SOLS Podcasts

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Peggy Coulombe: Hi, this is Peggy Coulombe and welcome to Science Studio. Do you remember when you first heard about genetics? My mind goes back to childhood and hearing about Gregor Mendel and his pea crosses. These days, more revolutionary techniques and medical genetics leap to mind.

We've had plenty of speakers talk about evolution in the biological sense, but how does a science evolve? Today we have a guest speaker, Nathaniel Comfort, an associate professor at Johns Hopkins University who will shed some light on what took the field of genetics from a monk's backyard to the heart of modern biomedical research. Welcome, Nathaniel.

Nathaniel Comfort: Thank you it's good to be here.

Peggy: So I mentioned Mendel who did his work in the 1800s but on your website you state that even in the 1940s human genetics was an "impoverished backwater of agricultural sciences." That's a quote. When was the turning point for genetics as a field, and how has genetics changed over the last 50 years or so?

Nathaniel: I would say that the field of genetics as a whole had a different turning than the field of human genetics. The turning point for genetics as a field was really in 1900, when Mendel's work was rediscovered and, over the following decade, the science of genetics was really born. The study of heredity evolved into this science of genetics and we got the term "gene" and so forth.

Anybody who has had college or even high school biology probably knows about Thomas Hunt Morgan and his fruit flies and so forth. So that all came in the 19 teens. Human genetics was in on that, right from the start. The first demonstration of Mendelian heredity in humans was in 1902 but after the beginning the field kind of lagged.

The turning point for human genetics was really not until probably the 1950s. So as I say, in the 1940s human genetics was a backwater of agricultural science. What does that mean? It means that genetics in the United States began as a field of plant and animal breeding and the people who studied the heredity of humans kind of tagged along with the plant and animal breeders. So the natural place when they started to create new academic departments of genetics, they put them in the age schools.

And so the people who were trying to study heredity in humans were down the hall from the people studying apples and breeding pigs and what not. The big question I am interested in is: how do we get from there to today where genetics is the core science of biomedicine. It's moved across campus to the medical schools. Most people who study human genetics are in med. schools now.

Genetics is replacing anatomy as the queen of the medical sciences. You know, anatomy was the foundation of medicine for 400 years and in the last 50 years that's switched and now first year medical students begin by studying genes and molecules and proteins. How did that happen?

Peggy: What types of things had to happen to cause it to take its present form?

Nathaniel: The turning point is really in the 1950s and it was a number of factors. It was institutional. That shift when they started moving across campus to the medical schools. But that happened at the same time as a number of technological and conceptual breakthroughs that made it possible saying that genetics really has something to tell the field of medicine.

Peggy: What were some of the first technological changes?

Nathaniel: Well, some of the technological changes were quite interesting. Any textbook of genetics in the first part of the 1950s would tell you that humans had 48 chromosomes. We now know that we have 46 but that wasn't discovered until 1956.

It was a combination of several pre existing very simple techniques. Like adding de ionized water to your cell culture so that the cells would swell and the chromosomes would separate and you could spread them better and see them. Things like that that enabled people to count the number of chromosomes correctly.

A “very high tech” technique instead of preparing them and embedding the chromosomes in wax and slicing them very finely, the “very high tech technique” of putting them on a microscope slide and swashing it with your thumb gave you much better results.

People more biochemically oriented also invented techniques for separating proteins of different sizes. Gel electrophoresis was invented about the same time. The techniques for culturing human cells, so that you could get enough cells to study and you could do experiments with them. Turns out ordinary human cells can be made to "mate" in a dish and that meant that you could do something kind of like breeding experiments, right?

You could get the exchange of genetic information. So these kinds of techniques enabled researchers to begin to identify chromosomal basis of human diseases, Down's Syndrome was found to be the result of an extra chromosome. Now we know it's 21. Various sex linked chromosomal diseases. Things call Klinefelter's Disease, Turners Syndrome and so forth. All discovered right after that break through in cytogenetics.

Biochemically oriented people could begin to look at the molecular basis of diseases. So those kinds of technical advances, coming at a time when a number of doctors were setting up divisions and departments of medical genetics in medical schools, and setting up connections and social networks so that doctors would send patients down to the genetics clinic when they know someone who had something that looked hereditary that they didn't understand.

Now those doctors had tools that they could use to begin to analyze what was going on. And so the social institutional and technical factors all kind of interplayed with each other to help create what people in the field called the birth of their field.

Peggy: Most people think of biomedical genetics as being very, very recent.

Nathaniel: Yes. It surprises a lot of people. Some of these fields that are so hot and trendy today have a very long lineage. We hear a lot about pharmacogenetics and personalized medicine as being the wave of the future, where we can identify individual differences and relate those to disease and hopefully develop drugs tailored to a person's constitution and so forth.

That goes back to the late 1950s. The term was coined in 1959 and it's based on some classic studies from the 1940s.

Peggy: Did philosophies like eugenics have any effect on the development on the field of biomedicine? I'm asking this because I looked through a list of some of your public locations and this one particular title leapt out at me. "Polyhybrid Heterogeneous Bastards: Promoting Medical Genetics in America in the 1930s and 1940s." Tell me a little bit about that.

Nathaniel: Well, yes, it did. The way the history of genetics and human genetics is usually told is that human genetics got it's start around 1900, as I said, but then it quickly got mired up in it's association with eugenics. Eugenics was defined in 1912 by one of the leading exponents, Charles Davenport, as the science of improving mankind through "better breeding." And it's true that a lot of human genetics was done by people who considered themselves eugenicists.

And the usual story goes that eugenics held back human genetics. Prevented it from advancing at the same rate that Drosophila genetics or corn genetics was doing, because the eugenicists were sloppy scientists, they were ideologically driven and so forth. So they kind of held back the science.

After the Second World War, and the depression and so forth, several things that made people realize that that was not the best way to do science, the geneticists and physicians got together and said, “Right. Let's remake the field along more rational and scientific lines. And do real human genetics now, OK?” The way to get the ideology out was to reorient it around disease, not to be worried so much about the genetics of feeble mindedness or how one becomes a ship's captain, but blood groups and specific Mendelian diseases.

At that point they got rid of all the eugenics and then human genetics could flower like all the others. What I'm finding that, first of all, some of the early human genetics that was associated with the mainstream eugenics, that it was much more mixed than we have given it credit for.

Yes, there was a lot of sloppy ideological science being promoted, being published, but there was also some decent stuff in there that you have to weed through to get to, but it's there. They were looking at the genetics of diseases as well. They were looking at things that are now very trendy, like the genetics of predisposition to infectious disease. Why is it that some people seem predisposed to things like tuberculosis or syphilis or cholera and others not?

Well, the eugenicists were looking at that too. So part one is that, not all of the early human genetics was bad. And part two is that the medical geneticists of the 1950s and '60s did not completely get rid of eugenics.

We tend to tell the story that human genetics realized that eugenics was bad and they remade human genetics without eugenics. I'm finding that what they actually did, was to say, it's not that eugenics were so bad, it's that we did it wrong. What we need to do is to remake eugenics in a more constructive, less ideological way.

So they got the race out of it. And started focusing more on population differences, rather than racial differences. But it surprises a lot of people who know a little bit about this history to learn that membership in the American Eugenics Society was soaring in the 1950s, and the American Society of Human Genetics had an intimate relationship with the American Eugenics Society and the president of one society one year, would be the president of the society the next year.

[laughs]

They organized conferences together, they published journal articles together. There was a very close relationship. I'm careful to say this is not the same eugenics as the 1920s. It's a different eugenics. But they called it eugenics. We have to recognize the eugenics itself evolved.

Peggy: How does our focus on gathering data to pinpoint which specific genes cause disease, actually distort our understanding of disease and prevent us from recognizing the importance of environmental factors? Nathan: There are a lot of ways to explain a disease. What's happening now is that modern biomedicine is beginning to try to explain all of disease in genetic terms. You will hear people like Francis Collins, the head of the National Institute for Human Genome Research, a leader in the field; say that all disease is genetic. That means infectious disease. That means everything.

Why is that? What does he mean? Well, it's not crazy, by any means. What he is saying is that all of those diseases involve proteins. Basic kind of molecule that's involved in everything interesting that goes on in the human body. And if it involves proteins, then it must involve genes, because that's where proteins come from. So in a sense that's right and I don't quibble with the science, but as a historian what I am interested in is what are the implications of that world view.

By the way, that observation about all disease being genetic, I have to cite my colleague, Susan Lindee at the University of Pennsylvania who has published on this idea. So the implications of that are, you can explain a given disease, susceptibility to tuberculosis or stroke or cancer or heart disease on a number of different levels. What causes cholera? Is the cholera germ? Is it exposure to filthy water? Is it urban poverty? Is it a social structure in government that creates ghettos for immigrants?

You can explain it on all these different levels. And in some sense, they're all right. And when you focus on the molecular basis, which is undoubtedly there. If you have a molecular answer to that question, then the medical solution that you propose will tend to be molecular. So my critique of "molecularization" of medicine is that it tends to focus our attention on things like pharmaceutical solutions as opposed...somewhat to the exclusion of other kinds of solutions.

Obesity is a great example. You hear that it is an epidemic in the United States today. Well, that's an interesting sort of metaphor in itself. We don't think of it as metaphor, but it is one.

Absolutely, there's a genetic basis to obesity. Some people are more prone to put on weight, given a certain caloric intake than other people are. There is no question that if you look for genes that predispose people towards obesity or form the molecular basis for that, you will find them. But my question is what kinds of solutions to this obesity epidemic are we being led to?

Obesity is calories in and calories out, right? If you have fewer calories in... So another explanation for the obesity problem is fast food and lack of exercise and too many video games and so forth. Does this molecular approach to medicine shift our focus and lead us more toward solutions where we say, all you need is this drug cocktail and then you can watch all the video games and drink all the soda you want.

Peggy: So there are no social interventions that are considered along with medical interventions? Nathan: I won't say that there are none, but rather it tends to focus our attention on the one, somewhat in exclusion of the other. Because those larger social problems are much harder to solve, right? The molecular stuff is actually easy.

We think, oh, it's so complicated with all this science and test tubes and pipettes and whatnot. But really, those are the easy problems to solve. The hard ones are how you get people to watch less TV.

[laughs]

Peggy: Definitely. So what made you want to study the development of the field of genetics and biomedicine? Nathan: Geneticists. I started out in science and realized that I loved the ideas of science, but I didn't really want to be a lab rat. I wanted to write about science. It seemed like there were two ways to go about that, either the history of science or science journalism.

I did both. I had the great good fortune to be, for about five years, the science writer at Cold Spring Harbor Laboratory on Long Island, which is a world class genetic center. And Cold Springs Harbor Laboratory was run by James D. Watson, the co discoverer of the structure of DNA. And they had two other Nobel laureates there on the faculty when I arrived: Alfred Hershey, one of the pioneers of bacteria phage genetics, the most interesting field of genetics in the 1950s and this quirky diminutive 89 year old lady named Barbara McClintock.

I got to meet all three of them on my first day at work there. I just went home on cloud nine. I just thought what a neat place. There was all this history, the beautiful setting. It is right on the water. This old whaling village, you know, converted into laboratories.

The romance of the place was just intoxicating. Even more important than the people were so interesting, I began to concoct any excuse, however flimsy, that I could come up with to go and talk to Barbara McClintock, you know. I had some problem and only Barbara could solve it. You go in there... I'd tell my boss I would be gone for 10 minutes and she'd smile, because she knew that any time anybody went to see Barbara McClintock it was at least two hours. So during what turned out to be the last year of her life, I got the chance to spend a number of hours talking and really got hooked. After a couple of years working there, I decided I wanted to go back for my Ph.D. in the history of genetics.

Peggy: You just mentioned Barbara McClintock and so I have a question here related to that: So given that the public has a stereotypical view about what a scientist is like and in academia we also have our images of the "right" sort of person for the right sort of work. What is the role of social iconoclasts in science, like Barbara McClintock? Well, we know what role she had in your life.

Nathaniel: There are a couple of different roles iconoclasts have. The obvious one is the role the person has at the time. Somebody like McClintock or like Jim Watson, who has a fresh approach, who is not bound by convention, who's bold enough to think about a problem in a different way can shake up a field, reorient it, raise new problems, push the research in different directions.

But an iconoclast in science also takes on a different aspect with passage of time. McClintock had a certain reputation, a kind of a myth about what McClintock contributed to the science and by looking at the role of the iconoclast, you can change the way scientists think about their own history. And that has a more subtle effect, but maybe if you do it well and a way they can hear, you might, I hope, make them a little more reflective about some of the things that they do.

Peggy: So tell me a little bit more about the work that you are presently doing.

Nathaniel: Well, my larger project is a history of human genetics. At the moment I am totally immersed in what has become sort of a spin off from that, which is a look at a particular set of experiments that were done on human beings. I'm not an expert on the history of human experimentation, although I'm rapidly boning up.

These were experiments on malaria in the 1940s and 1950s, trying to find new drugs to treat malaria, particularly for the soldiers who were in the Pacific theatre during World War II, in Korea in the early 1950s, then in Vietnam. We've spent a lot of time with putting soldiers in malaria areas in the 20th century.

And because of this urgency, they put this research on the fast track. They didn't waste a whole lot of time working with testing these drugs on animals, they went straight to humans. And the humans that they could work on were prisoners. So I'm looking at this malaria research project at Stateville Penitentiary in Joliet, Illinois. This is not Joliet Prison; this is a very old and sort of famous prison in lots of country and western blues songs. But Stateville was built in the 1920s to relieve pressure from Joliet.

And I'm looking at these prisoners as model organisms. They are often called human guinea pigs. So what is the role of the guinea pig? And I looked at this I realize they are not just guinea pigs, they are not just the research subjects in the project, they are also the technicians, secretaries, occasionally the researchers. They are the reagents in the projects. In the sense of feeding the mosquitoes and giving the mosquitoes, cultivating the malarial strains that they mosquitoes would then become infected with so that they could infect prisoners.

This research was being done in the prison hospital. There are no guards around. It's academic physicians from the University of Chicago who are made medical officers of the army. And it's them and the prisoners and that's the whole research.

The prisoners are moving back and forth from experimental subject to experimental object to researcher, so it becomes this kind of surreal example of conduct of research. And what makes it even more interesting is the physical structure of the Stateville Prison, which is based on the early 19th century ideal prison developed by the English philosopher, Jeremy Bentham. And this is called the "Panoptican".

Peggy: So tell me, what is a Panoptican?

Nathaniel: A panoptican was a round structure with the cells all the way around the periphery with glass on the outside so light could shine through and a central guard tower that was shuttered. The guard could rotate 360 degrees and view every prisoner in the place, but with the shutters the prisoners never knew when they were being watched. All they knew was that they were always could be being watched.

The French philosopher, Michel Foucault analyzed the panoptican in a very prescient and insightful way. He recognized that the sort of developing Bentham's ideas. The panoptican was a way of changing the dynamic of discipline and punishment.

So that it became internalized. You didn't have to use brute force. You would cause the discipline to be embraced by the prisoner himself and you would change the dynamic of the relationship of the prison structure to the prisoner.

It just fits exactly what's going on here. Because these prisoners are in fact experimenting on each other, right? Malaria is a very nasty disease and these drugs also are experimental and they were testing them at very high doses sometimes. You know, they were really sick people for weeks on end and sometimes for months. They were avid to do this.

The combination of experimentation and punishment and discipline breaks down all the boundaries of what we think about the way science works and the way medicine works. It's a fascinating case. I'm having a lot of fun with right now.

Peggy: So how did you get an idea to do this case study in the first place?

Nathaniel: Well, as I say, it was a spin off from my human genetics work. I mentioned pharmacogenetics, which is one of my interests in this project. The classic first paper in pharmacogenetics was a little short article in the Journal of the AMA, published in 1957.

Peggy: Just to let people know, JAMA is the Journal of the American Medical Association. So...Please continue.

Nathaniel: And in it he's citing examples of hereditary variation in response to drugs. Which is a pretty good definition of pharmacogenetics and one of those was sensitivity to a particular anti malarial drug, called primoquin.

Turns out about 1% of caucasians and about 10% of men of African descent, African Americans and Africans, when they take these drugs, experience a severe hemolytic anemia. Their red blood cells rupture and they become very sick.

That led me to this Stateville project. One of the things they were focusing on in the early 1950s just before this JAMA was published was exactly that: the sensitivity to this drug primoquin. So as I started reading those papers, just to understand this other pharmacogenetics paper, I started getting deeper and deeper into this and the deeper I got, the stranger it became.

Peggy: Nathaniel, I want to thank you so much for sitting down with us today.

Nathaniel: It's been a pleasure.

Peggy: And this is Peggy Coulombe and you've been listening to School of Life Science Podcast, Science Studio. Our theme music comes from the website "Magnatunes" and was composed by Yongen from the collection "Moonrise." School of Life Sciences in the College of Liberal Arts and Sciences on the Tempe campus of Arizona State University.

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The birth of a science: genetics and biomedicine

Transcript - [Printable PDF format]

SOLS Podcasts 2008