The experiment was so elementary, and the results so surprising, that researchers working with San Diego’s Vical Inc. couldn’t really believe what they were seeing. It all seemed too simple.

They had been injecting submicroscopic fatty globules containing DNA or RNA into mice to see what would happen. The idea was that the fat globules, called liposomes, would be taken up by cells. The cells would use the genetic material inside to make proteins they couldn’t otherwise make.

The researchers found moderate success with that, but the rigors of science demanded that the experiment have a “control” portion--injecting the raw DNA or RNA into the mice to show that the liposomes themselves were making it possible for the new genes to be incorporated into the cell’s processes.

It turned out the cells like the raw material even better and began making the new proteins for as long as six months.

“This was a big surprise, and that’s really what you’re looking for in this area,” said [Dr. Philip Louis Felgner (born 1950)], director of product development at Vical. Felgner worked on the experiment with [Dr. Jon Asher Wolff (born 1956)] and others at the University of Wisconsin at Madison.

Researchers spent several months longer trying to find flaws in their methods or their conclusions. The literature of science is littered with examples of experimental results that deserved the label of too good to be true, explained [Dr. Karl Yoder Hostetler (born 1939)], vice president for research and development at Vical.

“We didn’t want any fiascoes,” he said.

Vical hopes that the results of this checking and double-checking, reported in today’s issue of the journal Science, will convert the company from a bare-bones start-up to a major player in the ranks of San Diego’s biotechnology community.

The company, which was founded in 1987, hopes to find financing to more than double its scientific staff of 22 as a result of the study. It is talking with several large drug companies to see if any would like to buy into the follow-up studies on the new gene transfer method, said Vical President Wick Goodspeed.

Some familiar names in San Diego science and business have played a role in Vical. Among them:

[Dr. Karl Yoder Hostetler (born 1939)], who is on leave from his longtime post as professor of medicine in residence at UC San Diego. His specialties include investigating ways to use lipid chemistry to improve the effectiveness of drugs.

[Dr. Douglas Daniel Richman (born 1943)], a founder and scientific adviser to the firm. Richman is a professor in residence of medicine and pathology at UCSD, specializing in virology and clinical trials of AIDS treatments.

[Dr. Dennis A. Carson (born 1936) ], also a scientific adviser to the firm. Carson recently resigned as head of the division of clinical immunology at Scripps Clinic to become head of UCSD’s new institute for research on aging.

Timothy Wollaeger, chairman of the board. Wollaeger formerly was senior vice president in charge of finance and administration for Hybritech Inc., the monoclonal antibody firm whose success was capped in 1986 with its $485-million acquisition by Eli Lilly & Co.

Howard E. (Ted) Greene, a director of Vical. He formerly was chief executive officer for Hybritech. Greene and Wollaeger were the driving forces behind Biovest Partners, a venture capital firm that financed several San Diego biotech firms.

W. Larry Respess, a Vical director. A leader in biotech patent law, he formerly was general counsel of Gen-Probe and Hybritech.

Until now, the best combination of science and business for Vical has been the multi-year research contract it received last summer from Burroughs Wellcome Co. to develop new forms of AZT for AIDS therapy. The study is investigating the idea that encasing AZT in fat globules would make it more powerful within the body.

The gene-insertion technique reported in Science this week is being suggested as a way to cause the body to generate proteins that would block persistent viral infections, ranging from AIDS to herpes. It also is seen as having potential use as a way to trigger cells to immunize the body against diseases, researchers say.

Vical is calling the new method “gene therapeutics,” to distinguish it from the traditional goal of gene therapy, which uses viruses to insert missing genes into the genetic codes of people with genetic diseases.

The so-called retroviral method has proved difficult and slow, despite several years of intense effort by research groups around the country, including a group led by Dr. Theodore Friedmann at UCSD.

Because retroviruses insert their own genetic code into the cells of their host, the method is also expected to be problematic as a gene therapy technique--since some scientists worry that this could harm the patient irreversibly in some unforeseen way.

Inserting the genes themselves into muscle cells--without any retroviral carrier--avoids this stumbling block entirely, [Dr. Philip Louis Felgner (born 1950)] said. The genes do their work of producing proteins, called expression, but they don’t seem to affect the cell’s own genetic structure, he said.

“People have worked in the gene therapy area for years assuming that a rather complex viral delivery system would be required in order to get expression. And we have found that you can do it very simply,” Felgner said.

It was the slowness of the gene therapy field that led Felgner’s collaborator, of the University of Wisconsin, to decide less than two years ago to get out of it altogether, Wolff said in a telephone interview.

Wolff was an assistant professor and a researcher in Friedmann’s UCSD lab before going to Wisconsin as an assistant professor of pediatrics and medical genetics in 1988.

“I had pretty much planned to get out of the gene therapy field because I got discouraged with the retroviral approach. Scientifically, it wasn’t very challenging,” he said. “Everybody was doing the same thing, and nothing was working that well.”

The results of the research contract with Vical, begun in January, 1989, have rekindled his enthusiasm, [Dr. Jon Asher Wolff (born 1956)] said.

He believes that, in the end, genetic therapies will involve a variety of techniques, not just the Vical method. But he and [Dr. Philip Louis Felgner (born 1950)] acknowledge that they expect some resistance to their ideas from the traditional gene therapy community.

“You’re talking about somebody who has spent his life in this field, and who would like to make the real breakthroughs that are going to allow it to be used in patients with diseases,” Felgner said. “There’s quite a bit at stake.”

Other collaborators with Wolff and Felgner on the research were [Dr. Robert Wallace Malone (born 1959)] of Vical and Phillip Williams, Wang Chong, Gyula Acsadi and Agnes Jani in Wisconsin.

Vical is planning to try to patent the technique, even though it involves no novel or complex steps unfamiliar to molecular biologists. In essence, it involves preparing DNA or RNA with standard techniques and then injecting it in the conventional way into muscle.

“The reason why we have patent position is that it was such a total surprise. Some of those things are the best patents you can get,” Felgner said. “Nobody who was ‘skilled in the art’ would have ever thought that what we have accomplished here was even possible. Nobody would have even thought to do the experiment.”

Xconomy San Diego —

The reaction on Wall Street was a little anticlimactic after the FDA approved a new hepatitis B vaccine last month for Berkeley, CA-based Dynavax Technologies (NASDAQ: DVAX).

Many investors sold stock on the news. In the days following the company’s Nov. 9 announcement, the price of Dynavax shares slipped about 8 percent, from $20.05 a share to $18.45 on Nov. 16.

For Dennis Carson, however, the FDA announcement represented the culmination of a scientific odyssey that took 21 years. To him, vaccines represent a paradigm in preventive health—even though vaccines take longer to develop and typically don’t bring the kind of financial payoffs that blockbuster drugs yield in the life sciences industry.

Carson, a 71-year-old professor emeritus at the UC San Diego School of Medicine, co-founded Dynavax in 1996 with the idea of developing a new hepatitis B vaccine based on short bacterial DNA sequences. The intended result would provoke a stronger and longer-lasting immune response, and Carson says that has been borne out. It may have been a long slog to win FDA approval, but “It hasn’t been a long slog because the science was wrong,” he said.

The recombinant vaccine, known commercially as Heplisav-B, is the first Dynavax product to win FDA approval, and the first new hepatitis B vaccine in the United States in more than 25 years.

The underlying idea, based on research led by Carson and UC San Diego’s Eyal Raz, is that “immunostimulatory DNA,” serving as the adjuvant in recombinant biologic vaccines, would be a kind of interchangeable part in an array of new vaccines. The idea is only now coming into its own. Carson, who still operates a lab at the Sanford Consortium for Regenerative Medicine, says similar DNA sequences could some day be used in other vaccines to stimulate an immune response to tuberculosis, malaria, flu, and even cancer.

Dynavax is now conducting trials of cancer vaccines based on immunostimulatory DNA oligonucleotides. The selected agents are injected directly into the tumors (for melanoma and head and neck cancers), or given by inhalation (in lung cancer).

Getting this far in hepatitis B, though, has required the patience of Job.

As a point of comparison, it took 13 years to win FDA approval for the chemotherapy drug 2-CdA (Cladribine), which Carson helped develop with Ernest Beutler, his mentor at The Scripps Research Institute. Yet in his office, which overlooks the Torrey Pines Golf Course and the Pacific Ocean, Carson takes a serene view.

“Twenty [plus] years sounds like a long time,” he said. “But for a vaccine that is given to a lot of people, and where safety is the prime issue, it takes a long time.”

Dynavax initially submitted its application for Heplisav-B in 2012. A few of the recipients in clinical trials had developed autoimmune diseases and cardiac events, so the FDA asked Dynavax to conduct an additional clinical trial in 2013 to determine if these events were related to the vaccine or just random. The FDA sought more information and analyses again in 2016.

Only large-scale studies could provide a definitive answer, and the company says its Heplisav-B studies included 10,038 patients altogether. According to Carson, an FDA advisory committee concluded that the adverse reactions were no more than could be expected by chance. Nontheless, they asked that Dynavax conduct post-marketing vigilance studies.

Dynavax plans to introduce Heplisav-B as its first commercial product in early 2018. The company managed to sustain itself initially through the support of individual investors and research grants from the National Institutes of Health. The company went public in 2004. “It’s wonderful in the United States that investors will keep pouring money into a company to keep it going,” Carson said.

There is no cure for hepatitis B, an extremely infectious virus that causes serious liver disease. While most people recover, about 15 percent of the cases become chronic—and can lead to liver cirrhosis and even cancer. Dynavax says results from one of its clinical trials (with 6,665 participants) showed that its Heplisav-B vaccine provided a higher rate of protection—95 percent versus 81 percent for Engerix-B, the current standard vaccine marketed by GlaxoSmithKline (NYSE: GSK).

• EVERSON: Dr. Carson, if we could, let’s start by discussing your family background and your youth. As you can see, I was able to find out a little bit of information online, but I still have a lot of questions. Do I have your correct birth date?
• CARSON: Yes. I was born on 31 May 1936, in Manhattan.
• EVERSON: Which area of Manhattan?
• CARSON: It was northern Manhattan. Shortly after, my family moved to Queens, which was where we lived until I was thirteen and a half. Then we moved back to Manhattan when I was going to high school.
• EVERSON: And when did you move to Queens?
• CARSON: I was three years old. I lived ten years in Queens, and then we moved back to Manhattan.
• EVERSON: What elementary school did you attend?
• CARSON: I went to school in PS-186 in Queens; one of the public schools. An interesting story is that one of my friends in elementary school, Mark Leslie, I saw about five years ago on television being interviewed. Mark was the CEO of Veritas [Software Corporation], a huge data storage company.
• EVERSON: I’ve heard of Veritas.
• CARSON: It’s worth billions of dollars. I got in touch with him after that, and we got together and reminisced.
• EVERSON: That’s great. Could you describe a little bit about your family?
• CARSON: My family were descendants of Jewish immigrants from Russia, Poland, and Hungary. Nobody had been a scientist before me at all. They were a Depression era family. My father was an optometrist, my mother was a homemaker.
• EVERSON: Did your father practice optometry in the U.S.?
• CARSON: Yes. But he had no specific science interest. I was wired for science from as early as I can remember. It just happened.
• EVERSON: Do you recall any examples of early interests in science?
• CARSON: I remember I never liked to read fictional books. I always wanted to read nonfictional books. I used to read Microbe Hunters and similar books, in fifth and sixth grade (1).
• EVERSON: Microbe Hunters—that book has, I think, influenced so many people.
• CARSON: Yes.
• EVERSON: I read it too when I was young.
• CARSON: I still like to read popular science books.
• EVERSON: Were you ever interested in science fiction?
• CARSON: Only non-fiction. I used to go to the library and go through reference books. I used to like reading encyclopedias. I remember that my parents sent me to summer camp, and the counselors got angry at me because I wanted to read science books. [laughter] I remember other examples of my early interest in science. As early as second or third grade, we had a little microscope club in school, with kids who liked to meet after school and go to ponds and collect things and look at them—then dump chemicals in and see what would kill them. When I was a fifth grader in biology, my parents let me have a chemistry laboratory in the basement and they signed off on a permit so that I could go down to Fisher Chemical and get anything. I used to run little chemical experiments in my home.
• EVERSON: You needed a permit?
• CARSON: Right. If you wanted to buy phosphorus or potassium or whatever, you needed one. I remember buying a Pfizer Advisor Lab Manual later—the basic lab manual for basic organic chemistry—and I used to do their experiments in the basement at home.
• EVERSON: This was all prior to high school?
• CARSON: This was actually the end of junior high and the beginning of high school. I always loved chemistry and biology. I think it was just genetic.
• EVERSON: It must be. Do you have siblings?
• CARSON: Yes. I have a brother who is a writer. He lives in Europe. He writes poetry, biographies, translation-type books.
• EVERSON: What’s his name?
• CARSON: Jeffrey Carson.
• EVERSON: Where does he live?
• CARSON: He lives on a Greek island called Paros. He runs a school there and writes.
• EVERSON: Did he move there from Manhattan?
• CARSON: Yes, in 1970—the same year I moved to California. He’s a published poet and a translator of modern and ancient Greek poetry. He also writes guide books and lectures. Students from U.S. universities can do a year abroad there. He has an approved program.
• EVERSON: Your brother is your only sibling?
• CARSON: Yes.
• EVERSON: You mentioned growing up with an interest in science, and that your family didn’t have any scientific background or interest. Was your family aware of your interest? Did they encourage it?
• CARSON: They encouraged it. It was the Atomic Age, and I wanted to be some kind of atomic scientist. I can’t say they understood it, but they certainly encouraged it. They had doctors in their family, although not direct relatives. I was very interested in medicine. Actually, I was interested in drugs from reading Microbe Hunters and books like that.
• EVERSON: This must have been around 1960?
• CARSON: No, this was the 1950s. When I was a little kid in elementary school they took me out of the regular class and tutored me for advanced lessons, and so I read all this stuff.
• EVERSON: Aside from science, were there other general family interests or activities that influenced you in your early choices in life? So, for example, what was the place of politics or religion or art in your household?
• CARSON: Well, my father was a professional musician. He had a second career. He was a pianist, a very fine pianist. He was out playing in dance bands, so we always had music around the house. My brother is a very good musician as well. Music was always a big household interest. I was never seriously interested in playing, although I took piano lessons. I loved music.
• EVERSON: Do you play now at all?
• CARSON: Not regularly—no time. But I did take lessons. However, relative to an oral history, I basically think I was destined to do what I did for some reason.
• EVERSON: Well let’s talk about high school. I know that you attended Stuyvesant High School, a well-known school in Manhattan. When did you graduate?
• CARSON: I graduated in 1962. Stuyvesant was a science high school. Very, very smart kids, mainly children of immigrants. It’s still around. The demographics change year to year with immigration. It is very competitive.
• EVERSON: It does seem like a wonderful school.
• CARSON: It is. At Stuyvesant we had to take a lot of extra science courses. And the kids were all very smart. I’ve run into many of them in subsequent years. It was so competitive, and it showed me that I could compete at high levels. I did well there. I never liked the laboratory work in high school or college, because I never wanted to do experiments where they told you exactly what to do and then you had to reproduce what was in the book. I hated that and I still hate that. I wanted to go home and do my own experiments.
• EVERSON: I’ve had similar experiences. At the time I thought it was odd that the experiments already had conclusions that you were supposed to come up with. And then once I got into a real laboratory I realized that that was not how they worked.
• CARSON: Yes, it was technical training only. In a real laboratory, 95 percent of all experiments don’t work if you’re really doing innovative experiments. But if you’re in a lab and you’re going for a grade, 95 percent of the experiments have to work. It’s a completely different way of looking at things. It’s like the typical training of a surgeon. I mean, you need to do it, but it was never much fun. I think what I really learned in high school was competition. We had one course where you had to do your own independent project for the Westinghouse competition. That was my favorite course in high school. We had to design and complete a project with an engineer who was supervising us.
• EVERSON: This was an individual project?
• CARSON: Yes. I was building an infrared detector. As a fourteen or fifteen year old, that was very exciting.
• EVERSON: Very exciting. I have the impression that a lot of people who have come out of Stuyvesant have become quite competitive in their fields.
• CARSON: A student from my own homeroom class is a full professor here at Scripps [The Scripps Research Institute]. A director at NIH [National Institutes of Health], a professor at Princeton [University]—I mean, they’re all over. I actually think those schools are extremely important for America, because they deal with immigrant families—all kinds of people—and they give them a very high quality, competitive education and they succeed. They’ve shown over and over that that model works.
• EVERSON: Are there other schools that you think are on a comparable level?
• CARSON: There is the Bronx High School of Science and others in other cities. They’re still the same—they haven’t changed. I loved doing those science projects, but I didn’t like doing the rote experiments. The competition let me know I could succeed. When I went to college, even medical school wasn’t particularly hard compared to high school.
• EVERSON: That’s impressive. In addition to that competition, were there other courses that stick out in your mind as having a big influence on you?
• CARSON: It was really doing the science project—that’s what I like to do. I don’t like to just do work—I want to invent something. To me, the fun of science is the ability to do something that has never been done before. Repeating something is not fun—it is just something to learn.
• EVERSON: You mentioned that you’re still in touch with some of the people there. Were there major people who acted as mentors or who were influences on your choices?
• CARSON: Well, a number of the teachers actually had Ph.D.’s. Some of the teachers back in the 1950s and 1960s had first gotten their jobs during the Depression, and they were overqualified because of the job shortages, but they had a state funded teaching job—that was the best they could get. They stayed there for years, and we were getting the tail end of them. We had highly qualified, intelligent professors, and they wanted to make sure that their students became well-known. It was a very good environment.
• EVERSON: They were both intelligent and understanding of the possibilities of career advancement for their students.
• CARSON: Right. They would give us outside readings and articles, not just textbooks.
• EVERSON: That’s great. That seems very important in science education—to get a sense of the actual people who are doing work and what’s happening out there.
• CARSON: Yes. Personally, I think you have to take the smart kids, get them together, and let them talk to each other.
• EVERSON: What about other activities in high school?
• CARSON: I needed to make some money, so I worked at the New York [Public] Library’s main branch, in the patent office. In those days you couldn’t get a patent online—you had to order a photocopy—so there was a basement way, way down in the library, where they had every U.S. patent. When somebody from a company would order a patent, they would send a gopher like me down there to pull it out, photocopy it, and then file it for shipping. I thought it was really exciting to see old patents from as early as the 1800s, with wonderful hand drawn diagrams. I got to look at a lot of patents, and I was very excited about the fact that publications die with time—nobody reads them in fifty years—but patents are maintained by the United States government forever. I realized that I wanted to get my own patents some day.
• EVERSON: I’m always fascinated reading patents. They’re an interesting piece of science writing.
• CARSON: The U.S. has a fascinating history of patents.
• EVERSON: Yes, and they’re so rich in information because they need to communicate information to people who don’t really know the value of the work.
• CARSON: You know, you would find the original patents there, just like in the U.S. patent office, with the yellow pages, and you had to be very careful. That was very interesting.
• EVERSON: So these were original patents stored in the library itself?
• CARSON: I think so. It was the New York Public Library, central branch. I remember that there were twenty photocopy machines that we weren’t allowed to operate because they were very expensive. We would look the patent up, make sure it was the right one, give it to the photographer, and then they would give it back. I thought that was neat.
• EVERSON: By high school, in the early 1960s, did you have specific goals in mind about where you wanted to go from there, or were you just generally interested in chemistry and biology?
• CARSON: I was interested in becoming an inventor and a doctor, but I wanted to get a liberal education. I wanted to understand politics. This was the beginning of the Vietnam era and I was growing up in New York. There was a lot of stress on people, so I picked a Quaker college near Philadelphia—Haverford College in Haverford, Pennsylvania—that had a good reputation. I actually had a general liberal arts education, not a science education. I took a lot of science in high school and I didn’t like lab work.
• EVERSON: Did it feel like a big change? A big switch in focus?
• CARSON: Yes, it was a big switch in focus, because college was a lot easier than high school. But I think what I really learned in college, which I would recommend to any scientist, is how to write and write fast. My brother is a writer, but I’ve probably written a hundred to a thousandfold more words than he has. I have to write two hundred-page grants and reviews. As a supervisor, I found that a large majority of scientists can’t write good English. By pounding away at it in college, I fixed that part of my skills. But I still hung out around the chemistry lab. I was a chemistry lab instructor in college, but not a chemistry major.
• EVERSON: You chose Haverford because it was a Quaker college that focused on a broad liberal education?
• CARSON: Right. My high school had five thousand students—all men, all scientists. I had a strong science background with very weak writing skills. I wanted to get a liberal education and I wanted to be within striking distance of my home.
• EVERSON: Is Quakerism part of your background in any way?
• CARSON: No. I was brought up a secular Jew, but I liked the Quaker orientation.
• EVERSON: Did you take science courses in college?
• CARSON: Yes. I took a lot of science courses, but I didn’t do a science major. I majored in history. I wanted to learn how to write decently. In high school they didn’t teach us how to write. They taught us science, but I couldn’t write an English sentence.
• EVERSON: I’ve taught history of science courses for science students who had a lot of difficulty with writing. We often taught the courses with writing as the primary emphasis—not to just fill them with facts about the history of science, but to teach them how to write. I think students really appreciated that.
• CARSON: Yes. I spent a huge amount of time writing in college. One experience had a lot of influence on me: I got a research science grant to work at the old Smith, Kline, and French [Laboratories] factory in downtown Philadelphia. I was assigned to the Women’s Medical College (2). Smith, Kline, and French had two products in those days: Thorazine and Contac. I remember going down to the old factory in downtown Philly and watching the machines that manufactured these pills at an enormous rate—drilling them out. It intrigued me to see how a drug could be mass-produced. This experience had an important influence on me. It piqued my interest in drug development. When I went to work in the lab, I had another experience that was very influential. I was assigned to a project to try to cultivate trichomonas, a vaginal infection, in mice. The professor working on it couldn’t get it to work. He’d been working on it for a very, very long time. I learned French in college, and found in a French journal some reports that said that the epithelium of the genitalia became much more prone to enrichment with nutrients in response to sex hormones. So I injected the mice with estrogen and then gave them the trichomonas. It worked beautifully. I realized then, and I still think this is true, that one key to advanced science and to making discoveries and inventions is the ability to pull data from sources that other people do not access, in fields that they do not access, and apply them to your problem. Reading the standard journals in the common subject areas seldom give you an advantage. You have to access an area that other people can’t. I look at a lot of journals in physics and chemistry now. I try to look outside of the mainstream journals to see what ideas may be useful. Sometimes it is a waste of time.
• EVERSON: Do you think that getting beyond that sort of specialization is important?
• CARSON: Yes. I think getting beyond specialization is very important to me. Anyway, after this experience, I realized I wanted to go into medical research.
• EVERSON: I see. Did you receive the summer research grant during your college years?
• CARSON: That was between my junior and senior year of college.
• EVERSON: When you did this lab work on trichomonas, were you still in college?
• CARSON: Well, I did it during the summer and then I continued working on it during the year. It was twenty minutes away by train.
• EVERSON: How did it happen that, with a liberal arts focus in college, you did so much laboratory work?
• CARSON: They had a grant program through the Philadelphia schools and I applied. I don’t know why they chose me, but it made a big difference. Industry-sponsored grants are very important. Before I took over the cancer center [Moores UCSD Cancer Research Center], when I was running the institute for aging [Sam and Rose Stein Institute for Research on Aging] here in San Diego and had discretionary funds, I focused them on undergraduates rather than on graduate students and medical students, because I felt that the graduate students and medical student were already fairly committed, but the undergraduates were not. They didn’t have a clear understanding of what it meant to be a scientist. They were taking all these courses, but from my own educational experiences I knew that the coursework had nothing to do with being a true scientist. For ten years we gave money to undergraduates to work on little science projects and a lot of them went into science. That’s very important—getting them out of the coursework. My son is an astronomer now, doing his post-doc. He became an astronomer because when he was at Pomona College in Los Angeles, he got a grant to work with a real astronomer at a major telescope.
• EVERSON: While in college, did you have extracurricular interests beyond your liberal arts studies and the sciences?
• CARSON: No, not really.
• EVERSON: In 1966, after you earned your B.A., did you have a clear goal of going into medical school?
• CARSON: Yes. I always wanted to be a medical researcher, making discoveries. I wanted to go back to New York very much. I only applied to one medical school, Columbia [University]. As a student, I was living in Manhattan and could go home for dinner.
• EVERSON: These days, as you well know, medical researchers can go to medical school or not, although most prefer to go, given the opportunities for access to clinical resources. At the time, was it always clear that you were going to become a doctor in order to do medical research?
• CARSON: A lot of my college classmates got Ph.D.’s, but I decided to get the M.D. My parents strongly encouraged me to do it, as you can imagine. Reading about the application of research, I though having an M.D. would be better because I didn’t want to do basic research—I wanted to do applied research, like drug development. Never in my career have I just done physiology. It has always been targeted, disease-oriented research. Doctors are in control of the process much more than basic scientists.
• EVERSON: I guess the influence in seeing drugs manufactured on a large scale at the Smith, Kline, and French factory must have been part of that interest?
• CARSON: Yes. I thought that was incredible—American manufacturing.
• EVERSON: Had you been to Columbia prior to going there for medical school? Did you know what the university was like?
• CARSON: I had some cousins that went there, so I knew all about it. Also, it was in Manhattan, which I knew very well.
• EVERSON: What were your general impressions of Columbia at the time?
• CARSON: It was a huge medical school with an outstanding biochemistry department in those days. A lot of the work that was first done with radioisotopes was done there. There were many distinguished scientists and a lot were very wealthy. They really spent money on the students. I can’t say it was all enjoyable, because again, there was a lot of learning rote skills. But when I was in medical school, I started getting involved in research. I worked in the lab of a professor named Elliott [F.] Osserman, who was a very distinguished scientist in both immunology and cancer. He was one of the pioneers in discovering immunoglobulins. He found a cancer called multiple myeloma, which produces immunoglobulins. He had hundreds of patients, literally, who were coming to him. But these patients all died because there was no treatment and they were producing these immunoglobulins. It made me realize that both a scientific issue and a clinical problem could be brought together. Also, with respect to manufacturing, I realized that the key to medicine was research. Health delivery couldn’t do anything without these steps, because if there was no cure for the disease, there was nothing to deliver. But when you have something to deliver, then companies will make it by the millions. Therefore, research was what I wanted to do.
• EVERSON: In medical school, did you see yourself going in certain clinical directions? I know that medical research was the ultimate goal, but were you focused on specific medical disciplines?
• CARSON: I wanted to do applied research, and I always liked the immune system and cancer.
• EVERSON: Were these interests developed during medical school?
• CARSON: I think they developed because I went to work with Dr. Osserman and he worked on the immune system and cancer. I don’t know exactly how I began to work with him, but it was a personal relationship that brought me into those fields.
• EVERSON: Was he your key mentor in medical school?
• CARSON: Yes.
• EVERSON: Did you have any other mentors?
• CARSON: My medical attending was Paul [A.] Marks, who became a well known scientist. He was president of [Memorial] Sloan-Kettering [Cancer Center]. But I think my mentor was really Elliott Osserman.
• EVERSON: How long did you work with him?
• CARSON: About a year and a half. During the latter half of medical school, we all had to do research projects and I did extra ones in the summer. I also saw some of the patients that he was treating, as well as doing research. It was the same type of thing I do now.
• EVERSON: What kind of laboratory work were you doing with him, specifically?
• CARSON: In those days, we were working on very early methods of tissue culture. Today we take tissue culture for granted. At the time it was much more complicated. We were using Eagle’s medium, invented by Harry Eagle, a scientist at [the Albert] Einstein [College of Medicine]. People had to think about what would go into the medium, and I was trying to start cell lines in leukemias and myelomas. We managed to get a cell line established for one kind of leukemia that hadn’t been grown before. In those days you had to experiment. We were using a lot of homemade reagents to get cultures. The ability to propagate cancer cells in culture turned out to be critical for understanding their biology and for making drugs that could detect them. It’s a very, very long and tedious process done by old-fashioned cell biologists and biochemists. That’s what we were doing.
• EVERSON: I think I must have benefited directly from that early research. I was working on chronic myeloid leukemia and culturing myeloid cells, and we had a very standard procedure, unlike you at that time.
• CARSON: There are still a lot of cancers we can’t culture. In general, people don’t work on them because it is too hard.
• EVERSON: So in 1970 you graduated from medical school?
• CARSON: Right. I was in medical school during the Vietnam War. I wanted to be a scientist, so I applied to the NIH in medical school—that’s what you did in those days. The NIH had a two-year delay, when you do an internship and a residency, and then can be assigned to the NIH. Elliott Osserman referred me to Henry Metzger, the head of the Chemical Immunology Division at NIH. He worked on immunoglobulins as a basic scientist. I was accepted into Henry’s laboratory as my NIH assignment, but prior to joining, I came out to [University of California at] San Diego for my internship and residency. I came to San Diego for two reasons: first of all, climate. Also, it was a brand new medical school—only three years old—and Eugene Braunwald was the chair of medicine. I told him immediately that I wanted to do research, and that I did not want to be a private practitioner. He let me cancel all of my electives in subspecialties and instead do research at the Salk Institute [for Biological Studies]. There, I began to do research with Martin [G.] Weigert, a famous immunologist. While other doctors rotated through their subspecialties, I was actually working at the Salk Institute. When I got there, I thought I had died and gone to heaven after living in Manhattan and Philadelphia. The Salk Institute was built on the Pacific Ocean. You saw endless sky.
• EVERSON: Yes, it is so beautiful there.
• CARSON: It was heavily funded in those days too by the March of Dimes. There were brilliant scientists. I couldn’t believe it. I thought, “Wow, you can do this for the rest of your life!” [laughter]
• EVERSON: You didn’t do any of the internship-based programs?
• CARSON: I did all of the basic medicine and I’m board certified in internal medicine, but I didn’t do any subspecialty rotations. It was very beneficial and I was very appreciative of my boss because I told him, “Prepare me for what I am going to be,” and he let me do it. I published three or four papers while doing my training. When I finished those, I was assigned to go back to the NIH to work at the medical school. I continued along that path of immunology-based research—chemical immunology, they called it. We did the chemistry and we did radiolabeling of the immunoglobulins. We made affinity labels so they could be modified to react chemically with their targets. I always liked the combination of biology and chemistry.
• EVERSON: That, of course, is a combination that contributes greatly to biomedical research. I guess this two-year delay opened your eyes to the West Coast quite a bit. Once you went to the NIH, did you have in mind a plan to come back to the West Coast?
• CARSON: No, I did not. I would have gone anywhere, but Jay [Jarvis E.] Seegmiller, who was a professor at UCSD [University of California at San Diego] and used to work at NIH, told Henry Metzger, “Send a fellow to work with me.” There had been a recent report of an enzyme deficiency, called adenosine deaminase deficiency, which caused a complete failure of the immune system to develop. This enzyme was just a housekeeping enzyme. Seegmiller, who is still here, was a medical geneticist and didn’t know immunology, so he wanted Henry to send him someone who could deal with this problem. I gave a journal club about it and thought it was a great problem to work on. I called it an experiment of nature. ADA has a profound affect on bolstering the immune system. It intrigued me. Also, I could come back to San Diego, which I knew and liked, so I took that post-doc position. Seegmiller is a very distinguished scientist. He was the first person to discover a genetic cause of mental retardation. It was called Lesch-Nyhan Syndrome. He discovered the mechanism—that’s what he’s famous for.
• EVERSON: Lesch-Nyhan is itself an excellent example of a simple cause of a very complicated phenotype.
• CARSON: Right. He had his notes that said, “Wow, the gene here is a simple cause of a complicated phenotype”—no immune system. He wanted to get into the action but he didn’t know immunology, so he called up Henry and Henry sent him me.
• EVERSON: That explains your moving from the West Coast to the NIH and back to the West Coast.
• CARSON: My NIH experience was also very important. It’s a shame that these sorts of opportunities don’t exist today. Because it was during wartime [the Vietnam War], we were highly paid. Life was pretty easy because we were actually getting paid at the level of an officer. It was extremely competitive to get accepted there, so the group of people who were NIH fellows during that era are the household names of medicine now. There were tremendous resources. I also saw patients while I was there.
• EVERSON: Yes. I’ve read about NIH in that period—its coming of age and its institutional growth. Of course, Marshall [W.] Nirenberg was doing the genetic code work there around that time.
• CARSON: Yes, he was there. Chris Anderson was down the hall. It was really amazing.
• EVERSON: Did you apply there in the first place because you knew its reputation by then?
• CARSON: I had to do something because of the draft (3). I knew I wanted to be a scientist so Elliott Osserman referred me to Henry Metzger, and I was accepted. Then Henry referred me to Jay Seegmiller.
• EVERSON: Right. Your story is a good example of the importance of personal interaction in science.
• CARSON: Absolutely. I’m still doing what they taught me. I haven’t changed. The only thing I’ve changed was going into biotech, because there was no biotech in those days.
• EVERSON: Could you describe the work at NIH in a little more detail?
• CARSON: At NIH, Henry Metzger had the foresight to realize that a growing field in biology was going to be receptors on cells, and how receptors interacted with extra-cellular molecules. As a chemical immunologist, he was trying to find a clean, high-affinity receptor system that he could study in detail. This was before any known signal transduction, which today is a dominant field in biology. He wanted to pick a field. First they worked on IgG [immunoglobulin G] receptors, but they were low affinity, so he didn’t like it as a system. Then he reassigned me and the rest of the team to work on IgE receptors. IgE is the cause of allergy. He brought back from England a cell line of a leukemia which fortuitously had an IgE receptor on it. So we worked on studying the affinity of the IgE to the receptor—how long it stayed on the receptor, whether the receptor shed or internalized, and how it began to signal. Again, these are the very early days of what we would now call receptor biology and signal transduction. That’s what we did there. Highly focused. Ultimately, I founded a company that worked in the immunoglobulin field, so it actually helped me.
• EVERSON: Then once you started working with Seegmiller, you worked on ADA deficiency?
• CARSON: Yes. My job was to figure out why an enzyme deficiency caused immune deficiency. The enzyme was called adenosine deaminase, which took a nucleoside called adenosine—a building block of RNA [ribonucleic acid] and DNA [deoxyribonucleic acid], and of ATP [adenosine triphosphate]—and degraded it by removing amine, hence adenosine deaminase. Everybody in the field was studying why adenosine and this enzyme could be important in the immune system. But after reading widely and thinking, I found out some inklings of research that led me to the conclusion that the real substrate for the enzyme—the more important substrate—was not adenosine, but deoxyadenosine, which, rather than being a substrate or precursor of adenosine or ATP, is a precursor of DNA. I came to the conclusion that, when degradation of deoxyadenosine was blocked, it accumulated into cells and was converted to deoxyadenosine triphosphate [dATP], which interfered with multiple pathways of DNA metabolism, including DNA synthesis and DNA repair, and ultimately killed cells in which the deoxyadenosine accumulated. The misnaming of the enzyme had led everybody astray. Having come to the conclusion that the deoxyadenosine rather than the adenosine was the bad guy, I had to figure out why deoxyadenosine would kill lymphocytes rather than other cells, because in these patients, only the lymphocytes were deficient. Everything else was normal. I began to study how deoxyadenosine was metabolized in lymphocytes. It turned out that lymphocytes are very unusual cells in terms of their metabolism because they circulate, and they rely on precursors in the plasma rather than making everything themselves. They are sort of like parasites. Rather than synthesizing everything themselves, they use plasma molecules, which enables them to conserve energy—lymphocytes have to go to tissue sites where there are low oxygen levels, and so they need to conserve their energy. As part of this adaptation, they were genetically programmed to salvage any deoxyadenosine present in the plasma and convert it immediately to dATP, which they would then use for DNA synthesis in the course of dividing and fighting infections. This process was controlled, however, by the deamination of deoxyadenosine, which prevented too much accumulation of deoxyadenosine in the cell resulting from this special salvage pathway. So in the patients who had the deoxyadenosine metabolism problem because of the genetic deficiency in the adenosine deaminase, the deoxyadenosine accumulated with time and reached massive levels—and this accumulation occurred only in lymphocytes, because of this peculiar metabolic adaptation—and then the patients died because of the resulting interference with all aspects of DNA and RNA functioning. It was a complicated history, or what we call an “experiment of nature”—an inborn error of metabolism that targeted a specific cell, based upon its special properties in the body.
• EVERSON: Has anyone suggested changing the name to deoxyadenosine deaminase?
• CARSON: The reason I bring it up is, and I’m not good at this, but what you name a molecule, and what you name a disease, and what you name a reaction is very important in how subsequent scientists are attracted to it and deal with it. You must know that and hear that over and over again, and probably hear many examples.
• EVERSON: Yes. The history of science is replete with examples of how conceptualizing something in a certain way ends up influencing subsequent research in certain directions.
• CARSON: For example, tumor necrosis factor is not really involved in tumor necrosis, but when you name things it forces scientists to follow specific roads. Then I thought that I should be able to mimic what happens with adenosine deaminase by making a drug that was an analog of deoxyadenosine, but that wasn’t a substrate for the deaminase. Because if you made an analog of deoxyadenosine that was a substrate of deaminase, the lymphocyte salvage mechanism would be even more active, trying to eat up all the adenosine in the blood. The drug would kill lymphocytes. When I left my post for my first job, I began to work to exploit that hypothesis. I moved over to Scripps Clinic, in 1976, in the clinical research department.
• EVERSON: Right. This work was your starting point?
• CARSON: Right. I already had the hypothesis from Seegmiller’s lab that we should be able to selectively kill lymphocytes if we had deoxyadenosine analogs that couldn’t be deaminated. Unfortunately, I didn’t have access to any. When I got to Scripps I found, again by reading the literature widely, that there was an enzyme in bacteria—actually, Lactobacillus, which is in yogurt—that could put a deoxyribose on any purine or primidine base—part of the building block of nucleic acids (deoxyribonucleic acid [DNA] and ribonucleic acid [RNA]). You put a ribose or a deoxyribose on a base to get a ribonucleoside or a deoxyribonucleoside, and then you put a phosphate on this nucleoside to get the nucleotide, and multiple nucleotides bound together make a nucleic acid. There were a huge number of bases available, because they’re easy to make. They’re just simple heterocycles—simple chemical synthesis. Many bases had been made by the National Cancer Institute. I thought I could buy all of these bases and then put the deoxyribose on (in the exterior isomer of the beta conformation) using a bacterial enzyme. I actually called up a yogurt company to deliver me about 100 gallons of yogurt. We had garbage cans of yogurt all around. We purified the enzyme and then called up all of the cancer chemists who were making different bases and made about twenty-five or thirty of these deoxyribonucleosides enzymatically. Then we screened them to see if they would kill lymphocytes, and, as a control, tested whether they could kill fibroblasts, which didn’t have that specific salvage pathway. After, I ranked them by the ratio of lymphocyte killing to fibroblast killing. 2- chlorodeoxyadenosine [2-CdA] had the best ratio, and I picked that for development. That took thirteen or fourteen years to develop.
• EVERSON: Fascinating. Before we continue with this story—in the middle of this work, in 1975, you did a rheumatology subspecialty?
• CARSON: Right. Seegmiller was in the rheumatology division and I had a fellowship that actually paid me to work in his lab—from the Arthritis Foundation—and then I got another fellowship from the Leukemia Society of America, so I did both. I was always doing both immunology and leukemia. I actually just spoke to the Leukemia Society of America. It was very, very important for me, as was the Arthritis Foundation fellowship—both were critical in enabling me to do the research. Again, during my fellowship, I saw a very limited number of patients, just the minimum number to get my board certification. They wanted me to go on the faculty, but I always wanted to do research. I did not want to become an oncologist. Oncology is a very demanding clinical field and patients are extremely complicated and require night call, and I didn’t think that I could be a good clinical oncologist and also devote myself to research. Rheumatology is an outpatient specialty without many emergencies, and it focuses on the immune system and lymphocytes. I thought I could marry my clinical work and my research work there—my partial research work in leukemia lymphoma.
• EVERSON: I was curious about how that fit in. So back to 2-CdA. I’m wondering which papers describe this progression of research around the drug’s development, beginning with the ADA research?
• CARSON: I think that the first time I wrote them, I was at a symposium in 1970. I proposed that these kinds of analogs that mimic the adenosine deaminase deficient state would be lymphocyte killing agents. I’d just begun to make and study them. The drug was finally approved around 1993. That timeline, from the scientist making the initial discovery to how long it takes for approval, has not changed.
• EVERSON: How involved were you in getting the drug from discovery to approval?
• CARSON: Initially, I made the drug while I was at Scripps. I actually had a manufacturing procedure, because I could use the enzyme to make it and I could purify it by running it down a column. I used an enzyme called transdeoxyribosolase to make the drug.
• EVERSON: Was this the enzyme that added deoxyribose to bases and that you had isolated from Lactobacillus in yogurt?
• CARSON: Yes. The National Cancer Institute made bases regularly, but ultimately I had to make the base myself because I personally only had a small amount. But as I mentioned, that was pretty easy. It was just a two-step synthesis, so I didn’t need to be a trained organic chemist to make it. Then I met another important person in my life. I was hired at Scripps and the chair of my department—then it was called Basic and Clinical Research, now it’s called Micromedicine—was Ernest Beutler, who is one of the greats in hematology. He wrote the standard textbook, he discovered G6PD deficiency, and he did many other things. I went to see him and said, “I think we can develop 2-CdA as a treatment for lymphoid diseases, but I don’t know how to go about it.” He said, “Don’t worry about it. I’ll help you do that.” Most of the 2-CdA development work—about 90 percent—was not paid for by NIH or by industry. It was paid for by philanthropy to Scripps and physicians donating their time. And there was something called the General Clinical Research Center, which was a grant that paid for clinical trials as a block, without having to get individual trials peer reviewed. Developing 2-CdA was scary all along the way because we were doing this without any industry support. Ernest was backing me up, but I was liable because I was manufacturing the drug. I made the drug—did the toxicology enamels, did the pyrogenicity, the stereogenicity, bottled it, made the labels, and initially gave it to patients. I tried to get liability insurance through the clinic—they had some kind of general insurance program—but they wouldn’t cover massive liability. I couldn’t get any liability insurance because I had a bunch of little kids as patients. Ernest was a tremendous source of support for me in convincing physicians to participate, helping the patients, getting philanthropy, and bolstering me up when it got scary, because when you do the early trials, patients die and there are adverse events.
• EVERSON: That’s incredible. That must have been such a learning curve for you.
• CARSON: Oh yes. Particularly because you think drug development is so hard. It’s not so hard. We made the stuff, it was pure, we recrystallized it, you get an NMR [nuclear magnetic resonance], inject it into rabbits and check that it is not a pyrogenic, do the sterility tests, place it in a minus 70 degree freezer with a lock—I had the key and my technician had the key. We got it tested by primates in very friendly primate centers. They did it for nothing.
• EVERSON: At Scripps?
• CARSON: No. Primate testing was actually done in Madison Lake, Washington. In those days, frankly, we didn’t use NIH money and didn’t cross state lines, so we didn’t need an IND [investigational new drug] permit for initial trials. We did not need an investigational drug permit from the FDA [Food and Drug Administration] because this was back in 1979 and 1980. Since was no interstate commerce involved or government money involved, we were advised to proceed locally with our own patients without an investigational drug permit.
• EVERSON: How clear was your understanding, and how clear were the regulations governing what you were doing?
• CARSON: They weren’t clear at all at that time. I didn’t know anything about patents. I didn’t know anything about government regulations. All I knew was that I thought we could treat patients with the drug and that I could make it. I had a boss who was very experienced and who was also the department chair. He said, “I believe in it and I’ll work with you on this.”
• EVERSON: It coincides, of course, with a lot of developments around recombinant DNA—in addition to the science, the attempts to develop, commercialize, and regulate it. Then in 1980 there was the Bayh-Dole Act, which allowed universities to patent publicly funded research. There were so many things happening in the field right at the same time. Were you aware of the broader developments in biotech?
• CARSON: I always liked to read a lot of journals. As soon as cloning came out, as soon as monoclonals came out, we immediately presented these at journal club. I was aware, but I was always on the applied side. I was trying to keep a heads up into how we could really use these things in a clinical setting. That would have been my focus. But, yes, I was very aware. I wasn’t aware of all the biotech developments, although Ivor Royston came to see me early on in San Diego just to talk about things.
• EVERSON: Well, your experiences with 2-CdA development are interesting.
• CARSON: That was a major part of my career—about fifteen years. The trials were done at Scripps in the General Clinical Research Center, and the patients were cared for by physicians at Scripps. We thought that we could treat leukemias and lymphomas—lymphocyte cancers—and tested a wide variety of them. One of them was hairy cell leukemia. The first patient treated, who was very ill, went into a complete remission and I think is still in complete remission. That was it.
• EVERSON: That’s incredible. Did you stay with the clinical trials through all three phases?
• CARSON: No. When we finished the second phase I got out and a bunch of good physicians finished it. The interesting part was, after we had these results, Dr. Beutler and I went to a chemotherapist at the M. D. Anderson [Cancer Center] who was the first person ever to treat leukemia back in the 1940s. We asked him to reproduce our results because we wanted to be sure that our results were caused by the drug. They opened a secondary trial there and reproduced our results, so we felt much better about it. At the end of the second phase, I stopped manufacturing 2-CdA because it was just too much work. I manufactured the drug for probably the first hundred patients—something like that—but then I got out of the manufacturing business. At that point, Scripps had a research agreement with Ortho [Biotech Products, LD], and they got Ortho to make it for them. The trials were done at Scripps for many years. I don’t know every detail, but ultimately the NDA, the new drug approval, was filed by Ortho. The data came from academic institutions, mainly Scripps and M. D. Anderson, by using what we now call non-GMP [Good Manufacturing Practices] product, because these academic labs were not GMP labs (4). The reason the drug got approved, even thought the product was not manufactured according to GMP regulations, was its clear efficacy. One group was dead and the other group was all alive, so it was approved. I think if you had a drug that completely saved lives from devastating disease, you could get around a lot of the red tape that companies are forced to go through today. The less efficacious the drug, the harder the approval process.
• EVERSON: Right. I’ve heard that story before. Once it was on the market, what was the relationship between Ortho, Scripps, and you?
• CARSON: Ortho had a master agreement with Scripps, meaning that Ortho—which is actually part of Johnson and Johnson [J&J]—wasn’t interested in 2-CdA at all. They just made the drug for a favor. They had no input into the drug.
• EVERSON: I was wondering about that. I thought I had read that J&J had done some clinical R&D on 2-CdA.
• CARSON: Very little. I think they made that up as a marketing tool or they did some at the very, very end. Of course, once the FDA was involved they had to audit all the books in order to verify results, and make sure the investigator was not lying. Ortho took care of that. After the original hairy cell success, 2-CdA was tried on a bunch of different other diseases, and they got involved in that. I was out by then, but I realized it sounded like a very interesting story—developing a drug in-house, all the way. There were no patents, we didn’t know anything about the FDA, and the biotech industry was growing up. I took another peek after the 2-CdA experience and I decided the biotech industry was created to fill the gaps that scientists were not qualified to do. They were there to bring biopharmaceuticals to the market. They’re experts in it. I decided to work in biotech—not internally, but to do further drug development work.
• EVERSON: It’s interesting that you carried 2-CdA right through that period of transition to the biotech industry.
• CARSON: As a result, I was well-equipped for biotech. I knew the time it took and the hurdles it took to do drug development. I never considered the academic model to be an ideal model after my own experience. Actually, I’m still fighting this problem today, because the NCI and the NIH say, “We want universities to develop drugs and therapeutics.” But universities don’t develop drugs and therapeutics. They make discoveries and find leads and do initial validation. The very complex process that leads to final approval requires an area of expertise that universities do not have.
• EVERSON: Vical [Inc.] was founded right in the midst of 2-CdA development. Is that correct (5)?
• CARSON: Right. I was an expert on nucleotides, and Vical originally was started, or beginning to be started, by my friend and colleague Karl [Y.] Hostetler. It was a drug delivery company. Karl was using things like lipids and liposomes to try to deliver drugs. Since I was an expert in nucleotides and nucleic acids, he asked me to join him as a cofounder of Vical. Vical did some initial experiments—these were the very, very early days of gene therapy—where Karl wanted to see if we took DNA vectors, which were just being developed, and put them in liposomes, whether we could do gene therapy in animals as part of drug delivery. In our initial experiments, it was discovered serendipitously that naked DNA, without the liposome delivery system, gave better expression in the muscle than the DNA encapsulated in a liposome. I wrote a letter—I still have it—in 1988, to the CEO of the company, saying this was a major discovery and it could have very interesting applications in immunology. In order for a virus to trigger an immune response after getting inside of a cell, it uncoats and makes a lot of proteins, which are then presented on the surface of the cell—so-called antigen presenting cells—which trigger an immune response. I realized that injecting naked DNA with a vector simply mimicked what a virus did. Some of the DNA got into the cell, uncoated, and made protein that would then be presented on the surface. Therefore, we could make a whole host of so-called naked DNA vaccines that didn’t require live viruses to transport them. I wrote a patent on that, and that became Vical. They’re still working on that. They’re a public company. The process has not yet been approved, but there are positive clinical results. It required a lot of tweaking, as you could imagine—but basically, it’s a naked DNA vaccine.
• EVERSON: With this discovery you found that naked DNA actually worked better than using liposomes, and the discovery was completely serendipitous?
• CARSON: Yes. It was completely serendipitous. The key point was recognizing the simplicity of the system taking the naked DNA up into the cell, and that an immunologist and a nucleotide metabolism guy could actually mimic what a virus did in the immune system. Vical got out of the drug delivery and gene therapy business and went into what we call the gene immunization business—using vectors for immunization. This is now a huge area of research. The discovery was patented—a very important part of the company going public being that they controlled the intellectual property for naked DNA immunization.
• EVERSON: When did Vical go public?
• CARSON: Maybe 1990 or something like that (6). It took a while. I didn’t know anything about biotech in those days, so I didn’t know anything about how many shares one usually gets, but it varied a lot. I just did what I was told. What was interesting was that I didn’t have a research grant to do the naked DNA. It was something where a company that has substantial resources working in an unrelated area can make a serendipitous observation, change course, raise money, and do it.
• EVERSON: Were you involved in trying to raise money—venture capital—for Vical?
• CARSON: I was not involved in any of the formal presentations that were done, but I was interviewed by all of the investors.
• EVERSON: Let’s move on to the next major stage in your career at the Stein Institute, beginning in 1990.
• CARSON: Yes. Dr. Seegmiller retired in 1990. I had been at Scripps for fourteen years, and he asked me to take over the Stein Institute he had founded. The Stein Institute for Research on Aging essentially covers all of the chronic diseases: heart disease, cancer, Alzheimer’s. I moved down the block to take that position. I thought fourteen years in one place was enough, although I was very happy there and Dr. Beutler was very good to me. This was something new. I didn’t want to stay in the same position too long, so I took the job.
• EVERSON: As director, I presume you were not in the laboratory as often as you would have been at Scripps?
• CARSON: I think as one gets older, you build up important skills. I had skills in crisis management and in industry. By 1990, biotech was really getting big, and the Stein Institute only had seed money. They needed to build the company, so I thought I could put those skills to use. At the same time, I also maintained an active laboratory program in both cancer and rheumatology and maintained contacts in biotechnology and industry. I was a consultant for Ciba-Geigy for the first five years of my position at the Stein Institute. That was actually critical for my other companies, because Ciba-Geigy paid for any patent I submitted. See, nowadays, if you submit a patent application at a university and you don’t have a sponsor, you can’t get the patent in most cases. It is very expensive; it costs multiple thousands of dollars to file a patent. Patents that come from academia are often not complete—they’re sort of partial—so universities typically have to go out and find sponsors before they file a patent. But I had my own sponsor, and it was terrific. They were looking for inventions so they paid for all my patents. A lot of my subsequent companies spun out of patents that Ciba-Geigy paid for. Later, Ciba-Geigy became Novartis [Pharmaceuticals Corp.]. They never developed any of my patents internally; the university owned them. I think another lesson in my own career, and in biotech in general, is the importance of having conditions to secure intellectual property when it is not completely developed. Otherwise you’re in a Catch-22 situation, where you need a sponsor to patent research and yet you need research data to get the sponsor. You can only go so far on your own. You can’t use NIH money to fund a patent application, and the university is quite limited financially.
• EVERSON: Can I ask a little bit more about the nature of your activities when you started the Stein Institute? You mentioned that you kept a lab while you had all of your administrative work as the director. How did you balance your multiple roles?
• CARSON: The Stein Institute did not have a clinical program; it just had a research program. I was involved in endowment building. Mr. [Sam S.] Stein gave us a substantial endowment and then, related to what I mentioned earlier about the importance of undergraduate exposure to science, we set up programs that gave money to undergraduate and summer students to work in different laboratories. We administered that. I also sponsored a program where faculty gave lectures we broadcast on UCSD TV around San Diego, to disseminate the excitement of science. It was not a huge administrative burden. Most of the administrative work was fundraising. We had a community of people that I had to interact with on this end, but I was particularly gratified to help students get excited about research. That particular field—aging— was not considered a sexy field at the time. “Who wants to go work on the aging and old people?” Now it is much more attractive. I thought it was really important to create a buzz around it. That was the center of my leadership over there. Clinical activities—taking care of elderly patients—were not part of my responsibilities. We were really focused on undergraduate and graduate priming, getting people to want to go into the field, and community education. We also gave start-up grants to faculty who weren’t in the field, but were willing to take the plunge.
• EVERSON: Was there a lot of in-house research?
• CARSON: In-house research was disease-based, so rather than studying the aging phenomena per se, it was divided into neurosciences, joints, blood vessels, and cancer.
• EVERSON: Right. It sounds like a fascinating way to combine research education, outreach, and application—very interdisciplinary and collaborative. Would that be a good description?
• CARSON: Yes. The Stein Institute was called an organized research unit. I’m also currently in an organized research unit [the Moores Cancer Research Center]. An organized research unit is the answer to the question, “What do you do when a university department doesn’t match the problem that you are addressing?” For instance, in which university department do you put diseases of aging? Is it neurosciences for Alzheimer’s? Is it oncology because it’s cancer? Cardiology because they get heart attacks? Aren’t some people studying why fruit flies get old? You need an interdisciplinary group. People create these organized research units, and they try to find a leader with wide interests and sufficient people skills to get very independent scientists to work together. That’s what we were trying to do at the Stein Institute and what I’m trying to do here.
• EVERSON: This reminds me of the early days of molecular biology, when new research programs were founded that were very consciously interdisciplinary, trying to avoid the traditional disciplinary structure at universities. I know that when Caltech’s [California Institute of Technology] Biology Division was created back in the day, there was a very similar story.
• CARSON: When I look at what happened to Caltech while Dr. Beutler was there, the idea of marrying engineering with some of the major problems in DNA and protein sequencing was incredibly successful. I still think that’s the best model for research—bringing people together with very, very different backgrounds and getting them to work together. In my current job at the Cancer Center, we have a Nanotech Center and a Discovery Center. In our building we have engineers, physicists, mathematicians in a building usually occupied by biologists and doctors. My interaction with them has been the most gratifying part of my new job. A lot of new stuff is going on—very interesting new stuff.
• EVERSON: I can imagine. I’d like to hear more about it. You were involved with the Moore Center while you were the director of the Stein Institute, correct?
• CARSON: I was also member of the Cancer Center, yes.
• EVERSON: So what does being a member entail?
• CARSON: Well, the Cancer Center has shared resources that one can use. I was allowed to use them because I was doing cancer research quite actively.
• EVERSON: How was the Moore Center founded? Who founded it?
• CARSON: The Cancer Center was founded by John Mendelson, who currently directs of the MD Anderson Cancer Center and developed Erbitux back in the 1970s. He was actually my first medical attendee when I came to UCSD as an intern. We’re now in our twenty-fifth year. They were not a comprehensive cancer center. A comprehensive cancer center is a National Cancer Institute designation for a center that does everything: research, clinical work, education, and community outreach. In 2001, the UCSD Cancer Center, which had previously focused mainly on research, was awarded a comprehensive designation with the understanding that the university would work to put up a building to make all of the different components of a comprehensive cancer center come together in a single facility. When this building opened in 2005, I was asked to become the director because I had worked in oncology, had excellent industrial experience, and knew how to run an organized research unit from my previous work at Stein. I really wanted to develop a model where we could facilitate new therapies in cancer, but I wasn’t naive enough to think that a university could function like a biopharmaceutical company. I knew we had to have some partnerships, and that’s what I’ve been working on since I’ve been here—building models of partnerships.
• EVERSON: I presume this is your full-time job now. Do you also have a lab here?
• CARSON: I do have a lab here. In fact, I have two drugs in development. I’ve arranged a 50 percent time commitment to running the lab and a 50 percent time commitment to running the Center. I’ve organized a lot of focus groups that I go to in, for example, drug development, engineering, and imaging. I meet with all the junior faculty, and I actually have a couple of chemists that I work with personally—and we have new drugs. It will be fourteen years before they’re finished, but they look very interesting.
• EVERSON: Outside of the Moore Center, do you still work with Scripps or UCSD?
• CARSON: I’m still on the Scripps faculty. I talk to my old boss, Ernie Beutler, regularly. I go to their retreats. I’ve worked very hard to get them to put a translational laboratory here because the UCSD Cancer Center is focused on integrating translational aspects of research. We were talking to protein chemists and molecular biologists at Scripps about having them run satellite labs here so they can translate their work. That’s progressing quite nicely. They do the basic work and when they really want to know how to develop it, they’re not going to just spin-off a company but really get it to the next stage. They can come here and people like me and my colleagues can help them.
• EVERSON: With the Moore Center and the Stein Institute as examples, there seems to be a very explicit realization that you have to create opportunities for translational and collaborative interdisciplinary work. Was there some point, do you think, that you and others realized that this sort of thing had to be done?
• CARSON: I realized it as soon as I finished developing 2-CdA. You can talk about doing everything yourself, but that’s not the way the capitalist system runs efficiently. You need a division of labor. There are things like intellectual property companies for a reason. It’s not industry versus academia—we have to work together. I actually spent a long time reading business books, trying to understand business myself, because I didn’t know anything about it. I’m quite dedicated to that too. We must have a partnership between the private and public sector if we’re going to maintain our technological edge in biotechnology and other fields like communications. We need to understand each other, and we need to do something mutually beneficial, that both maintains academic freedom and enables companies to make profits. I don’t think this issue has been solved yet, and I think it is evolving all the time. The so-called organized research unit is best equipped to help deal with those problems, at least from the academic side. It’s not a solved issue—it’s still a struggle.
• EVERSON: It is an ongoing issue, absolutely. I think within universities there has often been a point of contention, not just regarding academic-industry relationships, but the relationship between doing curiosity-driven research and doing research that you want to apply very specifically. A center like this seems to be a great way to clarify the nature of these relationships.
• CARSON: Right. One of the things we’re working to do is move away from just sponsored research by industry to what I call collaborative research, where the division of labor is clarified: we do a service that we do better than anybody else, and then industry does a service, and then we have agreements that describe how intellectual property and potential profits will flow. Who does discovery better than us? Industry doesn’t do discovery like academia does. We do assay and lead generation very well. They do optimization, formulation, and manufacturing really well. Universities do early clinical trials where it just involves a few patients. Industries do later, stage three trials well. I’m working very hard now, trying to develop these research collaborations that don’t actually involve money at all, but involve a division of labor between the academic and the biotech community.
• EVERSON: Right. Can I ask you about some of the other companies while we’re on this topic?
• CARSON: Triangle Pharmaceuticals [Inc.] was founded in 1995. The AIDS epidemic developed in the 1980s. Early on, with the discovery that AZT could help to treat infection, scientists realized, “Hey, we better understand nucleotide metabolism and purine metabolism in lymphocytes.” Only about ten people in the country worked in that field and I was one of them. I spent my career working on nucleotide metabolism and lymphocytes. Ray [Raymond F.] Schinazi from Emory University, as well as Karl Hostetler and I from UCSD, founded Triangle Pharmaceuticals together with the late Dr. David [W.] Barry, who had actually supervised the AZT program at Burroughs-Wellcome. When Burroughs was acquired by Glaxo [Inc.], that program was disbanded, but Barry still wanted to try to develop antiviral nucleosides and nucleotides.
• EVERSON: Whose initial move was it to found the company? Were you contacted by someone and asked to join?
• CARSON: Karl and I always wanted to do it, and I knew Ray. We came together, but didn’t have anybody with industrial experience. When the AZT team became free, we knew them already, so we launched. They developed some anti-HIV drugs—quite good ones—that were purchased by Gilead [Sciences]. The drugs are in the clinic. I’m not the personal synthesizer of them. My role there was trying to tell them, “These are the pathways of metabolism in lymphocytes and these are the types of drugs you need.”
• EVERSON: With a group like that—their expertise and experience with AZT and your expertise in nucleotide metabolism—I presume there was a lot of interest in the company.
• CARSON: It went public in one year.
• EVERSON: Where did the initial funding come from?
• CARSON: Venture capital. Forward Ventures, [Inc.].
• EVERSON: So your involvement was clarifying the science around nucleotide metabolism in an advisory role?
• CARSON: I was on the scientific advisory committee. I was not a board member, nor was I involved in management or strategic marketing decisions. However, there was a huge knowledge base they needed in order to build these drugs and I had that background.
• EVERSON: And Dynavax [Technologies] (7)?
• CARSON: When I was at Vical—remember they were doing the gene immunization as preventative vaccines? I was very interested in immunotherapy. That means not preventing a disease by immunization, but treating a disease by immunization. I was trying to think of how one could exploit this in the commercial arena and the disease I thought would be best to study was allergic disease, because patients already got allergy shots but they weren’t very effective. That was the only disease where there was approved immunotherapy. The problem with allergy shots is that half the time when a patient gets the allergen injected in them, they actually get an allergic reaction to the treatment rather than immunization—even though they may respond. I came up with the idea that, if you could get the DNA into the cell and manufacture it like a virus, there wouldn’t be any allergic response and you could still do the immunotherapy for allergy. That was the patent portfolio and the idea that lead to the starting of Dynavax. Subsequently we found that it is not necessary to use naked DNA. You can mimic the same thing by taking protein allergens and covalently coupling them to DNA. The DNA actually shields the allergen from reacting with the antibody. The DNA also manipulates the immune system via a whole new type of receptor. Dynavax’s first product is an allergy immunotherapy. The clinical data has been reported and we had a press release yesterday. It all looks very, very good. I think it will be a product.
• EVERSON: Just yesterday? Fascinating.
• CARSON: Yes. Yesterday afternoon they reported their second/third phase clinical data. It’s a public company. I’m an insider, but as far as I can tell, it works.
• EVERSON: What is your specific work with them?
• CARSON: I was the inventor. And Dr. [Eyal] Raz—he’s now a professor, but at the time he was my post-doc—was my co-founder. We were working on allergy immunotherapy together. Remember, I worked with Dr. Metzger way back, so I knew the allergy field. I knew the allergy field, I knew the nucleotide metabolism field, and then I worked with Vical, so it came together with Dynavax. With allergies, it is a much harder route to develop a product, because allergies are not seen by the FDA as a high priority disease. You need a tremendous safety profile. It is a very expensive process, but I think the technology does work and it will be a product.
• EVERSON: Phase two trials were reported, right?
• CARSON: There were about seven hundred patients in the trial, but it was an efficacy trial, not a registration trial. With diseases like allergies, you need to do very large trials because there is a major placebo effect and people say they have allergies but don’t so they’re complicated trials. A lot of trials are done in Canada, actually, which has a huge hay fever problem.
• EVERSON: I didn’t realize that – I’m from Canada. And Salmedix, [Inc.]?
• CARSON: Salmedix was a cancer specialty company—a specialty pharma company. In other words, it didn’t do initial synthesis of drugs. It was dedicated to a niche treatment of cancers, particularly blood cancers. I’d worked in the hairy cell leukemia field and other fields where big pharma wasn’t interested, because these were considered to be minor diseases not affecting enough people. The idea behind Salmedix was that I had tremendous connections in the field of leukemia and lymphoma and I thought that there were a lot of drugs out there that might be useful for these diseases that big pharma would ignore. It was called a specialty pharma company. The company had some internal drugs and some drugs they were licensing. They were just sold to Cephalon [Inc.] for one hundred sixty million dollars last year. Cephalon is continuing the development of Salmedix’s portfolio. That’s what they call a specialty pharma model, which is extremely popular. It wasn’t something that I had great interest in, but I thought that my expertise in leukemia would work for this one—and it did.
• EVERSON: Does the Orphan Drug Act come into play with the specialty pharma company?
• CARSON: Yes. They’re all orphan drugs and you can sell them for seven years under the Act. But to develop a compound for an orphan drug, you need to have people who really understand the disease and who have access to the academic leaders in that disease for their support. There are a lot of special issues that you don’t have in common diseases. Academic investigating can make a big impact.
• EVERSON: Were there other people involved in founding the company?
• CARSON: Yes. Just like with Dynavax, I worked with a student, Lorenzo [M.] Leoni. I also had a very good friend, David [S.] Kabakoff, who had been a very successful biotech CEO. He became CEO of Salmedix. I had friends in the venture capital community, so I actually didn’t go out and raise money. I just called them up.
• EVERSON: Great. Okay, now I’d like to ask you about some of your awards. You were elected to the National Academy of Sciences in 2003?
• CARSON: Yes.
• EVERSON: I understand it’s pretty rare for an MD to be elected.
• CARSON: Yes, there are very few doctors because they usually get their rewards financially and from patients, while basic scientists get their rewards from certificates and societies. Rightfully so, the National Academy focuses more on the basic scientist.
• EVERSON: Can you describe the story of that election? How did you find out?
• CARSON: Well, Dr. Beutler, Dr. Seegmiller, Dr. Metzger, and Dr. Weigert, and all the people I’d worked for were members of the Academy. Everybody—even Dr. Raz, who has passed away. They were working on my behalf. I think I was elected because I did one major thing: I developed a drug—including doing the basic science and the applied science—that effectively treated a disease. That allowed mentors who were members of the Academy to push my case. Now that I’m in there, I realize how complicated it is getting elected. There are so many different levels. How does one evaluate a scientist? All I can say is that it is better to do one or two things well than to do a lot of things. To get elected to that organization, you have to write what you’ve done in fifty words or less. That wasn’t very easy in my case.
• EVERSON: In addition to the National Academy, you were awarded the Arthritis Foundation Lee C. Howley Sr. prize in 1987. You mentioned the importance of the Arthritis Foundation already, as enabling you to focus on medical research.
• CARSON: Right. They supported me during my whole career. I had a whole area of research that didn’t ultimately lead to a drug, but that involved understanding the role of lymphocytes in arthritis. Because I could do chemistry as well as biology, I did an awful lot of chemical approaches to arthritis and other diseases that nobody else could do. That spawned a lot of other kinds of research. That’s why I was involved in that.
• EVERSON: Can you describe the American Association for Cancer Research Bruce Kane Memorial Award you won in 2004 in some detail?
• CARSON: That’s an award for drug development. That’s one of the oldest awards in the AACR. It’s for the old timers who are involved in making drugs—guys like me and also people from industry.
• EVERSON: Then, most recently, you received the 2005 BIOCOM Life Sciences Award, sponsored by BIOCOM and the Chemical Heritage Foundation.
• CARSON: Yes. That was because I’ve been involved in the biotech industry in San Diego for a long time, and because I’m heading a big organized research unit now.
• EVERSON: Have you been involved with BIOCOM in the past? Do you know much about BIOCOM?
• CARSON: Well, as head of an ORU [organized research unit], it’s important that I interact with these different organizations because they act as conduits to industry. We have an industrial advisory board here. As I told you, I’m trying to create a partnership model where the biotech industry works with academic institutions, so seeing people at BIOCOM and related institutions is an important part of my job.
• EVERSON: Is BIOCOM’s major role to connect people like you to people in industry?
• CARSON: They’re also involved in education, which I’m very interested in. There are high school students they pay or support to work in labs, which I think is an excellent program. The nice thing about the Chemical Heritage Foundation, too, is its educational role. I think that is very, very important nowadays, when people get discouraged from what they read in the newspapers regarding whether or not they should go into science.
• EVERSON: Yes, definitely. We have a large educational program. I guess that’s a major challenge for group likes BIOCOM and the CHF, to promote the study of science in such a context.
• CARSON: Yes. There is a tendency now for people to take an easier route, and you can see how it happens. It takes something like fifteen years to develop a drug, or to be elected to a major science organization. You have to do this one thing for so long, and when you start your project you don’t know whether that thing is going to work. There are many, many reasons not to do it. What I think places like BIOCOM and the Chemical Heritage Foundation do is find those students who are genetically programmed to do that, and get them in an environment where they will take off.
• EVERSON: Can I ask about your views of the biotech community in San Diego? What is your general impression of the current state of the local industry itself, and the work that’s being done at places like Moores and Scripps and the Salk Institute? San Diego seems to continue to have a very strong presence in this field.
• CARSON: We have over two hundred biotech companies in San Diego. I think there are a number of reasons for that. One is the level and caliber of academic science here. , Another is the success story going back to Hybritech [Inc.] and Idec [Pharmaceuticals], which showed that people could make money investing here. Also, there is the availability of a workforce coming from the university. Something that I don’t think is fully appreciated is the tremendous immigration from Asia and Mexico, which is providing staff at all levels for running these companies. Finally, there is actually land available to build on. San Diego has a lot of things going for it that you can’t reproduce in other places. Plus, it’s just a hop, skip, and a jump down here for all of the VCs from Menlo Park. I think it’s a terrific place to do biotech. My concern is that there is more and more regulation occurring now in California, and it is getting quite expensive to do business for a lot of these companies. We’re still doing very, very well, but I don’t think the biotech industry can sit around and assume that there is not going to be competition from the Pacific Rim, Europe, and other places. We really need to be thinking of new models that exploit every conceivable advantage that we have. The situation will not stay static. BIOCOM and similar institutions should be at the forefront of thinking about these matters—not just lobbying government and complaining, but actually figuring out how we can maximize our competitiveness in the environment which we’re given. I think this is a very important role for such institutions. I think these loose organizations enable a distribution of labor and collaboration even among industry, if the legal people can get around it, and they can help make sure that immigration persists so that we get a continued flow of scientists. There is a whole group of things that they need to be involved in.
• EVERSON: What other roles do you think government should play—aside from immigration policy—in the future of San Diego biotech, to ensure that it remains competitive?
• CARSON: There need to be tax incentives to encourage companies that are creating jobs to stay and maintain their operations here in San Diego. I think some of these new reporting rules, like the Sarbanes-Oxley Act (8), are providing very high financial burdens on small companies, discouraging them from going public, and instead leading to mergers, which results in biotech companies in San Diego usually closing down because the merging partner is a bigger company at another site. We need to make it possible for small companies to go public by decreasing the cost of being a public company, and then they’ll grow endogenously.
• EVERSON: Right. Could you discuss the Sarbanes-Oxley Act and its effects on biotech in more detail?
• CARSON: I’m not an expert on them, but a major consequence is that it now costs millions of dollars to provide accounting regulations on how a company is operating, distributing its buying, and dealing with its directors. For a non-profitable biotech company that requires equity, it just raises the cost of doing business. When a company must decide to sell itself or go public, if going public raises the cost of doing business to a very high level, then it will decide to sell itself. But when that happens, the jobs associated with that company disappear. One problem with these regulations is that they want the benefits of the industry but they don’t want the costs.
• EVERSON: You mentioned that BIOCOM and similar institutions have a role to play in such policy matters. What role do you see institutions like UCSD and the Salk Institute playing?
• CARSON: Well, this is something that the Moores Cancer Center does: we have forums where we bring in industry representatives and we have academic investigators talk about some of the things that we can do that they can’t do and how we can work with them. For example, we have tremendous imaging facilities, x-ray and such. We have access to large numbers of biochemical specimens. We have people working in very weird disciplines that might be useful to industry, like collecting sponges from the bottom of the sea and oceanography. Organized research in the university can provide ideas, collaborations, and services that are really unavailable even in a very large private sector organization. Because university and similar institutions are sort of disinterested third parties, where we have a day job and we don’t have to make money in business, this creates a relaxing environment in which people from industry can network with each other.
• EVERSON: One more question: we’ve talked a lot about how you balance your academic research interests and your administrative work. What about work in general and everything else in your life? You must be a very busy person—where does your personal life fit in?
• CARSON: I sold my home to move next door to my work. I live in an apartment next to the university now. I couldn’t maintain a house and my wife was quite active in the Cancer Center. Our children are grown. For the moment, this is our life. Right now I’m very concerned about getting our new facility up and running and developing the interactive model I talked about.
• EVERSON: Okay, great. Well, Dr. Carson, those are all the questions I have. Was there anything else that you wanted to add?
• CARSON: No. I hope I was helpful.
• EVERSON: Very helpful. Thank you so much for your time.
• CARSON: Thank you.
• [END OF INTERVIEW]