Chapter 03: Medical School with a View of How the Basic Sciences Might Address Clinical Problems

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Chapter 03: Medical School with a View of How the Basic Sciences Might Address Clinical Problems

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Dr. DuBois begins this chapter by noting that in '79-'80 he had a vision of how basic sciences observations about drugs could be used to address clinical problems. He elected to go into gastroenterology at through his medical program at UT Health Sciences at San Antonio (MD, 1985). During the summers he conducted research in Dr. Raymond Burke's laboratory, characterizing selenoproteins. He explains that he also had the opportunity to work with Thressa Stadtman, who discovered selenoproteins, through a fellowship program at the NIH (1983-1984). During that time he made advances to that work by identifying steps required in purifying the proteins. Next, Dr. DuBois talks about his internship and residency at the Johns Hopkins Hospital (1985-88), where he worked with Dr. Victor McKusick, who was working on cloning all the genes affected when a cell is stimulated to grow. Dr. DuBois explains that he worked on an RNA binding protein, Nup475, a project he continued working on as a Research Associate to Daniel Nathans at the Howard Hughes Research Institute (July 1988-March 1991).

Identifier

DuBoisR_01_20181113_C03

Publication Date

11-13-2018

City

Houston, Texas

Topics Covered

The Interview Subject's Story - Professional Path; The Researcher; Overview; Definitions, Explanations, Translations; Discovery and Success; Personal Background; Character, Values, Beliefs, Talents; Influences from People and Life Experiences; Professional Path; Evolution of Career; Inspirations to Practice Science/Medicine; On Research and Researchers; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; Professional Practice; The Professional at Work; Collaborations

Transcript

Raymond DuBois, MD, PhD:

So kind of during my third year in graduate school, I decided I probably needed to go to med school, and I can tell you, the people in the Biochemistry Department weren’t very happy about that.

Tacey A. Rosolowski, PhD:

Why?

Raymond DuBois, MD, PhD:

Because they, they thought it would be selling out one career to take on another.

Tacey A. Rosolowski, PhD:

Right.

Raymond DuBois, MD, PhD:

They didn’t really see it as a merging of the two areas at the time.

Tacey A. Rosolowski, PhD:

So this would have been ’81 or in ’80.

Raymond DuBois, MD, PhD:

Well, ’79, ’80, during that time.

Tacey A. Rosolowski, PhD:

In ’79, ’80, you’re thinking about this, yeah.

Raymond DuBois, MD, PhD:

Right.

Tacey A. Rosolowski, PhD:

And this, I mean no one had even articulated the word translational science.

Raymond DuBois, MD, PhD:

No, no, no. They didn’t really see them connected. Either you did clinical research or you did basic research.

Tacey A. Rosolowski, PhD:

Right. I remember John Mendelsohn [oral history interview] telling me, in his interview, that he was keeping a diary when he was in his undergrad, and he actually had done a year abroad I think, and was writing in his diary about this possibility of taking basic science observations and applying them in clinical settings and it’s like yeah. I mean people were—it was sort of in the ether but it hadn’t become a thing yet that was named.

Raymond DuBois, MD, PhD:

Yeah, right. And they really didn’t have a lot of organized MD/PhD programs, so you sort of had to find your own way.

Tacey A. Rosolowski, PhD:

But fortunately, you didn’t take the advice, you stuck to your guns. [laughter]

Raymond DuBois, MD, PhD:

Yeah. No, they were very negative and at the time, they had a rule in place at UT Southwestern, that they wouldn’t take anybody from the Graduate School as an applicant for medical school.

Tacey A. Rosolowski, PhD:

Really?

Raymond DuBois, MD, PhD:

Yeah, they wouldn’t. I wasn’t allowed to apply to that medical school, so I applied to all the whole UT System schools, other than UT Southwestern.

Tacey A. Rosolowski, PhD:

Now did you have an idea what that next step might look like, applying basic science in clinical settings?

Raymond DuBois, MD, PhD:

Yeah. I think because I had done so much work on drug metabolism, steroid metabolism and things that happen in the liver. I really did think about gastroenterology ultimately as an area of interest, so very early on, I formulated the idea to go into gastroenterology, because of the experience in cytochrome p450 field. Luckily, life is crazy, how certain things happen, but one of the faculty at UT Southwestern, Dr. Ray Burke, B-u-r-k-e, he was a hepatologist there and I had done a rotation in his lab before I joined the Waterman lab. Unbeknownst to me, and I didn’t even know it, but at some point he transferred as faculty, to UT Health Science Center in San Antonio. I got accepted to most of the schools that at that time were part of the University of Texas System. I was not eligible for UT Southwestern and I decided to go to San Antonio because it was closer to my home. My mom had a weird illness at that time that eventually she got over, and so I thought it would be better to be closer to home. Dr. Burke had taken on a faculty position down there as well and he became my advisor. And so I started just the regular medical school curriculum, which is pretty set, and then after the first year they allow you to do research, and so I did summer research in his laboratory, which was part of the Gastroenterology Division there.

Tacey A. Rosolowski, PhD:

So how did you like medical school?

Raymond DuBois, MD, PhD:

Well I didn’t like the first two years, I mean it was very rote memorization of just knowledge from metabolic pathways and algorithms, and it wasn’t very exciting but it was important to learn all that information. After the first year I thought, well maybe this is not exactly what I should be doing, but I did well and I was able to make good grades and pass all the tests and all that stuff, but I didn’t like that. I really enjoyed it after we started the third year and really got involved in clinical rotations, and then it all made a lot more sense and that really made it worth it.

Tacey A. Rosolowski, PhD:

What was happening with your basic sciences during this time? Do you put it on hold when you were doing your med school program?

Raymond DuBois, MD, PhD:

That’s why having Dr. Burke there was so important, because essentially, I could work in his lab during the summer and do research projects, and he worked in a whole different area. He worked on what we call selenoproteins. Selenium is an element that is part of some of the proteins that are important to protect against oxidative damage in cells. Glutathione is an enzyme, or a protein that has selenium, and then he discovered a new selenoprotein, called Selenoprotein P, and so I was working on trying to characterize that, and that becomes very important later in the story.

Tacey A. Rosolowski, PhD:

Selenoprotein P, all right, I’ve got that down. I’m excited. I want to hear about selenoprotein P.

Raymond DuBois, MD, PhD:

During my third year, after I finished the clinical rotations, we could do externships or rotations away, and there was a woman at the NIH, that worked in the intramural program in Building 3, her name is Thressa Stadtman, S-t-a-d-t-m-a-n.

Tacey A. Rosolowski, PhD:

I’m sorry, I glitched that.

Raymond DuBois, MD, PhD:

Stadtman. It’s D-T, or I can send it.

Tacey A. Rosolowski, PhD:

I’ll make the list so we can correct it.

Raymond DuBois, MD, PhD:

She turned out to be a very amazing scientist. She had discovered selenoproteins in bacteria and how they control growth and all kinds of things in bacteria, and she was a major player in the field. We were having trouble purifying this protein, and so the idea was for me to go to that lab and try to use some of the techniques she had used on the bacterial proteins that she purified. This was probably in ’84, ’83, ’84.

Tacey A. Rosolowski, PhD:

Oh, okay. Where was she?

Raymond DuBois, MD, PhD:

She’s at the NIH in Bethesda.

Tacey A. Rosolowski, PhD:

Oh, okay at NIH. I missed that on your CV.

Raymond DuBois, MD, PhD:

I don’t know if I had that on there or not, but that was an important time, because I worked with a postdoc and we worked day and nigh, with different approaches, to try to purify it, and he was using much more modern techniques than we were using in Texas.

Tacey A. Rosolowski, PhD:

Now you say day and night. What do you mean by that?

Raymond DuBois, MD, PhD:

I mean I literally would come in at seven or eight in the morning, and we would stay there until ten o’clock at night, and sometimes we would stay there all right, if he had a purification run that we were doing.

Tacey A. Rosolowski, PhD:

Right.

Raymond DuBois, MD, PhD:

Luckily at that time in Bethesda, there was no security at the institute, so I stayed in a house that rented a room in a house close by, and I could just ride the bicycle in and out, and so it was really access.

Tacey A. Rosolowski, PhD:

I ask because lab work like that really is a labor of love, you just have to put in the physical time, you know you really do. Yeah.

Raymond DuBois, MD, PhD:

Right, right, I really got into it.

Tacey A. Rosolowski, PhD:

What was the postdoc’s name, do you remember?

Raymond DuBois, MD, PhD:

Mark Sliwkowski.

Tacey A. Rosolowski, PhD:

Mark Sliwkowski?

Raymond DuBois, MD, PhD:

Sliwkowski. It’s a Polish name. S-l-i-w-k-o-w-s-k-i. He now is—he was a major scientist at Genentech and he discovered the Her2 treatment for breast cancer. We’ve been friends ever since this time.

Tacey A. Rosolowski, PhD:

That’s so cool.

Raymond DuBois, MD, PhD:

You meet some interesting people.

Tacey A. Rosolowski, PhD:

And it gets to be a small world at that. Well that’s very cool, so that’s interesting.

Raymond DuBois, MD, PhD:

We were able to make an advance. We didn’t purify it to total purity, but we were able to add some steps that made a difference, and so I wrote everything down, documented everything, brought it back to the lab, and then they continued to work on this after I went on to my next thing. So after medical school, you match into a residency for clinical training, and Dr. Burke was my advisor. We had two or three long talks about this and one idea was just to try to stay in Texas and continue some of this research. He actually said you know—and this was the first time somebody supported the idea—“You should go out to another place and experience another culture and really see what the world is all about.”

Tacey A. Rosolowski, PhD:

Well see, you didn’t crash and burn at the NIH, right?

Raymond DuBois, MD, PhD:

Yeah, three months, it was okay. So I applied to a lot of different programs. I applied to Duke and Johns Hopkins and Yale and other places, and went out for those interviews, and I really hit it off really well with the chair of the Department of Medicine at Johns Hopkins. His name was Victor McKusick and he’s the father of the gene, basically. He’s described a bunch of inherited diseases and a very eclectic person. I mean he’s really a very strange man, but very learned, and for some reason we hit it off, mainly because he found out that I went to college on the Houston Livestock Show and Rodeo Scholarship. He was real excited about that, because he had never heard of anybody on one of those scholarships going to Hopkins before, so that was a very big plus for him. Some people would see it as a hillbilly country hick or something, but he didn’t see it that way.

Tacey A. Rosolowski, PhD:

How did he see it?

Raymond DuBois, MD, PhD:

He said that you know, it gives you a different perspective on things, and he wanted people that come from all different parts of the spectrum. I matched at Hopkins, and so I went to Baltimore and did my internship and residency. And then the other—it was really fortuitous, but this work with Dr. Stadtman really helped me, because I wanted to do a postdoc after my clinical training, with Dan Nathans, who had won the Nobel Prize for discovering restriction enzymes. A lot of people applied to his lab and it was very competitive. In fact, one of my friends applied and he didn’t get accepted for a position, and I applied and he wanted to know who my people were that would recommend me, and so I put Thressa’s name on there and it turns out he was a friend of hers, because he had worked at the NIH previously. She gave me a really good recommendation, so I was able to get into his lab and that was a great training experience.

Tacey A. Rosolowski, PhD:

So what did you get from that experience?

Raymond DuBois, MD, PhD:

Well, you know, people who have Nobel Prizes get treated differently, they look at research differently, and no small project was going to cut it in his lab. He really wanted to move the needle and do things that were really going to make a difference. So, one of the big projects that a bunch of us undertook in the lab was to clone all of the genes that are affected when you stimulate a cell to grow, and it turns out to be a lot of genes, I mean there were over 300 genes. His lab had developed a new technique where we could isolate those genes, that others couldn’t yet do.

Tacey A. Rosolowski, PhD:

That sounds like an amazing goal.

Raymond DuBois, MD, PhD:

Yeah. No, I mean he really had high hopes for everything and I had never been exposed to anybody who was like wanting to hit a homerun every day, but it was a great experience. I worked on one of the genes, it was called Nup475, and it was the 475th clone, and Nup because it was a nuclear protein. So I cloned it, I purified it, I studied what its properties worked and looked at the sequence carefully, and it turns out it was an RNA binding protein. At the time, we thought it was a DNA binding protein, so we were a little bit off there. We published that work on it and then eventually, an investigator at Duke had followed up on it after I had left the lab and showed that it played a very important role in lupus and the pathophysiology for lupus in women. So that, I wasn’t able to make that discovery, but at least being involved in something that turned out to have a clinically relevant effect.

Tacey A. Rosolowski, PhD:

All these tiny building blocks being established, piece by piece, and then finally something comes of them. Yeah.

Raymond DuBois, MD, PhD:

Right.

Tacey A. Rosolowski, PhD:

How exciting.

Raymond DuBois, MD, PhD:

Obviously, that was a great experience and there were lots of really top scientists working in his lab, at all different levels.

Tacey A. Rosolowski, PhD:

Now how were you being trained to think about research questions and research design, I mean all that kind of thing.

Raymond DuBois, MD, PhD:

Well, it was very rigorous there. Dr. Nathans met with everybody once a week for several hours. At those meetings, we had to present our experimental design, our data, and he rigorously went over it. When I did some amino staining for this protein and showed that it was in the nucleus, he actually wanted to see what I was observing in the microscope, so he would—he said, “Come get me when you get the stain, I want to see what it looks like.” So I brought him down and he got to see what the stain looked like under the microscope. Usually we take pictures of it and show it at the lab meeting, but he was very engaged, very rigorous and with high standards, and so we had to do everything multiple times to prove that it was the right observation. When I wrote the paper with him, it was a rigorous process that we went through at least thirty different drafts on it. It was a good example, a good mentor, and I think that it was just a wonderful experience. And then following that, so I had finished the postdoc with him, and then he gave me a position as a research associate in the Howard Hughes Institute that was there, and so that was also good, to have that on your CV.

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Chapter 03: Medical School with a View of How the Basic Sciences Might Address Clinical Problems

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