problem.
MEYEROWITZ: That's something that'd be completely unfamiliar today. The only other thing I remember about it is that in the usual tradition of oral thesis committees they asked me to leave the room when they were done and they would deliberate. I went back to the lab and worked. Later on I found out that they expected me to hang out in the hall and were kind of surprised to say the least that I hadn't stuck around to find out whether I had graduated. I don't think it even occurred to me that they wanted me to stick around in the hall. I thought I was done and I just left.
ZIERLER: Maybe a good sign your dedication to the research that you went right back to the lab.
MEYEROWITZ: Either that or complete inability to pick up on what to other people are obvious social cues.
ZIERLER: [laugh] After you defended were you focused exclusively on postdocs? Had you considered faculty opportunities at that point?
MEYEROWITZ: It didn't work that way. You couldn't really get a faculty position in biology without doing a postdoc first at that time. Or now, really.
ZIERLER: What postdocs did you consider? What was available to you?
MEYEROWITZ: I really just wrote to one guy. It was Dave Hogness who was at Stanford and I thought it'd be nice to see the West Coast. I felt a little bit lemming-like about my progress in life. I had grown up in the Washington area. I spent my summers in South Carolina where my grandparents lived. I went to college in New York which was even colder and I went to graduate school in New Haven. It was like being inside a freezer in the winter and I'd had enough of that. I mean the next thing would've been to live at Hudson's Bay, so I thought I'd move somewhere else. At that time the Hogness lab was introducing molecular gene cloning as an approach to development. It seemed like the obvious place to go and I wrote to Hogness and he accepted me. Probably these days you would ask more than one person, but as we've already established I was pretty naïve about this stuff.
ZIERLER: When did you first learn about Hogness' work?
MEYEROWITZ: I don't remember. Maybe when he gave a seminar at Yale. It might've been around 1975 or '76. I can remember that I asked his host if I could speak to him and he said no. [laugh] So, I didn't meet him until I got to his lab.
ZIERLER: Did Hogness have an appointment in the school of medicine or was it in biology?
MEYEROWITZ: Medicine. He was in the biochemistry department in the medical school which is very much a basic science department. There's no medicine being done there of any sort.
ZIERLER: Was that interesting for you to be in a medical school?
MEYEROWITZ: The biochemistry department is interesting indeed, but as far as the farther reaches of the medical school, about as far as I ever got to it other than the cafeteria is the genetics department next door to the biochemistry department. That was a basic science department too. I really had no interaction with the medical parts of the place.
ZIERLER: Was there anything significant about Hogness' lab being in the biochemistry department as opposed to the biology department?
MEYEROWITZ: Beats me. I think the biochemistry department in those days was where all the action was in terms of gene cloning because the biochemistry of DNA replication had long been a topic there because of Arthur Kornberg and his various students who were on the faculty. They had the enzymes if you wanted to do this stuff. If you were in the biology department you couldn't have done it. You couldn't have gone to the next lab over and borrowed a tube of DNA polymerase.
ZIERLER: What aspects of your postdoc did you see as a continuation or a refining of your graduate research and what were new areas for you to pursue?
MEYEROWITZ: Everything was pretty much new. I'd never really done any biochemistry. The equipment that they had there, I'd never used any of it. I arrived extremely naïve. I'd never done reactions in test tubes with anything other than stains for nervous system tissue. There's very little I did as a graduate student that couldn't have been done in the 19th century. Maybe if people had sufficient knowledge of genetics in the 19th century. There's no method that I used that wasn't well known in the 19th century. At Stanford there was a lot of application of spectrophotometry and centrifugation and incorporation of isotopes and things like that which was all new to me in the biochemistry department.
ZIERLER: Did you specifically want to get out of your comfort zone? Was that something you wanted to gain?
MEYEROWITZ: I don't think I thought about it really. Of course I was open to new experiences, but I don't think I gave it a whole lot of thought. I just thought the subject they were working on was interesting. That some of the questions that I was asking at Yale could probably be answered if I knew some more about the genes that I was studying.
ZIERLER: Like what? What kinds of questions?
MEYEROWITZ: The way I looked at the communication between the eye and the brain was to look at mutants that affected the organization and the development of the eye and then saw whether they had effects on the brain. When the brain was wild type genetically and the eye was mutant the brain showed a mutant phenotype, and then I'd do it the other way. I'd make the brain mutant and the eye wild type and the phenotype of the brain always followed the genotype of the eye. I had a list of genes and I knew they were doing interesting things in the development of the eye, so I thought the next step might be to try and find out what it is those genes might be doing. That was the big question in developmental biology at the time and going to Stanford would enable me to learn the methods that would get me to the gene level as people were just at that time first beginning to do in bacteria.
ZIERLER: More broadly how mature or not was gene cloning at this point?
MEYEROWITZ: It was a couple of years old. People had just started to do it. There were some limitations that the libraries people were screening were cDNA libraries; genomic libraries were just coming along. The genomic libraries that existed were very small insert libraries. The ability to screen for particular genes was exceedingly rudimentary. A lot of the methods that got everyone around the limitations of cloning genes in those days were developed and being developed in that biochemistry department at the time.
ZIERLER: In what ways was this new field able to have you pursue questions that simply were impossible before?
MEYEROWITZ: In every way. I had genes, they had names, they had chromosomal locations. I knew that they did interesting things when you knocked them out. Development didn't occur correctly and it didn't occur in ways that indicated very interesting functions for the genes and then that's as far as you could get with it until we could clone the genes and sequence them and see what sort of biochemical items they coded for.
ZIERLER: What would you say some of your key findings were during the postdoc?
MEYEROWITZ: I didn't learn that much other than the methods. I cloned some genes that were regulated by steroid hormones to see about hormone regulation of genes. Eventually at my own lab at Caltech right after I got here I sequenced them. We began to learn about the regulation of the genes. We did promoter trimming and all those sorts of things. We had a pretty good idea of what sorts of regulatory molecules might be binding where on these particular genes.
There's some other things that came out of the work. We sequenced the genes and we found out that the genes were evolving in a rather peculiar way. We got into evolution a little bit. The genes were active in the salivary glands of the flies and salivary gland chromosomes are quite peculiar in their structure and the active genes they were associated with particular microscopically visible structures. It was maybe - in the terminology of today it could be said that we were also studying chromatin modification and chromatin level regulations of genes.
ZIERLER: When you say they're peculiar in their structure, peculiar relative to what?
MEYEROWITZ: To a typical chromosome. Even a metaphase chromosome in a fly which is condensed or an interphase chromosome which is just loose DNA strands that fills the nucleus. The chromosomes in Drosophila salivary glands are polytene chromosomes so they consist of about a thousand strands of DNA. It's a thousand-fold times more DNA than there is in the regular chromosome. They're all aligned in register. If you look at them under a microscope it's an enormous thing and it has little stripes all over it and you can identify particular chromosome regions including the one with your gene in it that are associated with a stripe. When genes became active the chromosome became more diffused and puffed out so that you could see where in the chromosome the genes are becoming active. I cloned genes that were involved in these chromosome puffs.
ZIERLER: Were computers relevant for this work?
MEYEROWITZ: For the DNA sequencing we wrote programs to analyze the DNA sequence. Eventually - before too long - they became commercially available, but initially we had to write our own.
ZIERLER: To clarify, did computers allow you to do things that simply were not possible otherwise or was it just more efficient?
MEYEROWITZ: It was just more efficient. The use of computers we used then, I mean I think to analyze the DNA sequences the way we did you wouldn't have wanted to do it by hand. But what the computers did for us was just string analysis. It wasn't anything special as far as computer programming went.
ZIERLER: Elliot, last set of questions for today. When you decided it was time to go on the job market what was available to you? What were you considering and why ultimately Caltech?
MEYEROWITZ: [laugh] That was another thing that is really from the past. It went in a way that's very different from the way things go today. I never applied for a job. I guess Hogness probably had enough of me and he told his friends that they should be looking at me for hiring and I got telephone calls. People called and said, "Are you looking for a job?" I guess I was one of the few people who cloned eukaryotic genes at that time. I didn't even have any published papers on cloning. I went and was invited to interview at Columbia and at Princeton, at UCLA, at Caltech, maybe other places. I can't remember.
ZIERLER: Were you firmly a west coast guy at this point? Was there no heading back East for you?
MEYEROWITZ: I probably considered it, and I'd gone back to visit Columbia. It didn't seem that appealing. This was the time when New York was bankrupt and it was pretty gritty. While I enjoyed that as an undergraduate…
ZIERLER: Different stage of life. [laugh]
MEYEROWITZ: Yeah, different stage. I knew by then that you can have great fun in New York if you're either poor or rich, but in between wasn't so great.
MEYEROWITZ: I would've been in that in between category as an assistant professor. Princeton just intellectually I didn't find any resonance with the people I talked to there. I think later on they ended up doing a lot of things that I would've been interested in, but at that time I didn't think there were colleagues that I would be that interested in. UCLA…pretty interesting. What it came down to was I was interested in developmental biology and in Drosophila genetics and there were developmental biologists or Drosophila geneticists at the other places —one or two—but at Caltech there were notably fierce developmental biologists and geneticists.
ZIERLER: Like who? Who are you thinking of?
MEYEROWITZ: Eric Davidson in developmental biology or genetics people like Ed Lewis or Seymour Benzer. Molecular biologists like Norman Davidson. I felt that I would probably do better science if I was in a place where there were people who could seriously criticize all the aspects of what I was doing and that in any of these other places there might've been a geneticist, but there wouldn't have been a developmental biologist or vice versa or something like that.
ZIERLER: Is this the fierceness…
MEYEROWITZ: I actually thought it would be a more hostile environment, I guess, if you want to summarize it. That's what I was looking for.
ZIERLER: The fierceness that you're talking about of these people at Caltech, that's what you were looking for. People who would really intellectually challenge you.
MEYEROWITZ: Yeah! Sure. How else do you learn anything?
ZIERLER: That's interesting. Was your sense that that reflected more broadly the academic culture at Caltech?
MEYEROWITZ: I'm not sure I had any idea what the academic culture at any of these places was like. It's just two-day visits. I knew the papers that the people there had written and what their subjects were. To the degree I had engaged with the people at Caltech I knew that they were interested in really engaging intellectually in discussion. That they would talk to me, that they would argue with me. The other places maybe not so much.
ZIERLER: Huh. That's interesting.
MEYEROWITZ: I don't know whether they'd have argued with me. They might not have even talked to me.
ZIERLER: Elliot, just to foreshadow to next time. Did you have any sense or was there any interest that you had that would suggest this transition to plant biology shortly after your arrived at Caltech? Or was that more about what was happening at Caltech after you arrived?
MEYEROWITZ: It didn't have much to do with Caltech after I'd arrived. I'd had the idea even when I was a graduate student that if you had a plant that was something like Drosophila there were some really interesting things you could find out because there are a lot of peculiarities of plant genetics that were not understood at that time. The genetics of plant development was essentially unexplored and so it was a big frontier. I thought probably if you could do genetics like you did with Drosophila you could learn a lot about plant development.
I got to Caltech without any—I know when I was at Stanford and at Yale I talked to people about plant development quite a lot. When I was at Yale I went to a plant development graduate seminar and I heard about plants in courses from Ian Sussex and Art Galston because I was interested and had this in mind. At Stanford I discussed it with Ron Davis quite a lot who is one of the faculty members there. What he told me, "If you try and work on something other than crop plants you'll never get any grant money." In the end he did too. He also started to work on plants, but it was a few years after I left Stanford. And after a period working on crop plants, he switched to Arabidopsis.
I guess I had this idea when I got to Caltech I needed to act on it immediately. I was teaching a graduate seminar in genetics. Ed Lewis had taught it and he just said, "You take this over." I said, "OK." All three terms a year I would teach a graduate seminar in genetics and meet with the genetics graduate students and we would go over papers. I think maybe even the first time I taught it—you would choose a topic and then you'd read papers on the topic and discuss it. I think I did plant genetics which hadn't been done before in the graduate genetics seminar there. I just got more and more excited about it as did some of my students and so we decided we were going to do it.
ZIERLER: Elliot, that's a great place to pick up for next time where we'll develop this intellectual trajectory further.
[End of Recording]
ZIERLER: OK. This is David Zierler, Director of the Caltech Heritage Project. It's Thursday, January 27th, 2022. I'm so happy to be back with Professor Elliot Meyerowitz. Elliot, today I'd like to pick up where we left last time when you explained the happenstance circumstances that you moved fully into plant biology, plant genetics. When that happened what were the big questions in the field? What was it that prompted you to make this shift in your research focus?
MEYEROWITZ: They were the same questions we were trying to answer with animals. In that respect it wasn't a shift. It's just that so much less was known about what was going on in plants. It seemed like a much bigger frontier, and they were questions of developmental biology. How cells know where they are in a developing organism and consequently can form patterns of cell types and how morphogenesis occurs, how shape change occurs to give organs their appropriate shape and eventually size. There was much less known about it in plants than in animals.
Also, it was turning out that in vertebrate and invertebrate animals the answers were pretty similar. There were families of homeobox genes of flies and mice and things like that. It looked like one would have to go to an evolutionarily more distant place to find out what had not been inherited in evolution doing the same thing for plants, and therefore what the principles were. That is, what fundamental functions were being done even if done by different types of proteins in plants which it turns out it is more or less. Similar functions do exist in a conceptual way, but they're not necessarily mediated by related proteins. We can begin to see how evolution has evolved development two separate times.
ZIERLER: Did these questions occur to you only once you started teaching these plant biology courses? Were you aware of these similarities before in your career?
MEYEROWITZ: No. I don't think it was known at the time. I couldn't have been aware.
ZIERLER: What were some of the breakthroughs that allowed for this realization?
MEYEROWITZ: What we had planned to do from the beginning was to apply what at that time was modern genomics to plants, which hadn't been done especially much. That is, to make recombinant DNA libraries of plant genetic material and to clone individual genes out. While there were cDNA clones studied from plants there wasn't a lot of genomic cloning at that time because the plant genomes on which people were working were very large. Technically it was extremely difficult to clone genes. A maize gene was as difficult as cloning a human gene. At that time the technology didn't exist to do that from genomic copies, rather than cDNA copies.
We went out and deliberately looked for a plant that resembled Drosophila that we could grow rapidly in the laboratory. One where you could get many generations of genetics done in a short amount of time, and that was small so that we could grow it at the laboratory - because we didn't have any field space to do it in. Most people don't. The genetics of maize that was state of the art at that time was something that was reserved for people who had gained some considerable amount of power in their university where they could access the field space, the irrigation, the tractors they needed. We looked for something small and then we wanted something with a small genome. Then the technical difficulties of the day in cloning genes wouldn't prevent us from doing what we wanted.
Arabidopsis was already known as an organism at that time that grew quickly, went through multiple generations per year, and that was small in size, and could be grown in a laboratory. We measured the genome and found out that it was very small and then went on to make recombinant DNA libraries and started to clone the genes. The first thing was just choosing the model organism. After that we started to look at mutations that caused homeotic effects in the development of flowers similarly to the homeotic mutations that Ed Lewis was looking at upstairs in flies. We rapidly were able to show how the action of some of these homeotic genes specified floral organs, the so-called ABC model of flower development which is still very much worked on in a lot of laboratories. It turned out to be essentially correct. It hasn't been modified very much. Then we went on to start cloning the genes, which turned out to be transcription factors, just as for the homeotic genes in flies and in mice as they were being discovered then. But not related; they're a different family of transcription factors altogether. The principle was that regulatory genes were specifying pattern in development of flowers and in flies, but the regulatory genes that evolved to do this evolved separately, from different ancestral gene families.
ZIERLER: The idea that there was less known about plants than animals at this point—what accounts for that? Why would that be the case?
MEYEROWITZ: There were people working on it, but any fewer people, and a lot less grant money. The funding that was available for plant research was directed very much to crop improvement which at that time didn't include a whole lot of basic research, genomics, or the type of developmental genetics we were doing. There was some, but not a lot. Just less effort, that's all.
ZIERLER: Can that be explained by the fact that a lot of animal research has goals in translational aims, not just fundamental research that might not be true in plant biology?
MEYEROWITZ: No, because it is true in plant biology. After all, people have to eat.
ZIERLER: Right. Absolutely.
MEYEROWITZ: We export a lot of food from the United States. It's a major part of our economy, and translational research is just as relevant there.
ZIERLER: I should refine that, Elliot. I meant translational in terms of health applications.
MEYEROWITZ: I think plant research isn't necessarily thought of that way. NIH never had any problem funding plant research, but they never funded very much of it because it's just the General Medicine institute that does that, not the others. The U.S. federal funding for basic science was and still is very much directed towards curing diseases of humans, especially of the old.
ZIERLER: Elliot, you emphasize the ease of the transition into plant biology. What did that mean at the level of instrumentation in your lab? Was there new equipment to get or you really didn't need any new equipment?
MEYEROWITZ: Same stuff.
ZIERLER: Which is what? What is the stuff? What are you working with?
MEYEROWITZ: At that time it didn't take much. We built some incubators ourselves by buying proportional controllers and having them control lightbulbs and things like that or most effectively a hair dryer to blow warm air. A dog hair dryer. But other than temperature control with lights in it that we built ourselves, all we needed were things we already had. Water baths, centrifuges. [laugh] In those days you used an ultracentrifuge to purify DNA. Not anymore. Vortex mixers. Nothing special. Microscopes.
ZIERLER: I'm curious if anything that Lee Hood was doing at this time—DNA sequencing, all of that—were any of those biotechnology advances relevant for you?
MEYEROWITZ: No. We were sequencing DNA, but we weren't doing it by the methods that Lee's lab eventually automated. That turned out to be a big boost to plant research as it became commercialized. We were doing Sanger sequencing by hand the same way everybody else was then. It was only later that Lee's lab sped that up by making machines that did it on a large scale, and with automation. Sanger sequencing was standard technology in Lee's lab and my lab and everywhere else, not developed at Caltech. Other than that, no. None of the things they were developing had any relevance for us.
We were colleagues—I talked to Lee about it. I talked to the people in his lab about it a bunch. We even published a paper with one of the people in his lab because she had expertise in protein sequencing, but that was Drosophila research, not our plant work. It was all very collegial and everything. We weren't relying on anything they were doing or vice versa, really. They weren't relying on anything we were doing either.
ZIERLER: Was there anyone else at Caltech working on plants at this point?
MEYEROWITZ: No. James Bonner had done so many years earlier in the 1950s and maybe early 1960s and I talked to him a lot about it. He was no longer working on plants; they were entirely working on animals at that time. There wasn't anybody else working on plants at Caltech.
ZIERLER: When you made the transition did you have graduate students who were already in train with research with Ph.D. projects in your previous research?
MEYEROWITZ: Sure. Absolutely. Some of the graduate students are the ones who drove the transition to plants. They did their Drosophila project; now they were looking for something new. Other students continued to work on flies, and we continued to publish on that for at least a decade after we had started to work on plants. It was a slow transition. We continued to do things with flies in half the lab and the other half worked on plants. Very collegial and it made for interesting group meetings.
ZIERLER: You mentioned the importance of picking plants that have a small genome. What's the range? What are plants that have a large genome versus a small genome?
MEYEROWITZ: A small one would be on the order of 100 megabases and large ones would be several gigabases like a maize plant. It's about the same as a human genome. The haploid genome is three or four billion base pairs. There are other plants that have much bigger ones like lilies that people have started to work on now that it's possible. They were particularly daunting at that time. A lot of the sizes weren't known. The methods we used to measure the Arabidopsis genome size were something that by today's standards we'd consider really historical. Nobody does it that way anymore.
ZIERLER: Do you see that kind of variance in the animal world as well from relatively small to enormous?
MEYEROWITZ: You do. Absolutely. There are newts and things with genomes as big as some of the plants, like lilies, and fruit flies have genomes not that much bigger than the Arabidopsis genome. So, yes. You do.
ZIERLER: Is there a way that you can look at either an animal or a plant characteristic and just have a sense of how large their genome is?
MEYEROWITZ: You can look at the chromosomes and if they're bigger the genome's usually bigger. If you consider that a characteristic. If you mean looking at how it crawls around or something, no. Absolutely not.
ZIERLER: I wonder…just some genetics 101. Why would a lily have such a large genome?
MEYEROWITZ: It's packed with remnants of retrotransposons. Its genome was infected by some sort of RNA viruses that replicated themselves and packed themselves at every place they possibly could without destroying the thing. They're still there for reasons not known. Either that didn't happen especially extensively in plants like Arabidopsis, or maybe there's selection against it because in a rapidly growing plant you can only—if the genome's really big it might take longer to replicate the genome. It might slow things down at least at a cellular level a little bit. Although that correlation is not especially precise. So it is possible that Arabidopsis evolved methods to get rid of the extra stuff. It's not really known, but the extra DNA is mostly just junk that's packed in the big genomes. They have the same number of genes and the genes are similar. Just in between the genes there's miles and miles of stuff you don't want to deal with as a molecular biologist unless you're a contrarian and you think this stuff must be doing something.
ZIERLER: The first project was maize?
MEYEROWITZ: No. It was Arabidopsis. There were other labs that were doing the maize stuff. That was the cutting edge of plant genomics at that time was done with maize. We never did anything with maize in my lab.
ZIERLER: What was the next project for your group?
MEYEROWITZ: After the flower development stuff?
MEYEROWITZ: Well, we did a bunch of things. We continued to clone the flower development genes and try to work out the gene regulatory networks that were responsible and methods so that we could do that. We also became interested in plant hormones which had been known and were an old Caltech tradition of study that the original plant physiologist in the Caltech biology division, Herman Dolk, had been working on. Auxin, the original plant hormone, one of the early plant hormones that was found. A lot of plant developmental biology and a lot of the questions we got about our work had to do with the potential involvement of plant hormones.
From my point of view knowing the animal hormone literature I thought there wasn't really enough known to say anything about plant hormones despite the many years of study that had been done. There were a lot of physiological experiments, what the plant biologists back then used to call spray and pray. For none of the plant hormones was there known what the mechanism of action was. None of the receptors were known. It wasn't known how they were perceived. It wasn't known what genes were involved. It wasn't known what the immediate responses were.
We had some interest in that and then opportunity came our way by a conversation I had at a meeting with a plant biologist at Michigan State named Hans Kende who worked on ethylene which is really the first plant hormone that was discovered in the 1890s. The textbooks say that auxin was the first plant hormone discovered because for some reason they never really thought about ethylene as a hormone back in those days. But it is. Plants make it and then they respond to ethylene that either they make or that their neighbors make as a stress response and a growth response. It is a ripening hormone for a lot of types of fruit. Not for Arabidopsis fruits, but for a lot of types. Hans had been working on ethylene and ethylene biosynthesis for many years. He had a graduate student who had some mutants that didn't respond to ethylene. The mutation could potentially have been in an ethylene receptor gene. Hans told me that his student was going to come to my lab as a postdoc. We were going to clone the ethylene receptor, which we did. In the end it wasn't his student who did it—it was one of my students who did it, but in collaboration with the postdoc who had come from Hans' lab. We got it done. That was the first plant hormone receptor and the first family of plant hormone receptors that were cloned in the mid-90s by us, rapidly followed by receptors for all the other plant hormones, of which all of them are now known. That was the first.
ZIERLER: With your work on plant hormones, I'm curious if you ever became interested in herbicides and herbicidal action.
MEYEROWITZ: Not really. More recently we worked on auxin and some of the major herbicides as you well know are auxin analogs, but we're not really worried about how they kill the plants. We're more worried about how the plants use the actual hormone, not the analogs.
ZIERLER: You mentioned the importance of ripening. Did that work have an impact in the world of agriculture at all?
MEYEROWITZ: No. Not that I know of. Well, it might've. There's probably some research in industry on ripening control with ethylene. There was a lot of interest in it at the time when we first did the work, but I didn't do anything with any industries about it. We patented some of the genes. I think Caltech might've licensed them to some of the plant biotech companies, but the typical thing there would be for them to not let anybody know what they're doing until the patent expires and then not have to pay when they commercialized it. As far as a I know the ethylene and ripening hasn't really been commercialized yet. We did, actually in collaboration with a group at the University of Florida, show that you could grow flowers like petunias and have them last forever (or at least months) sitting in a vase if you eliminated their ethylene response. We thought that might be interesting to florists, but actually not because it would ruin their business.
ZIERLER: [laugh] Right!
MEYEROWITZ: Businesses sell people flowers after the flowers they previously bought wilt. If we prevented them from wilting they would be…we thought maybe it would help them with their inventory problems, but there was a severe lack of interest from the floral industry in ever going this direction. I suppose it'd be like finding a way to actually end sin. You could never convince a church to get into that because it would ruin their business model.
ZIERLER: [laugh] What were some of the key findings from your group in plant hormone research? What were the big questions? How did you contribute to them?
MEYEROWITZ: The main question was how the hormones were perceived, what sort of receptors they had. We answered that for ethylene. It turned out to be pretty interesting. Soon enough, afterwards, other people answered it for the other things. We didn't stay in ethylene research for that long. We just answered the problem in which we were interested and like for most projects in my lab when postdocs who were working on it left they took the project with them and I found something new to do.
ZIERLER: The phrase "how they were perceived"—what does that mean in this context?
MEYEROWITZ: Ethylene is a gas. It wafts through a cell. It's not soluble in water. There's probably not a whole lot of it inside the cytoplasm, it concentrates in membranes. How is it that a plant knows that it's being exposed to ethylene? Typical hormone receptors in animals and in plants are all proteins. They bind to the particular hormone and then as a result of that binding do something. What we found was that there's a membrane protein, a set of them, that bind to ethylene and as a result of that initiate a phosphorylation cascade. That (the cascade) was worked out by others, not by us, that it changes gene expression patterns in plants. What we found was the initial step was ethylene interacting with the protein. It worked in kind of a funny way which was a surprise and turned out to be a theme in plant hormone biology which is that in the absence of ethylene the receptor prevented the signal. In the presence of ethylene it did nothing.
ZIERLER: Is the work on plant regeneration, would you put that within the general category of plant hormone research?
MEYEROWITZ: We use hormones to cause regeneration, but we're more interested in the regulatory genes in that case. Not specifically what the hormones were doing. I think that's an important part of it for sure. We're getting back to that now with cytokinins which is another class of hormones we've been studying for the last decade or so. We didn't clone the cytokinin receptors. Other people did that. It turned out they were closely related to the ethylene receptors, so they popped out rather rapidly after we cloned the ethylene receptors.
ZIERLER: The way that you emphasize that…at least in the beginning you needed species with small genomes given the capacities of your lab. Had your lab grown or the capacity had grown so that you could take on a wider variety of plants?
MEYEROWITZ: It wasn't the capacities of my lab that were a question. We could do anything anybody else could do at a small scale. It was the available methodology that made it such a big and expensive project that only the richest human genetics lab could do that sort of thing. Even not that. It was the methodology that changed, but that's changed for everybody. Anybody can clone a gene from anything now.
ZIERLER: What were some of the developments that allowed for that to happen both on the computational side and the sequencing side?
MEYEROWITZ: It wasn't just sequencing. It was just being able to screen large enough libraries and methods of screening for particular sequences in libraries representing the genomes. The earliest screening of human genomes were done with hundreds of agar plates that were poured into cafeteria trays. The efficiency in throughput of that sort of screening is very low. You had to look at a lot of clones, plasmids, or bacteriophage clones that contain the genomic DNA. It was other labs, not my lab, that slowly turned that into a very high throughput business that you could do at very high density.
The sequencing again, it was slow and done by hand when we started with it—when everybody started with it—but at this present point you can do a huge amount of it. Rather than cloning genes you might just sequence a whole genome and look for the gene in which you're interested. As far as the bioinformatics were concerned back in the 1980s we were writing our own DNA sequencing programs because nothing was available. The student who did that has gone on to a very successful career in bioinformatics in industry…having written the DNA sequencing programs for our lab initially. But very soon because a lot of labs were sequencing that became commercially available and was improved very rapidly by people with a lot more expertise than we had. We were just the beneficiary of the development of genomics. We didn't really contribute much.
ZIERLER: Beyond the obvious efficiencies what did these technologies allow you to do? New questions to ask, new approaches in the research?
MEYEROWITZ: In most research there comes a point where more is better.
MEYEROWITZ: In the case of sequencing DNA that point has been reached. You can think about doing—for example, look at populations of plants instead of individual plants and you can just sequence them all and see how they're different for evolutionary questions. These days you can even do a mutagenesis and just sequence the mutant, sequence the whole genome, and see which gene it is rather than going through a laborious process for finding the gene by genetic mapping the way Morgan would have done, and which is how we initially did it. It's sped everything up. You can answer questions at much bigger scales.
ZIERLER: You mention that there was a line of research that you had taken back up about 10 years ago, but I missed the word. What have you been doing…long word started with a "c," I believe.
ZIERLER: That's it.
MEYEROWITZ: It's one of the classes of plant hormones. Traditionally there are five chemical plant hormones that are the classical hormones. The cytokinins are one of the group of hormones that are these classical hormones. Since the Arabidopsis revolution and the molecular biology revolution there are now five more plant hormones, so they're 10 at the moment that are chemical and hundreds that are peptides that are not small molecules, but are peptides of which our lab also was a pioneer in in some ways. Many ways. Which was another one of our projects showing that plant cells communicate with each other by peptide hormones and finding receptors for some of the peptides which is now also a big business in the plant world. There are hundreds of those. We've gone back to one of the classical plant hormones, cytokinins, which are adenine derivatives that are important in regeneration and also in controlling cell division. They were discovered in the 1950s at the University of Wisconsin as cell division hormones. Until last year it wasn't known how the cytokinins caused plant cells to divide, but we know now.
ZIERLER: Elliot, over on the administrative side when you were executive officer in 1995—it's so interesting at Caltech—what aspects of that were like a department chair at a different university and what were not like that at all because of course there's a division chair at Caltech?
MEYEROWITZ: The division chair is sort of like a dean. Depending on the division chair they have executive officers who do some of the administrative tasks that a department chair would do without having any of the power that a department chair would have. I didn't do much. I think I revised the curriculum for the division at one point. I'm trying to think of what else I might've done. We did a complete revision of our undergraduate curriculum and a few things like that. The biology division at the time was maybe 35 faculty members. The division chair didn't have that much to do and the executive officer certainly had less to do.
ZIERLER: Did you see when you were named as division chair in 2000 that the executive officer position was sort of training grounds for that?
MEYEROWITZ: Absolutely. I thought one of the key things that I had to do as chair was get executive officers who were potential material to be the next chair. That's a key to any chairmanship anywhere is that one of the key things that you have to do is train your potential successor so there's somebody ready to take over when the time comes. If you don't do that you're leaving the place in a bad state.
ZIERLER: As division chair what perspective did that give you on the division overall that you might not have appreciated earlier?
MEYEROWITZ: I don't know. I got to know some of my colleagues better than I might've otherwise. The ones who complained a lot I got to know better.
MEYEROWITZ: I saw how the structure of a modern university worked or modern institute of technology. Interactions of the administration and the trustees certainly was all new to me. The vice presidents for finance and those sorts of people. Seeing how the budget worked gave me a much clearer idea of what the whole thing was about.
ZIERLER: What about interactions with other division chairs? Was that a regular meeting?
MEYEROWITZ: Every month the institute academic counsel meets which is the entire administration of Caltech. It's the six division chairs, the president, and the provost. We met every month for basically a whole day and discussed all sorts of issues about the Institute. As far as working with other division chairs, that worked very well when I was chairman. In particular the chairs of engineering and chemistry and I all felt that there should be a concentration on biological sciences that were the coming thing for Caltech and for the world at that time. The engineers established a bioengineering program and we hired a lot of faculty into that who only much later moved into the biology division under my successor, that added 10 or 11 new people to the biology division when the people from engineering moved over.
Similarly the chemical engineers started to become very much more biological. The chairman of Chemistry at that time was David Tirrell who's the provost now who we worked with on that. The chairman of engineering at the time was Richard Murray who's now the chairman of the Biology Division. You can see the influence that had. That really enlarged the biological sciences across the campus. The other division chair in Geology, Ed Stolper, who also later became provost, we worked out a geobiology program together that had started under my predecessor, John Abelson. That's revolutionized the geological and planetary sciences division here and created a new field at which Caltech's a world leader.
ZIERLER: What is geobiology? What does that mean?
MEYEROWITZ: The history of the Earth is an important thing to geologists. How the materials and the minerals in the earth formed. It's turned out that a lot of that has to do with biological activity. Tectonic plates are moving around without any biology, that's for sure. The deposition of minerals and things often has recently been discovered to be not something that happens deep in the earth at high pressure and at high temperature where all these minerals were thought to have crystallized, but a lot of times due to the actions of bacteria that are reducing or oxidizing particular minerals and creating new minerals. The bacteria in the environment are one big part of the world of mineralogy and of geology. Paleontology has always been considered a part of geology and that's very much biological. The sorts of expertise developed for looking at the ages of things in the geology division here, mass spectrometry and the sort of things that people like Lowenstam did and Sam Epstein did decades and decades ago turned out to be a great combination with biological aspects of geology that are now being developed over in the geology division. They just hired a paleontologist. Paleontological ecology. It's a big Caltech thing and it's one of the big successes here.
ZIERLER: Elliot, I'm curious just by virtue of being at Caltech with geobiology now have you ever gotten involved in astrobiology?
MEYEROWITZ: [laugh] In a way, but only through committee work. For many decades I've served on National Academy and National Research Council committees that advise NASA about their space flights, manned and unmanned, but mostly manned. Experimental biology in manned space flights. It's more of a hobby rather than being related to anything I've ever done in the lab. It's never had anything to do with anything I did at Caltech, but I'm on one of these committees now doing the decadal survey of the needs for space biology for the next 10 years. I've been on many of them. I know people from that community and I have enjoyed learning about it, but it's more of a hobby than anything having to do with Caltech.
ZIERLER: It's funny because for all of the excitement about finding life beyond Earth people tend to think along the terms of animal life or whatever that might look like. People really don't talk about the possibility of finding plant life on other planets.
MEYEROWITZ: It's not going to be animals or plants that evolved. Maybe bacteria or something like them. There isn't the slightest bit of evidence that there's life anywhere except on Earth. Zero. Period. It's just fiction. You can talk about it all you want, but it's fiction. It's not science.
ZIERLER: It's fiction for now at least.
MEYEROWITZ: You can think about what the characteristics are that might lead to life and how life might've originated. That's science. Therefore, see whether those conditions might possibly apply somewhere else in the universe which surely they do. Beyond that you can only study any of these things on Earth.
ZIERLER: What about biosignatures? As our capabilities to detect exoplanets get better and better, what might plant biologists contribute to biosignatures?
MEYEROWITZ: I don't know. There are chemical signatures of life like hopanes and steroids and things that are stable chemicals, but they may not characterize life on other planets. You might be able to tell from the wavelength of light reflected back that something like photosynthesis is occurring. If photosynthesis is a characteristic of life anywhere else even if there were life anywhere else which there may not be.
MEYEROWITZ: That's JPL stuff. Caltech is quite expert at that. Christian Frankenberg is one of the world's experts in measuring photosynthesis from space and multispectral analysis is a real Caltech specialty, but it doesn't have anything to do with what I do or anything going on in the Biology Division really.
ZIERLER: Elliot, to go back to your explanation of the growth of biology over this period. Did having David Baltimore as president—obviously as a biologist—did that make an impact in biology at all?
MEYEROWITZ: Oh, yeah. Consider it as a feedback situation. The trustees and the chairs of divisions and other people at Caltech saw a big frontier in biology, so they went out and looked for a biologist to be president. When they found one he came in and very much motivated all these other divisions to hire biologists and to create biology as it is at Caltech now which is very strong. Right now the physicists are looking for biologists which they didn't when I was chair, but they are now. David really got all that stuff started and created a lot of enthusiasm for it. It was the intention from the beginning. That's why they hired him. That's one step and then he took the next step, so it continues going and who knows what the science of the 22nd century will be. I think everyone still agrees biology is the one of this century.
ZIERLER: Now is that a two-way street? The idea that the physics people were looking for biologists—is the biology department looking for physicists?
MEYEROWITZ: Always. Biophysics has always been a big strength in biology here at Caltech and much more so since the bioengineering program has developed. Absolutely.
ZIERLER: Elliot, moving closer to the present. Tell me about the circumstances leading to you becoming an HHMI investigator.
MEYEROWITZ: They had a competition in which they specifically said that plant researchers would be invited. They normally only asked for applications for investigator-ships for people from four to ten years after they've had their independent labs. In this case they suspended the upper limit because they had deemphasized plants so strongly previously. At that time they wanted to get about 15 investigators to work in plant biology because they thought it would be an important part of their portfolio. I applied and got one.
ZIERLER: What has that allowed you to do that otherwise might not have been possible or more difficult?
MEYEROWITZ: It's huge because they fund people, not projects. You get the money every year regardless of what you decide to do so you can change what you're doing on a dime. You can start a new project anytime and have enough funding really to be serious about it without having to get several years of preliminary results and then write a proposal to some federal agency after having taken all the ideas out of it so that they won't cut it to pieces. It's a completely different way of doing science really, to have stable funding at reasonable levels.
ZIERLER: It's a fantastical notion, but is that the model that really all science should go on in terms of funding based on what you're saying?
MEYEROWITZ: I think it should be a mix of project funding and funding of people. Not everybody can prove that they were a great scientist once and are going to do it again. Somebody has to do it the first time. I definitely think there should be funding for projects and funding for people. Stability of funding and higher funding, everybody wants that. Sure, those are characteristics of the HHMI program. There's another element to it which is it's a private foundation. The bureaucracy of getting and spending the money is pretty minimal.
ZIERLER: What would be an example of having this leeway, being able to change on the dime in terms of the next project to work on? What would be an example of how that's worked to your lab's benefit?
MEYEROWITZ: The past couple of years we've been studying an alga that's of no particular interest to anyone except us because we think the developmental biology of it might be different from other things. It has what look like leaves and stems and roots, but it's all one cell. Any textbook of multicellular development or of developmental biology will tell you that development is essentially a phenomenon of multicellular organisms. It has to do with cells becoming specialized in particular patterns. But this alga is not doing it that way at all. We can start working on it and are really getting some things done immediately with our Hughes funding. We now have an NSF grant that's about to come in to fund a lot of that work. I don't think we would've gotten it had we not done the preliminary work with the Hughes funds.
ZIERLER: Elliot, let's move over to the teaching and mentorship side. First, among undergraduates what kinds of classes do you teach at Caltech?
MEYEROWITZ: I've taught a lot of different things over the years. The first year I was here I taught biochemistry because the guy who taught biochemistry left and the chairman (Norman Horowitz) just said, "We need you to do it." I had been promised a year off from teaching my first year, but it needed to be done, so I did it. That was my first class; I only taught it once. Then they got a real biochemist to do it, fortunately for the students. I took over the genetics curriculum from Ed Lewis who was getting to an age where he didn't feel like doing it anymore. He asked me if I'd teach all his classes and I said, "Sure"—being young and not that bright.
MEYEROWITZ: I taught introductory genetics for the better part of two decades and I taught a graduate genetics seminar which is what really got me into plant research because I taught it on plants as I probably mentioned in the last session. Bi 204 that I took over from Ed. [laugh] It was quite an interesting seminar because it was a graduate student course, but there were very few graduate students who ever turned up. It was pretty much faculty members and postdocs. I taught that for quite a while. Eventually I had done that for long enough. I taught a human genetics class with Barbara Wold. Not my expertise, but I thought we should do it. I taught a developmental genetics class with Paul Sternberg for many years, Bi 190 and…I forget what some of the other classes I taught were. I've long taught the required graduate student course in responsible conduct of research (Bi 252). I don't know how long I've done that—maybe for 30 years or so with Paul Sternberg. I don't know. I relieved myself of most of my teaching responsibilities when I was chairman. Since then I taught Bio 1 after I was chairman, the introductory biology course to non-majors. This spring I'm going to teach a new course in plant and soil biology.
ZIERLER: A general question I'm always interested in…this historical shift in interest among undergraduates where computer science is really the dominant major at Caltech right now. How has that translated in terms of the kinds of classes that students are interested in taking in biology? How are they trying to combine interests in biology with computer science?
MEYEROWITZ: I don't really know. I tried to figure that out when I taught Bi 1, but I'm pretty sure I didn't figure it out.
ZIERLER: What have been enrollment numbers like for biology undergraduates over the years? Has it been steady?
MEYEROWITZ: No. I think it's much smaller now than it used to be. When I was chairman we probably had 75 to 100 majors total; 25 a year or something like that. I think it's maybe more like 10 per year now. I'm not sure. You'd have to look it up. In part that's because the bioengineering program has gotten a lot bigger. In total maybe the numbers for bioengineering and biology might be the same. It's become much more computational and physical and engineering-like which is something I pushed very hard when I was chairman and my successors have too.
ZIERLER: So, bioengineering would suggest that students are more interested in applications and not so much the fundamental research?
MEYEROWITZ: No. Not in the Caltech context. It's really fundamental research, more quantitative perhaps, more quantitative approaches to things. Trying really to measure things. Not only explaining things verbally, but having explicit mathematical models which are much more easily transferable between labs. If you send the equations you're working with and the parameters that you used to somebody else, they will get the same result you did. If you send a diagram of a gene regulatory network where there's names of a bunch of genes with arrows going between them and stuff like that, that's nothing really. Computational modeling is a way of making your hypothesis much more explicit and testing hypotheses in computers before you do the experiments.
ZIERLER: Moving on to your graduate students. It's always a dangerous question for fear of leaving somebody off the list. I wonder if you can talk about some of your most accomplished graduate students who have passed through your lab over the years.
MEYEROWITZ: I haven't had that many graduate students. It's mostly postdocs who have passed through my lab over the years. I have graduate students who have done exceedingly well. They've all gone on to really good careers. I'd have to get the list out to make sure I'm not forgetting anybody like you said. Among my earliest graduate students, the one I started the plant work with is Bob Pruitt who's a professor at Purdue now. Caren Chang was in the lab at that time, was the first person to clone and sequence an Arabidopsis gene. She's a professor at the University of Maryland now. John Bowman was a graduate student at that time who is the person who did the experiments for the ABC model. He's a very distinguished professor at Monash University in Australia and a member of the Australian Academy of Science. I could go on. They've all gone on to do various things, some in industry, not in academia. My last graduate student who graduated a few years ago is running a plant-based cheese company now that apparently is quite successful.
MEYEROWITZ: Your Domino's pizza or something like that will soon have cheese made from plants.
ZIERLER: [laugh] Any rhyme or reason to the fact that you've had more postdocs than graduate students?
MEYEROWITZ: I think it's in part that since I'm the only plant researcher here students don't come to Caltech when their primary interest is in plant research because that would mean exactly one laboratory. There'd be no choice and we don't have any educational program in plant biology besides the plant courses I've taught (that I didn't mention before). I taught one a few years ago. I basically haven't taught plant biology and neither has anyone else. It wouldn't be a place for a plant scientist to get trained in the modern era. I think that's one reason. Other than that I don't know.
ZIERLER: Have you pushed particularly as division chair to broaden plant research at Caltech?
MEYEROWITZ: No. I didn't do that when I was chair. I thought we should be trying to solve major problems in biology. The major problems I thought we should be trying to solve are how a cell works, how development works, and how the brain works. Two of those certainly could involve plant biology, but we never specifically looked for plant biologists in our job searches. We look for people who look like they have the most advanced and exciting approach. About 2% of the biological science research funding in the U.S. at that time was in plants and the rest was in animals or fungi or something like that. The number of people who applied to our positions was proportional to the funding. None of the plant biologists who applied ever quite made it to the top. I didn't feel it was appropriate to push that.
ZIERLER: Moving on to postdocs. Who have been some significant postdocs who have come through your lab?
MEYEROWITZ: I would hate to leave anybody out. Unless we're going to do this for hours I would be leaving them out because it's 80 or 90 people—
ZIERLER: Oh, wow.
MEYEROWITZ: —of whom at this point five are in the National Academy of Sciences. There's at least two in the Royal Society. They're leading scientists all over the world. German National Academy of Sciences Leopoldina. They're top scientists all over. The prime minister's science advisor in India was a postdoc of mine. They're not all still in experimental science. I would say some of the leading plant biologists in Germany were either postdocs of mine or students of Detlef Weigel, who was a postdoc in my lab. Leading people in English science—Robert Sablowski at the John Innes Institute was my postdoc. I could just go on forever.
ZIERLER: Go on and on. That's great.
MEYEROWITZ: There's a lot of them who are really successful. Probably 10 or 12 of them teaching in the University of California system and really leaders in their parts of the field. My postdoc Steve Jacobsen is an HHMI Investigator and National Academy member - is one of the world leaders in epigenetics of plants and animals. Xuemei Chen, who was an HHMI Investigator, is a National Academy of Science member, Professor at UC Riverside.
ZIERLER: You can go on and on.
MEYEROWITZ: They've been extremely successful. That's the real product of my lab is these postdocs. Of course, I had very little to do with it. I just watched their shadows move by my door as they got their research going in the laboratory.
ZIERLER: Elliot, I always like to ask about significant awards. Not so much on the ego part, but as a way to understand how your peers are recognizing your work. Maybe we start with the Genetic Society of America Medal in 1996. What is the Genetic Society of America?
MEYEROWITZ: It's a standard biological scientific society. A society that has a journal called Genetics that's been published since 1916. It probably went to the Society in around 1920; it was started independently. They publish a journal, they have annual meetings for all sorts of genetic research organisms and more general meetings. They have close relations to the American Society of Human Genetics. It's a typical scientific society. It raises fees from memberships and journal sales although that business has become very different recently. They promote the science, promote education in the science, and communication between scientists as a nonprofit organization.
ZIERLER: What were you being recognized for with that award?
MEYEROWITZ: I think that particular one was for people who had made some major contributions to genetics over the past few years. It's for younger scientists' work. A lot of these societies give out awards every year. The Plant Biology Society does and they all do. It's part of what they do. It makes you feel good and it's a way publicizing to younger generations particular paths to success that they can look at as models, I guess.
ZIERLER: The following year the International Prize for Biology from the Japan Society for the Promotion of Science. First, did you get to go to Japan for that?
MEYEROWITZ: Oh, yeah. Met the Emperor. Talked to him. Sure.
ZIERLER: What was that like?
MEYEROWITZ: He was a biologist. It's not the present Emperor; the last one - he was a fish taxonomist.
MEYEROWITZ: I asked him about that. They had a laboratory at the Imperial Palace. I never saw that, but I had an opportunity to talk to him. I asked him if he had any time for scientific research anymore. He was funny. His English was very good. He'd spent the war with an English nanny I guess when he was a child. They got him out of Tokyo and somewhere where he wouldn't get bombed. He said, "I used to publish one or two papers a year. Since my accession to the throne, not a single paper."
ZIERLER: [laugh] That's great.
MEYEROWITZ: He seemed like a quite interesting guy. He had this whole row of people sitting next to him looking at their watches the whole time. I imagine his life was pretty controlled. Poor guy. That was particularly a good piece of fun because my wife's mother was from Japan. We invited a bunch of her cousins to meet the Emperor which changed my status within that part of her family. That's for sure.
ZIERLER: Oh, that's great.
MEYEROWITZ: From some foreigner, their distant relative, to being somebody who got them an introduction to the Emperor. The Empress was very nice. She went and personally talked to all of the cousins at one reception. They were very good at that sort of stuff, the previous Emperor and Empress. I assume the current ones are too, but I don't know anything about it.
ZIERLER: The National Academy in 1999 gave you the Richard Lounsbery Award. Who was Richard Lounsbery? What's the award for?
MEYEROWITZ: I don't remember. I knew at the time, but I don't know. These are sorts of award, somebody endows them and I think that one's for biological scientists and it alternates between a French and an American scientist every other year or something like that. There's some committee that decides who gets it. I don't think that was…was it 1999? Was that the year I got that?
ZIERLER: I believe so. Yeah.
MEYEROWITZ: I see. I don't remember very well anymore. It was a great honor, of course. I remember the award ceremony in particular because I think they were giving some award to Arnold Beckman that year who was a great benefactor of Caltech's whom I'd never met. He was sitting there with all the rest of us getting the award. Of course, he got all the attention—well-deserved.
ZIERLER: Your election to the Academy in 1995—what was that like?
MEYEROWITZ: I got a phone call one morning from a bunch of colleagues who I respected. The older colleagues told me I'd been elected to the National Academy of Sciences. I thanked them very much and it woke me up. As soon as I was off the phone I ran to Caltech and went to the library to look up what it was because I had no idea. [laugh]
MEYEROWITZ: There was much less information on the internet then. I had to go to the library. I'm getting out the Encyclopedia Britannica to try to figure out what I had just gotten into. It turned out that it's sort of like a high school honor society, but at a bigger level—to get elected to it. Then I found out very shortly afterwards that it's actually a serious organization that advises the U.S. government and that once you're elected to it if you choose you can get involved in these consensus studies that they do for all sorts of aspects of science as advice to government and nongovernmental agencies, but a lot of advice to government. I have gotten involved with it like this NASA stuff we talked about.
ZIERLER: The Wilbur Cross Medal at Yale—would that be Yale's version of the Distinguished Alumni Award?
MEYEROWITZ: Yeah. Pretty much the same thing, but don't ask me who Wilbur Cross was.
MEYEROWITZ: I'm sure I knew at the time, but I don't know now.
ZIERLER: Did that involve a talk? Were you able to talk about your work for that recognition?
MEYEROWITZ: I don't think I talked. I think I just showed up at graduation and got the Wilbur Cross Medal and I think the other guy who got some other award and gave the talk was the then president of Mexico. He was an incredibly charming guy. He was funny as hell. Zedillo, I think his name was. Yeah, they chose the right person to give that talk.
ZIERLER: A more specific question. When you got the Harrison prize from the International Society of Developmental Biologists I wonder what that might have suggested about the impact of your work more broadly on developmental biology.
MEYEROWITZ: I don't know. I guess that enough people have recognized that plant development was an important part of the field, but I think they had probably given those sorts of things to plant biologists before. I'm not sure. You'd have to look at it. Again, I don't remember it that well. There's some International Society of Developmental Biologists meetings that I went to back when you could travel before the pandemic. They're really good meetings. I guess they gave me a medal. [laugh]
ZIERLER: You received the Balzan Prize with Chris Somerville. Did you collaborate with Somerville?
MEYEROWITZ: Not scientifically ever. We're friends. I just talked with him the other day. We did collaborate in trying to develop Arabidopsis as a model system because in the early ‘80s his lab was one of the few other labs trying to develop Arabidopsis as a model system—in his case for plant physiology and plant biochemistry. Also, plant molecular biology. My lab was developing it for plant molecular biology. There were a couple of other labs developing Arabidopsis genetics of various sorts. We all got together and created all sorts of committees and review articles and things of this sort to try and persuade other people to join us so that the work could go that much faster and also because we were enthusiastic about the progress that could be made.
ZIERLER: Tell me about the time when you were president of the International Society of Plant Molecular Biology. That was just honorary?
MEYEROWITZ: In that case more or less because the way that was structured at the time was that it was a society of societies. All the national developmental biology societies belonged to this society so there wasn't really much to do except have an international meeting.
ZIERLER: Is the same true of the Genetics Society of America where you were president?
MEYEROWITZ: No. That was a real job. [laugh] When I was president of that or president of the Society for Developmental Biology in the U.S. those are concerns where their budgets have to be planned and boards of trustees engaged - like any nonprofit. You're essentially the CEO of it, have to make sure the budget balances, have to make sure the paperwork gets done, invest the excess, and have some investment committee. All those sorts of things. Those were real jobs although you come in as vice president, you do it for a year, then you're president for a year, then you're past president for a year. You're involved in it for like three years and then somebody else does it, so it's not a permanent job. But yeah, you have to understand how a foundation or a nonprofit works and make sure the contracts with the people who are publishing the journal are lucrative and drawn properly. You have to deal with the lawyers and all that sort of stuff.
ZIERLER: Elliot, bringing our conversation up to the present. I wonder if you can explain a little given what different topics you've worked on the role of intuition in your research. How do you know what's interesting, what to work on next? Is it all about curiosity? Is there a theme that you can look back on that says it all makes sense that I did these projects in this order?
MEYEROWITZ: If so, I haven't figured it out. I think it's a mixture of things that I find interesting and things that my students and postdocs find interesting. They have some say in it. And there is the case of the ethylene receptor. Hans Kende just told me I had to clone it. I respected Hans so much that I just saluted and we did it.
ZIERLER: At a broad level then—what you've done in your career at Caltech—what are those big things that have made you interested? Sparked a curiosity?
MEYEROWITZ: I'm still really interested in how development works and how a cell knows where it is in a developing organism. We know a lot more about that now than we did when I was a graduate student. We knew nothing about it. It's still an interesting and not fully solved question. Another level of things that people haven't paid much attention to until more recently is morphogenesis which is another characteristic of development. Not just the cells knowing where they are and turning into the right cell type, but forming into organs that are the appropriate shape and size. Then you begin to involve not just gene regulatory networks and signaling molecules like hormones or peptides signaling between cells, but also the physical forces that make things take on particular shapes. What we found out recently is that those physical forces act just as much as hormones do to control gene expression so that there's a larger picture of chemical communication between cells and physical communication between cells that together create pattern in developing tissues including the shapes of the tissues, the morphogenesis. I think that's where the frontier is now is, to figure out how the mechanics and the chemicals work together to make pattern formation and morphogenesis really part of the same process, not part of different processes.
ZIERLER: To develop that a little further—things that were really not understood when you started in this work that are understood now. What are they? What do we understand now that we didn't when you first started thinking about these things?
MEYEROWITZ: What are the molecules that one cell puts out that signal the adjacent cell, other than some of the standard hormones? What are the proteins that receive those signals and what are the signal transduction pathways? We knew that such existed when I was a graduate student, but none of the details of any of them were known. What sort of processes are occurring in the cell to cause it to reorganize itself to change its shape? We knew that the cytoskeleton acted and provided force and things. Everything about how those things are organized and coordinated is new.
ZIERLER: What about things that were not known then and are still not known today?
MEYEROWITZ: [laugh] We still don't know how many of the mechanisms by which plant cells perceive directional mechanical forces or mechanical forces at different levels. Certainly in plants we don't have the mechanisms or the receptors for those yet. That's what we're working on now.
ZIERLER: Last question looking to the future. What are the things that you want to focus on for your lab? What are those big questions out there?
MEYEROWITZ: I want to change developmental biology for plants and animals so that the combination of mechanical and biochemical interactions is seen as causal. That we understand how it's causal in the feedbacks between mechanics-gene regulation, gene regulation-mechanics, mechanics back to mechanics, and genes to genes is all explicit, so that we can model it exactly in computers and have a completely predictive science of developmental biology.
ZIERLER: Is this something that computers will be able to do in the future that they have not been able to do as of yet?
MEYEROWITZ: They get better and better every year. Sure, it gets easier and easier. When we first started doing computational modeling and development we could take a model with 20 or 30 parameters and change one or at most two parameters at a time and see whether the model could output the result that we knew was the real one. And therefore, get some idea of the robustness and stability of the model with parameter changes and think about what parameter changes that we might be able to replicate in a laboratory experiment. It would give us results, but now you can do them all at once and completely get the landscape of the robustness of the model and the places where the model is sensitive to the sort of changes that we know are happening in the biological organism. It's much bigger. We used to have to use big computers to solve little strings of partial differential equations or differential equations. Now people just go home and do it on their laptop. It's completely different.
Look at it this way. We know that this will succeed. The human body is a type of computer and it develops. So does our plant. It's a type of computer and it develops so there isn't any reason why we can't have a silicon computer simulate that. No reason at all.
ZIERLER: Elliot, it's a pretty amazing list that you rattled off in terms of developments of what we understand now. In very rough terms how do you understand that as a function of improvements in technology and computation, improvements in scientific imagination and hard work? What's the balance? How do you understand how this has all happened?
MEYEROWITZ: I'm not sure what the balance is, but both are necessary. As an example—and I've written articles about this—this ABC model of flower development, we didn't use a single method for that that wasn't available 50 years earlier. The conceptual framework was different.
MEYEROWITZ: Somebody could've done that 50 years earlier. All the mutations existed. The ability to cross existed. Just nobody thought to do it because they weren't thinking about the thing the same way. Some of it is really conceptual, but then methodologically if we want an explicit simulation in a computer of what we're doing and numerically solving differential equations you couldn't do that 50 years ago. If you did it 50 years ago you needed a computer as big as a building and the methods for numerical solutions were very slow. There the technology has totally made a difference.
Or in the sort of genetics that we did 30-40 years ago which was exactly the same sorts of things that T.H. Morgan's lab did in the 1920s here at Caltech. Now we just sequence the DNA. Or if we want to put a new gene in we don't do it through 17 generations of crosses. We just drop it in there with a molecular method, one generation. Those methods have made it possible to do a lot more things a lot faster. Methodological, sure. The microscopes we use now, we can see things we never could've seen before. As a result, we can design experiments that we never could've considered before. The equipment is really important, but then the concepts are really important too.
ZIERLER: The emphasis on the ability of simulation to really revolutionize the work…to clarify, the simulation does what? Does it refine the experiment? Or does it in some ways stand in for experimentation and observation?
MEYEROWITZ: It does at least two things—more than two—but at least two. One is if you have a hypothesis, if you make it explicit by writing a set of equations and it gives you the biological result when you put it in your computer you know that your hypothesis is plausible. You don't know that it's correct. If you can't get it to work you know you're missing something and you can go back and look for it. Just by circulating from one computer model to another you can get to a hypothesis that's testable and that you know is realistic. You then go do experiments to change things and see if your model is predictive. If it is that's a hypothesis test that involves computation in which the hypothesis is encapsulated in a series of equations that you've written. It's represented by a series of equations. You can do hypothesis testing and show that you have or have not falsified the hypotheses in silico and then you can try it in vivo
ZIERLER: It prevents a lot of wheel spinning it sounds like.
MEYEROWITZ: That's one thing. Another is if you want to get more philosophical about it epistemologically these sorts of models provide a type of confirmation for classes of hypotheses that somebody like Achinstein would call independent warrant where if you can have an analog of the system you're studying as inspiration for modeling the system: like bouncing billiard balls for an ideal gas as Maxwell did in the 19th century. It's in his papers. Achinstein would say that it adds positive evidence that the hypothesis could be true because the fact that you can use an analogous system and get the same result shows that what you're talking about is at least feasible. Maybe it's even beyond just hypothesis testing and a slight move towards not just being able to falsify your hypothesis, but being able to add positive support for it by showing that a known system can produce similar results.
ZIERLER: To stay on the philosophical realm…I wonder if there's a negative impact of simulation. In other words, to the extent that it provides a winnowing of testable hypotheses that are worth your time, is there something lost in the process of a wider lens of trial and error?
MEYEROWITZ: Not that I know of.
ZIERLER: In terms of even the kinds of questions you're asking?
MEYEROWITZ: I don't think we're limited in the kind of questions we can ask by our desire to write computational models or have collaborators write them. (I don't do it myself.) No. I don't see a limitation there. There may be a philosophical limitation which I call the Delbrück hypothesis. It's not Max Delbrück. It's his son Jonathan, who's a lawyer, who once told me that the reason he went into law rather than science was that he thought that scientific progress is impossible because all you can do is falsify a hypothesis and there's an infinite number of possible hypotheses so you're not making any progress.
MEYEROWITZ: At a minimum being able to test your hypotheses faster means that you're not making any progress at a much greater rate.
ZIERLER: [laugh] That's great. Elliot, two last questions—one retrospective, one looking to the future. As you look to all of your papers, all of your experiments, all your collaborations, does anything stand out as having the most impact in the field?
MEYEROWITZ: You can assess that by looking at which of the papers are more cited, I suppose. The highlights I guess are establishing Arabidopsis as a model system and getting its genome sequenced which was from my part committee work. I ran the committees that helped to organize that. The ABC model of flower development which is still explanatory and says a lot of things about how flowers evolve. The peptide signaling in plant development and meristem control, that's a big one. The ethylene receptor as a model for other plant receptors, that's a big one. Then I would say the evidence that we've been generating the last few years for mechanical forces acting as morphogens in development. That would be the five highlights that I would pull out. I'm sure I've forgotten something and thereby insulted someone.
MEYEROWITZ: Someone who was in my lab, who did it.
ZIERLER: The citations of course is outward looking. For you, what about work that stands out as being most satisfying or even fun to be a part of?
MEYEROWITZ: It was all fun because as one of my British colleagues always puts it, it's just amazing the lives we live. We're paid to have fun.
ZIERLER: Yeah. That's great.
MEYEROWITZ: We are.
ZIERLER: Finally, Elliot, in looking to the future. Of all the things to work on what's most important to you? What are the unsolved questions out there that for however long you want to remain active are most important to you?
MEYEROWITZ: I'd like to get a better appreciation of how plants develop and grow. I think that information will be useful to people who are trying to grow plants, but I'm more interested at the basic level.
ZIERLER: The basic level, but then at some point there will be translational applications, perhaps.
MEYEROWITZ: There already are for some of the things we've done. Some of the flower development stuff is very much used in agriculture. Not that I had anything to do with its being used in agriculture. We published it and other people adopted it which is the way it's supposed to be.
ZIERLER: The way it's supposed to be.
MEYEROWITZ: Yeah. I think a lot of the other stuff is going to have influence. The work we did on the peptides, I think that's now being used very much for architectural design of crop plants.
ZIERLER: Well, Elliot, on that note it's been a lot of fun talking with you. I'd like to thank you so much for doing this.