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Current Research Activities
We are using molecular biological and microbial genetic techniques to study the molecular mechanisms of bacterial pathogenesis.
What's a virulence factor?
That's being debated among scientists. But to give you a simple-minded answer, it's anything that the bacteria produces that is necessary for causing disease. The complexity comes in because anything that's essential for the life of the bacteria would fall into that category, but we don't mean to include that. So, in fact, it should be anything that's required for causing disease but not for surviving in the laboratory situation.
What's cooking in the lab?
Let's start with the enterotoxigenic E. coli. These are bacteria which cause diarrhea in people. They cause the diarrhea by attaching to the intestine and producing toxins. We're studying the pilli, which are little fibrous structures extending from the bacterial surface, which attach the bacteria to the human intestine.
So I should tell you about the disease: This is traveler's diarrhea for adults, and for very young children and infants, especially in developing countries where hygiene is not what it is in our country, this is a very serious life-threatening illness. Traveler's diarrhea is obviously not that life-threatening, and you only consider it serious during the few days that you have it, and then it goes away and you don't have to treat it. But for very young children and infants, they lose so much water in the process of this diarrhea that it frequently leads to death.
This disease is comparable to cholera- in fact the toxin is almost identical to the cholera toxin. And the organisms are related, as well. I don't know that it would be an organism that would be targeted for vaccine development in our country, I doubt that, but world-wide it is a very important organism. It is one of the things that the World Health Organization is very seriously concerned about; diarrheagenic disease, of which this is one.
So first of all there are a lot of pilli, and they're on the bacterial surface, so they're a good target in terms of developing an antibody. And they're also the first thing the bacteria needs to attach to the host before it can cause disease. And of course you would like to stop the disease process at the earliest possible stage before you start to get sick at all. So if you can block attachment of the bacteria, you should be able to prevent the disease.
So a pillus-based formulation would be one candidate for a possible vaccine. There are also are enterotoxigenic E. coli that cause diarrhea in domestic animals, and they actually use a commercially available vaccine that's based on the pilli for those bacteria. One assumes that it's effective, because if it wasn't I don't think farmers would spend their money on it, and it is, I believe, being used successfully today.
That gives us hope that we could develop a vaccine based on these pilli. The other thing is that people who have had diarrhea caused by these organisms actually produce antibodies to the organisms. One therefor believes that that's a pretty good candidate for something that will produce immunizing antibodies. So we're interested in understanding more about the structure of these pilli, one of the reasons being in order to know what would be a good way to develop a vaccine.
There are a lot of different antigenically related pilli on human e-tac strains. So they share certain properties in common, and they have other properties which are very different. And we would of course like to have one vaccine which would react with all of them. What we've recently discovered, or what my former post-doc, who is back in Australia now, recently discovered, is which of the proteins in the pilli is the actual adhesant which attaches the pilli to the human gut.
We know that there are four genes needed to make these pilli. The pilli consist of two proteins, one of which is the major protein constituting the shaft of these long hair-like structures, and hairy sacolarus, my Australian post-doc showed that there's a separate protein on the tip, and he's recently shown that the tip-protein, which is the actual adhesant, we've actually identified a specific amino acid in the tip protein, which, when altered, genetically changed, by site-directed mutagenesis, that you need this amino acid in oder for the pilli to adhere, and that this is conserved in at least one other, probably in all, human e-tac pilli strains. So we're currently engaged in a collaboration with Dr. Mike Levine's lab at the Centers for Vaccine Development in Maryland, where they're going to find out whether the mutated pilli are still able to adhere in human intestinal tracts, with human trials. We're pretty excited about that.
What about the gender imbalance in the upper reaches of academia?
MIT prides itself on the fact that it's always been co-educational. In fact, when I was at MIT, Mrs. McCormik, the wife of the McCormik reapers McCormik, who was probably in her 90s at that point, had all the women in the biology program over to dinner, and she proceeded to tell us what it was like when she was a biology student at MIT- not a graduate student, but an undergraduate.
Did you ever experience any discrimination as a woman in the sciences?
I don't think so. And I would perhaps like to point out that in the department of microbiology and immunology here, we do not have a gender bias in the faculty, at least not a significant one. I think that there's certainly a question of the different disciplines [of science]. I remember vividly attending a meeting one summer at a location where there was another meeting going on at the same time. And they lined us all up to take photographs at one point. So there we were, at least a third of us were women, from our conference, and then came along the people from the other conference. And there were two women in the whole 150 or 200 or so folks that were there. And those were the polymer chemists. Interestingly enough, those two women were very senior. There were no junior women at that conference. I don't know what happens with polymer chemists, but I think that there is a discipline-related situation.
I never perceived that it mattered- perhaps because there were so few of us, we weren't treated differently. Although perhaps it was the group of people I was with- I was with the molecular biologists at MIT. I studied with Sal Valeria who won the Nobel Prize, and there were other people of that caliber there, and I don't think they ever really thought about what sex anybody was.
What's your philosophy of teaching?
I only teach graduate students, so that makes a big difference, right there. The first thing that we do in the course that I direct, which is introductory bacterial genetics, is to give out a little list of the goals of the course, and the philosophies, and the idea is that we are there to help the graduate students learn what they need to know, which is how to design experiments and think critically about experiments. Not to memorize facts, and to be able to evaluate the literature for themselves, and to present it to other people. Those are the goals that we try to accomplish.
It's not easy for the students- every one of them comes up at the end of the course and tells us that it was a very difficult course, but I think they learn what we want them to learn. It's the first course that they take in graduate school, and it's probably the first time that they are made to think for themselves. Not to say that they never think for themselves before that, but here that's the goal of the course.
What sustained you through the rigors of a Ph.D.?
I guess I never thought of it as difficult, first of all. It was because I wanted to learn certain things, and to learn more about how things worked in nature, I guess. These were tools that I was having the opportunity to learn how to use, in terms of lab courses and other types of courses. So once you get to the graduate-student stage, I think you're taking the things that are really of specific and focused interest to you, at least in our programs- there are programs which insist on your taking a lot of other stuff, too, and from then on it should all be fun.
Were there any twists along the way? How did you get interested in research?
I think most undergraduates don't have any idea of what they want to do, when they start. I went to a liberal-arts college, so I had the opportunity to explore. It was clear that mathematics was not my field. But it was also clear that history was not my field- and that may have had to do with how it was taught more than anything else. In terms of a career in academics, I don't think that most undergraduates have much of an appreciation of what that means, actually. Now, perhaps, there is a little bit more savviness, if I can use a word like that, because I think we provide more research opportunities for undergraduates, like the SURE program, from other colleges where they may not be exposed to this. At my undergraduate college we had very little research going on. Our professors at that time did very little serious research because it was a small teaching institution- I went to Swarthmore. We didn't know much, really, about what it was like, except, interestingly enough, from previous students who came back and some of them were doing research at the University of Pennsylvania.
I think nowadays, and certainly in the biological sciences, there are plenty of summer research opportunities open to anybody from any college, and so probably students do have a better understanding of what research means, and if they're interested in that, they should be able to find that out early.
Do you agree with the statement that currently there is an oversupply of Ph.D.s in the biological sciences?
I don't think that's true, and I don't think anybody is suggesting that- not in the biological sciences. I think that just the opposite is still true- I think we're still trying to fill positions. I can remember the last time that this was suggested. I went to a meeting on transposition and DNA recombination at Coldspring Harbor, and there were people from all over the country, from all the big schools, Nobel Prize winners and so forth saying 'we need to cut down on the number of graduate students we admit, because we don't have the jobs for them.'
Next year the biotechnology industry opened up, and we could not produce Ph.D.s fast enough. I think we're still in that kind of a situation. I don't think that it's difficult for a good person to get a good job. I think you have to be a little bit flexible about what you're going to end up studying. I think that most good people have broad interests and could pick out many different things that they are interested in studying. You also certainly have to be geographically flexible, and not say 'I have to live in Atlanta.' It's possible to do that, but it would certainly restrict the kind of jobs that are open to you.
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