Robert Sinsheimer is a geneticist who has worked in the most prestigious institutions in the United States.

In 1977 he left Caltech to become the chancellor of UC Santa Cruz. While at UCSC he convened a meeting of the country’s leading geneticists to propose the effort that was to become the Human Genome Project.

Upon retiring as chancellor at UC Santa Cruz, he joined the research effort of Dr. Michael Mahan at UCSB. Mahan’s team currently works to produce vaccines for a variety of diseases.

From his window office in Biological Sciences II, he reflects on his life, on his science, and on the science of life.

-Josh Braun, science editor

You were the progenitor of the Human Genome Project?

It turns out, apparently, that that’s true.

Can you tell us a bit about the original effort?

Yes, well it’s kind of a curious history, but what you’re referring to is that we had a workshop in May 1985. The purpose of the workshop was to consider whether it would be feasible to sequence the human genome, and I convened this workshop. I was at that time the chancellor up at UC Santa Cruz.

With the help of some of the faculty there, we drew up a list of all the leading people who were doing sequencing at that time. There were 15 of us all told and we had a three-day workshop. It was very interesting.

You have to understand at that time the only genome sequenced was that of a small bacterial virus – one I actually worked on in 1977 in Sanger’s lab. That was a little over 5,000 nucleotides. Then in the interim period they’d been getting to bigger viruses. They’d done one with 50,000 and they were working on some human viruses with about 100,000 nucleotides. So it was quite a stretch to think of doing 3 billion.

So I think many people were pretty dubious. But we talked about it for three days and we talked about the potential for scaling it up and for automation, because if it were to be done the way we were working we were going to have to have thousands of coolies doing nothing but sequencing.

But it seemed plausible to us at the time that a lot of the steps could be automated, that sequencing itself could be automated so you weren’t just working with gels all the time. Machines could be used to remove the challenge. The improvement of computers would make the handling of the data – the informatics part – possible.

And so by the end of the meeting, the majority of the people thought that it probably was feasible. There were some who, to be honest, didn’t think it was important or worth diverting so much energy. We estimated at that time it would probably cost about a dollar a base to complete the project.

That sort of awed a lot of the biologists there. It didn’t bother me. That’s interesting in itself, I think, because as chancellor I had been involved with some of the “big science” projects. We had at Santa Cruz a high-energy physics group, and they would be going off to work at Fermilab and so forth. We also had a very outstanding astronomy program and we were in the middle of trying to raise money for a 10-meter telescope, the Keck Telescope, which was going to cost a lot of money itself.

Thinking in such terms, 3 billion dollars over 15 years didn’t sound like an unreasonable thing to request, given, as it seemed to me, the importance of the project for biology, for medicine and for evolution. Plus, there was the fact that if we developed all this technology, we would then have the means to sequence all kinds of other things. Some people thought we should first do bacteria and Drosophila [flies] and so forth. In a scientific sense that was logical, but I felt from a political sense that to get the money it had to be the human genome.

Now you might say, why did I start doing this? I would say there were several threads that all came together. Back then the first genome that was ever sequenced was a bacteriophage – a virus that my lab had pioneered. We’d spent years purifying it and got the genetic map. One of my students actually went over to Sanger’s lab and showed them how to perform the process. So I was interested – and of course it is always of interest — to know the sequence. I was interested in sequencing from that point on.

Another factor was that as chancellor – and as a scientist and as a biologist for that matter – we had a good program in biology but it wasn’t what you would call a first-tier biology program. I wanted to think of some way to put it in that category.

In astronomy, we had one of the two or three best programs in the country, if not the world. Other programs were also first-rate. The biology program at the time was good, but not quite up there with the others. So I started thinking of how I could jumpstart it. That takes money.

So I had this idea that maybe we could set up an institute for human genome sequencing. I didn’t think we could do the whole thing, but with an institute with an endowment, we could play a leading role. But that still takes money, so I’d really better be sure we can do this.

That’s when I convened this meeting. And then after the meeting I did try to raise the money from other sources, private sources, and obviously was unsuccessful. But the idea took hold.

It did raise a lot of opposition among biologists for two reasons. One, they were scared that this would be the beginning of “big science” in biology and our little cottage industry of a few students and one faculty member was doomed to be overwhelmed, which has partly come true. They were also afraid that if we got this project going that it could take money away from the things they were already doing. We tried to persuade them that this would not be the case. Usually you could get this as an add-on.

Then interestingly enough, the Department of Energy took it up. I wasn’t too involved with that at the beginning. DOE had a biology program starting at the end of World War II that was primarily concerned with the biological effects of radiation. But frankly that had been done. There wasn’t a lot more to learn and so I think they were looking for something to do. So they latched onto this. I was actually on one of their committees that drew up the program for them.

Then when DOE started to do it, then the National Institute of Health said, ‘we’ve got to do this – we’re biomedical.’ So they got involved. The two of them persuaded Congress to pursue it. As you know DOE and NIH got Jim Watson to be the first head of it, but he left because he didn’t get to do everything his way. Then they got Frances Collins, who’s been superb.

So what do you think of the Human Genome Project now that the first draft is finished, having been there at the beginning?

Well it is a draft. It’s sort of finished in quotes because, while they do have practically all the sequence, there’s another process you have to do called annotation. This is identifying where exactly are all the genes, and what should we say about what they do? That’s only about half done.

It got pushed up, as you know, because of competition from Celera. And I have to say that is something that I never ever thought about, that there’d be a private industry that wanted to make money out of this. That is something that never occurred to me. It’s there, but it’s something I never thought of.

I do object to the idea that you can patent genes. To me that doesn’t make a lot of sense. The gene is there. If you change it or at least tie some function to it, maybe that makes sense. But there has to be some utility, not just trying to patent something that already exists.

But I think it’s great and I think there’s no doubt that having this information can go a long way. You can use DNA sequencing to get much better clues about evolution. And having genome data and the ability to do human genomes, you can use this data to look for individual variations.

You and I are about 99.9 percent the same. We differ in about 0.1 percent, but that’s still 30 million bases. So if you look throughout the population, you find that there are a lot of places where people differ by a single base.

Then you can begin to try and correlate these with various genetic diseases. There are some that are more complicated like heart disease or diabetes, but I think it’s going to really pay off.

We’re learning a lot about finding a lot of genes. A lot of our genes are not much changed from what they were in Drosophila or the roundworm. After all we still have to have cell division and a lot of the same functions. Evolution proceeds through changes in development. We ‘re trying to figure out what those changes were.

I think some of the most interesting things will come when we look at some of the higher primates. We’re only about one percent different than the chimpanzee and yet look at them. There are a lot of important differences – or at least that we think are important. We can start to make some sense out of some of them.

You’ve been a serious proponent of scientists for social responsibility. What about the Ethical, Legal and Social Implications Commission of the Human Genome Project? Is it all you’d hoped for?

I think it’s a good idea, but no. I’d have to say it’s too low-key. I can’t say it’s had a lot of reach. I see things coming up now like stem cells and cloning. Strictly speaking it’s not ELSI, but I wish they could have been in there ahead of the game.

I think it has come up with some good reports. It’s given some thought to some of the major questions. There are complicated issues to get into, even aside from things like cloning which involves a whole mess of social and ethical views. There are things like genetic counseling and what you can tell people and relatives of people. I think ELSI has put out some useful material and suggestions.

If you had decided not to be a biologist, what would you have done?

I chose the best profession. There can only be second best. I chose this a long time ago and it’s been a golden age for biology. We’ve made more progress in the last few decades than in all of previous history. Before I thought about becoming a biologist I thought about becoming a physicist, though.

What are you working on at the moment?

Well I’ve been working in Mike Mahan’s group. Basically we’re trying to use our knowledge of microbial genetics to produce vaccines. It’s interesting because it’s a field that sort of languished for years because we had antibiotics and people thought we didn’t need anything else. But as you know, bacteria are becoming resistant to all of our antibiotics.

In Mahan’s lab they discovered a particular gene, which in turn serves as a control for other genes that are involved in infections. So by turning this off, you make the bacteria non-infective. But it is still able to be a very good immunogen. So right off you have the makings of a vaccine. We still have a lot to learn about what genes are being turned off and what they do during the infective process and so on. That’s what I’m trying to work on.

I should also point out that we’re also trying to exploit the use of bacteria as a platform. Obviously it has the ability to get into the immune system where it’s a very potent immunogen without producing toxic side effects. Well, we think that’s great because maybe we can put other kinds of antigens onto that – say for viruses –not the whole virus but the antigen. If that would produce an immune response, it might produce an immunity to that virus. In other words we’re using it as a platform for other antigens. And that seems to be doable. It opens up a lot of potential for future research.

What is the most interesting thing in biology today?

The potential for learning how the central nervous system works is beginning to take shape. If you’d asked me 10 or 15 years ago I would have said it’s a great field, but I don’t know how we’re going to crack it. But I do think it’s coming together.