60 Years in Science: An Interview with Charles Weissmann

Eric Sauter of News&Views recently had the opportunity to chat with Charles Weissmann, chair of the Department of Infectology at Scripps Florida who is retiring April 30, about some of the experiences and insights he has gained during his 60-year career in research.

You became interested in science at a young age. In general, do you think scientists are born or made?

The way I look at it, some brains are wired in a way that make them susceptible to a scientific education, which probably has to do with innate curiosity. But a lot is history, such as who taught you what—so it’s both the environment you grow up in and your own nature.

Were you born in an environment where scientific curiosity was rewarded?

Oh no, my father was a businessman. My mother was a piano teacher originally. There was nothing scientific at home. If anything, my parents were more on the artistic side.

You initially became a doctor?

Yes, because that was the way to get into biochemistry in Switzerland at that time, in the 1950s. There was no way of becoming a PhD in biochemistry—there was no such thing. You were either a medical doctor or a chemist. If you wanted to become a biochemist, you usually first became an MD. 

You spent time with a country doctor, which convinced you not to pursue medicine as a career.

I went on house calls—alone. The GP went skiing and left me to take care of his patients. I would do this for three or four weeks at a time. What I shook me up most was a patient wanting a tooth pulled. Because that’s what a general practitioner had to do out in the country. They had no dentists in these villages, they were too small, so the GP did everything—deliver babies, pull teeth, and so on.

Were you good at pulling teeth?

I was supposed to take a course during my medical education, but I didn’t. So when the patient arrived and wanted his tooth pulled, I said, “Are you sure?” He said, “Absolutely, this tooth has to come out.” I said, “Well, I’m busy now, come back in the evening.” That was so I had a chance to read up on how to pull a tooth—what tools to use and so on. 

Was it a successful operation?

Well, by the time the patient came to the office in the evening I was ready to do it and—it was like in a bad movie—I was going to inject the patient with local anesthetic when all of a sudden the door opens and the GP walks in, back from vacation. He says, “What are you doing?” and I replied nonchalantly, “Oh, just getting ready to pull a tooth.” He said, “Let me do that, I like pulling teeth.” “Well, if you insist...” 

The doctor takes hold of the tooth and it immediately breaks off, which is just about the worst thing that can happen, because then you have to dig out the root. But the GP was not at all disturbed. He took out his instruments and started digging the root out of the silently suffering patient’s jaw. I broke out in cold sweat thinking that this could have happened on my watch…

Are there any real differences between how scientists are taught now, compared to how you experienced the process—first becoming an MD and then learning the science?

A scientist is really taught during his thesis work. That’s when he or she stands in front of the bench and learns how to handle things. One of the most important things you have to learn is how to think about solving a problem. It’s interesting that I often found it a longer process to train a person with a medical background or even a physics background than one with a chemical background. They usually don’t have the experience of breaking up a problem into its parts and dealing with each part rationally, and applying the appropriate controls. It’s a different mindset. 

You have characterized the lifespan of a scientific paper at about three years...

That’s how long people are aware of them, if at all. Most papers don’t even get read. It’s very rare that a name gets attached to a discovery. The Watson-Crick determination of DNA structure is one instance. There’s a little joke that used to go around. A man gets introduced to Francis Crick and exclaims, “Oh, I thought your name was Watson Crick.” Many really great scientists who laid the foundation for important developments are forgotten. 

You also said that those papers were overshadowed by the satisfaction you felt about training graduate students—around 100 I think you said.

I only realized how many people I trained after I retired from Zurich. [Weissmann joined the Zurich-based Institute of Molecular Biology as director in 1967.] We had a 30-year anniversary, so I made a list—it became quite long. Many of the people on it have done extremely well, quite a number better than I have. It was a pleasant realization. I hadn’t quite realized how many people were passing through my lab—and how many good scientists there were among them. 

What made you come to Scripps Florida?

What attracted me was [former Scripps Research president] Richard Lerner and his attitude towards science. His motto was, “Do good science and good things will happen.” That’s what really attracted me. It has been the driving force in my own career.

How do you view the notions of basic research versus what we might call applied research?

It’s like asking the question, what’s more important—a musician who plays the music or a composer who writes it? You need both. One without the other is incomplete. Sometimes one individual does both well—the same in science.

Do you see yourself as doing basic research?

Yes, although I’ve done applied research. I’ve been there with the whole interferon episode. [In the late 1970s, Weissmann was the first to clone the human interferon alpha genes and produce interferon in bacteria. Interferon plays an important role as the first line of defense against viral infections and is currently still the most important drug in the treatment of hepatitis C.] I enjoyed it but didn’t want to stay in it. I never left the university, never fully committed myself to developing companies and so on. I did it once with Biogen, which was interesting and enjoyable and that was it. The company started with a $600,000 investment and turned into a multi-billion-dollar company. But once the company was successful, it didn’t need me anymore and I had no interest in becoming management. I have even managed not to become a dean in my academic career. When you reached certain seniority at Zurich University, you were obligated to serve as dean for two years, but somehow I managed to escape.

One time you said that you had produced a great study—on prions—that didn’t really help anybody. Can you elaborate on what you meant by that?

I get tired of reading papers that end up saying that this might be useful in curing cancer or Alzheimer’s disease. My point is that maybe the research is not going to cure anything but it might lay the groundwork for deeper understanding of biological phenomena and it may or may not be useful later. For example, consider plasmids, these bits of DNA in bacteria that are responsible for drug resistance. People worked on them for years because they were interesting, but it was all pretty useless stuff. Yet a whole technology developed out of these plasmids when it became possible to cut and paste other DNA into them and put them back into cells. Suddenly, you had recombinant DNA technology. So out of this playing around with plasmids, you ended up with a technology that is the basis for almost our entire biological science today. It all came out of just “playing around.”

How do scientific ideas occur to you, for instance the notion that eliminating PrP from the mouse would make it less susceptible to prion infection? [PrP is the naturally occurring prion protein; after infection with mad cow disease, these proteins are converted to the disease-linked misfolded form.]

It was a logical progression. The hypothesis was that PrP was converted to infectious agents and the best way to prove that was somehow to prevent an organism from making PrP. I knew at that time that people were working on the procedure to knock out genes, so I put two and two together. Often in science you pull things together that appear unrelated. You just happen to have them in your mind. It so happened that I thought of it and another group thought of it but we were faster than the others—quite a bit faster it turned out—so it was a considerable success: we created a mouse that was genetically resistant to prion disease. 

The general public still has this idea that scientists experience constant Eureka moments.

There are such moments and they occur very rarely. That wasn’t one of them. Sidney Brenner (2002 Nobel laureate in Physiology or Medicine) likes to say that ideas are the garbage of the mind. Everybody has ideas. Executing is the key. You‘re dependent on people who are able to do the experiment. At the time, we wanted to develop a mutant mouse that lacked PrP. I had a colleague, Michel Aguet, who was extremely good as an experimenter and he acquired the technology to generate knock-out mice. The technology is very demanding; you have to be able to do a lot of things with your fingers and be very dexterous. We were lucky to have Michel in our institute.

One Eureka moment occurred when I recognized that viral populations are heterogeneous, pretty much what we also found with prions later on. That’s what we now call quasispecies, and it explains why viruses like HIV can resist antiviral drugs so well. That paper was published in Cell in 1978. It was a real Eureka moment when I held the film up to the light and realized what it meant. 

Were you surprised when you found that prions could undergo Darwinian evolution? That seems like a fascinating feature.

A biologist would say, “What else would you expect?” Because that’s the way nature works. If you think that just a few billion years ago there were only one-celled entities, or an even more primitive life form, and that now you have us, thinking about how we got to be what we are, you realize the power of the process called evolution. Living entities change, and those whose change promotes their survival outgrow their competitors. Nonetheless, we were surprised when we found that prions, which consist only of protein, were subject to the same process.

Obviously, the personal computer has helped science evolve. 

I started using one when the Mac came out in the early 1980s. They were fantastic compared to what we had before, which was nothing. In the beginning we would clone and sequence interferon genes and, to compare these sequences, we typed them out, cut strips, and moved the strips back and forth until we found a match. We did entire papers by hand. It was brutal. But what changed science even more than the computer has been access to the literature through the Internet. Simply being able to get the information without having to get out of your chair. Younger people don’t know what it was like going to the library to look for a volume. Oh, the volume isn’t there, somebody took it. “How can I get hold of him?” “Oh, the guy’s on vacation.” Now, in seconds you have all the information you need, sometimes even too much.

What is the most challenging aspect of science right now?

We used to think in the ‘90s that if you understood how a gene promoter works, using a few transcription factors, you would understand what’s going on. Then it started getting more complicated, orders of magnitude more complex. Now, with the advent of non-coding RNAS, micro RNAs, the network is so complex that the major challenge is going to be to understand how all these parts mesh into a system. 

This is an enormous challenge, an informatics challenge, because no mind can actually reconstruct all the interactions. You begin to realize that evolution has led to a complex system with a built-in redundancy that allows it to work even if some parts go wrong. It’s quite amazing. The more we learn, the more we see even more components involved. Uncovering how they interact is a big challenge. But it’s dwarfed by the challenge of understanding how the brain develops and works. This is the field I would engage in if I were at the beginning and not at the end of the road. 

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