Saturday, April 5, 2008 | While University of California, San Diego’s Dr. Ajit Varki concentrates his research on the tiniest fragments of life imaginable, he applies the results of his labor to much larger questions, like how, why, and when people became susceptible to certain diseases over the course of human evolution.

Early in his academic career Varki was committed to becoming a practicing doctor, but while in medical school he realized the value of pure scientific research, and made the decision to diversify his expertise. He is now a member of a rare breed of academics called physician-scientists, traditional doctors who also pursue scientific research.

Varki is a professor of medicine and cellular and molecular medicine, and co-director of UCSD’s Glycobiology Research and Training Center. To help the university address what he calls the “silent crisis” of the physician-scientist decline, Varki also serves as the associate dean for physician-scientist training at the university.

Varki sat down with us to discuss why the number of physician-scientists has decreased in recent years, what this decline means for the public, and how studying human evolution can improve our understanding of human disease.

You have a background in a variety of fields, ranging from physiology, medicine, biology, and biochemistry. This gives you a unique perspective on the state of medical education and general scientific research. The last time we met you mentioned that the number of individuals who are both physicians and scientists are on the decline. Why is that? And what are the implications of such a decline?

Historically, medicine has always been considered an art, a trade, and at some point, medicine had kind of a shotgun marriage with science in the 20th century. To cross between these two fields, you need people that have both brains: the brain of a scientist, and the brain of a doctor. I am an example of somebody like that. I am a physician-scientist.

The declining number of physician-scientists is due to a number of different factors. One of them is that during the Korean and Vietnam wars there was a draft, and if you were a medical student you had a high chance of being called up for service. The one legal way to avoid going to these wars was to join the United States public health service, particularly the National Institutes of Health, and do scientific research. That resulted in the wonderful training of these fantastic people, and these people are the ones that came back and staffed many of the medical schools.

But we don’t have a draft any more, so that incentive is gone. Now these people are affectionately known as the “yellow berets.”

Another major problem is actually debt. Many students who graduate medical school these days have a couple of hundred thousand dollars of debt. It’s very expensive to pay to go to medical school, and to get a Ph.D in a scientific field adds a substantial amount of debt.

It’s a silent crisis that is going on, and my prediction is that it will result in the downgrading of the quality of medical education. This decline means that the development of new ideas, new sciences, and new therapies that are eventually used to save lives will become much harder to move from basic research to the clinic.

In recent years you have devoted your diverse expertise toward the emerging field of glycobiology. What exactly is glycobiology? What are some of your most recent advances in the field?

When I first got trained as a hematologist, and was looking at cells in the blood, I realized that all of these cells are not just little billiard balls, actually it’s as though they are covered in the Amazon rainforest [with everything that is green being chains of sugars]. In other words, the cells in the body are not like the planet Mars, it’s like the planet Earth, it has all this stuff on it, so I wondered why is it that nobody studies these [sugar chains]?

Everyone has heard of how proteins and DNA are the core building blocks for the recipe of life. But it turns out that these [cell surface]sugars are much more difficult to study. Again, it’s sort of like the analogy of the Earth, maybe you can study the surface of the Earth, and its general features, but when you start looking at the trees, and the branches, and the leaves it’s a lot more complicated than that.

I started to look at what the consequences are of these cells being covered by these sugars. As you can imagine, if you are a virus attacking one of these cells, the first thing you are going to [meet] are these sugars [chains]. So, they have many biological roles and relevance in medicine.

I chose to study a class of these sugars, which are called sialic acids, which are found on the outermost tips of these trees, if you will. They tend to be the targets for many bad guys, like malaria, or influenza. A lot of our work has been focused on understanding the sialic acids and what they do in the body. For example, we found that part of the way that cancer cells invade the body, and get around parts of the body involves sialic acids. We’ve shown that sialic acids can alter the way that the immune system functions.

We’ve shown how these sialic acids can make the difference between whether a particular virus can attack you or not, so it has a lot of ramifications.

We’ve also learned that humans as a species have uniquely different aspects of sialic acids that make us different from our closest evolutionary cousins, the chimpanzee. That has become a very important part of our lab now, understanding how these changes in sialic acids occurred during human evolution, and what is the impact on not only the process by which humans emerge, but also, how it affected our susceptibility to certain diseases.

You have applied your research in this field toward a collaborative project that involves a multidisciplinary approach to “exploring and explaining the human phenomenon?” The project is called the Center for Academic Research and Training in Anthropogeny. Tell us about the origins of the CARTA project?

In 1984 I was giving a patient a horse serum for a certain treatment, and the patient had an allergic reaction, which I thought was not surprising because it was a horse’s serum. It turned out that the patient was allergic to the sialic acid in the horse serum. So, I asked, well how can that be? Sialic acid is everywhere, how can you have an allergic reaction to a sialic acid? Ten years later I, along with Elaine Muchmore here at UCSD, found out that the reason is because humans are missing one form of sialic acid that horses have, chimpanzees have, and other animals have.

That resulted in my discovering in the mid-nineties that humans are uniquely genetically deficient in making this one sialic acid, and the mutation occurred during human evolution. At the time it was the first known genetic difference between humans and chimpanzees. Humans and chimpanzees are very similar and back then there were hardly any known genetic differences. And the big question was: what is the difference? And we happened to stumble upon the first known difference.

So I decided to educate myself on evolution. I did it in two ways: I went to a primate center in Atlanta, where I educated myself about chimpanzees. The other way was to simply go around La Jolla and talk to people that knew things about different fields that I didn’t know much about: evolutionary biologists, neuroscientists, anthropologists, and linguists.

I started these discussions in La Jolla in the mid-90s, and in the late nineties, Rusty Gage, a neuroscientist at the Salk Institute said, why don’t you get all of these people together to talk about this evolution at the same time?

One thing led to another and we had people from around the world meet, and talk about this topic. Peter Preuss, one of the regents of the University of California, gave us some money for that first meeting. Then the Mathers Foundation that was supporting my research said why don’t you have more of these meetings?

So for the last 10 years we’ve had these informal meetings where people from many different fields come together and talk about exploring human evolution.

My feeling is the only way to really tackle big questions about human evolution, is to take such an approach. Some people call this multidisciplinary, or interdisciplinary, I have suggested that it should be called “transdisciplinary” because it transcends disciplines.

After all what are disciplines? Disciplines are artificial barriers that humans put up, just different ways of looking at things. And really there is only one body of knowledge, it’s a continuum.

In the last year or two, the Mathers Foundation said, “You can do more than this.” We agreed, so I asked Rusty Gage, a neuroscientist at the Salk Institute, and Margaret Schoeninger, an anthropologist here at UCSD to join me as co-directors of the proposed Center for Academic Research and Training in Anthropogeny.

Now the term Anthropogeny, is not one that is very familiar to many people, it’s actually a very old term, it’s just fallen out of use over the past century or so. Basically it means explaining the origins of humans, so it turns out that it’s the perfect word for this field.

Anthropogeny we feel is an overlapping field that allows us to hear from neuroscientists, from population biologists, from linguists, molecular biologists, geneticists, social scientists, artists, climatologists, computer scientists, and so on. Almost every discipline that is represented at UCSD on this mesa has something to contribute to this subject.

What have been some of the preliminary results of these collaborations?

As I told you, we found this one genetic difference between humans and chimpanzees, but we had a common ancestor with chimpanzees about 6 million years ago. So somewhere during that time, our ancestors lost this gene, we asked, when did that occur? That is not something that I as a physician or molecular biologist could determine, I needed help from evolutionary biologists, who can understand how to study the DNA, and can make predictions as to when the event occurred. So we got involved in collaborating with population geneticists, and evolutionary biologists, who can make calculations based on genes and so on. With their input, we were able to find that this change occurred about 2-3 million years ago, but we needed independent corroboration.

We knew that humans were missing this particular sialic acid, so we knew that if we got some bones from chimpanzees and humans, we should see a difference. So we actually got some samples from skeletons from the Museum of Man, and we saw that, yes, we can tell difference between human and chimpanzee bones just by looking at the sialic acids.

We wanted to get some fossil bones to see if we could detect exactly when the genetic change occurred, but fossil bones are very precious, you can’t just go in and grind them up at any time. Most of the time fossil researchers don’t want to allow someone to do this type of thing with their fossils. But because we had built up this whole multidisciplinary approach, the fossil researchers were willing to talk to us.

We teamed up with fossil researchers in Europe, Indonesia, and Africa, and started looking at fossil samples, and by doing that we were able to get independent evidence that the sialic acid change occurred quite a while ago. This helped us to really say that this 2-3 million year time point is very important.

Has this lead to advances that are particularly important to medicine?

Again, let me give you examples from my own work, which can explain why the strain of malaria that infects a chimpanzee does not infect humans, and the malaria that infects humans does not infect chimpanzees. Others who are following up on our work may be able to explain the origins of the worst forms of malaria that are killing us now.

We also have some evidence suggesting why it is that humans don’t get the bird flu that easily, but what might lead to that kind of evolutionary jump occurring. On the other hand we have evidence that changes that occurred in the immune system of humans may explain why chimps get infected with HIV, but they don’t get AIDS, whereas humans do get AIDS.

Basically it’s a whole complex series of findings that have implications for a number of human diseases, not just human origins.

— Interviewed by JOAQUIN SAPIEN

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