Drawing the Human Blueprint

Molecular biologist Leroy Hood has set out to solve 3 billion mysteries: mankind's genetic code. INTERVIEW

IT looks like something you'd find in a high-school science lab: a two-foot-tall model of a strand of DNA made of wooden balls painted red, white, and blue. It stands beside the desk in Leroy E. Hood's office here at the California Institute of Technology - where, for that matter, the athletic-looking Professor Hood, dressed for work in a short-sleeved plaid shirt and khaki slacks, could well be your classic high-school biology teacher. And that's just fine with Hood, a molecular biologist who is a leading researcher in the race to chart humanity's genetic blueprint. ``I got into science because of three superb high-school teachers,'' he says. That was in Shelby, Montana, where his graduating class had 40 students.

One of the teachers, who taught math, had planned to go to medical school but ``got so entranced with teaching that he stayed in [Shelby] the rest of his life.'' Another was a ``spinster social studies teacher who had been around for 30 years and had seen everything.'' The third, a former Navy meteorologist who had gone to Caltech, taught chemistry and biology.

``My senior year I helped him teach the biology course, and I did it by reading Scientific American and giving lectures on current topics,'' he says. ``My father was an electrical engineer, and both my parents had degrees,'' he recalls, adding that it was expected that he, too, would go on to college. When he went on to undergraduate work at Caltech - as a National Merit Scholar and as Montana's first Westinghouse Science Talent Search winner - he had already chosen biology as his field. But it was not until his first year in medical school at Johns Hopkins University - where he went to learn ``all about human biology'' but with no intention of becoming a physician - that he hit upon his area of research.

Returning to Caltech to pursue a PhD, he worked with Prof. William Dreyer. It was a relationship that would significantly shape Hood's career.

``Dreyer's vision was, `If you want to change the world, go develop new tools,''' Hood recalls. Brilliant people, he adds, will always find innovative approaches to interesting problems. But ``it's the tools that set the spectrum of opportunities.''

Now, as head of a team of researchers who jokingly call themselves the Gang of 70, he spends much of his time developing the instruments that are central to genetic engineering - the highly complex protein sequencers, DNA synthesizers, and specialized computer chips that have revolutionized molecular biology. Using a technology that chemically color-codes the four different DNA components and then reads the colors with a laser beam, Hood and his colleagues are beginning to unravel the precise sequence of the 3 billion nucleotides (the building blocks of genes) that make up the human genome, or genetic ``blueprint.''

His work has also forced him to become a generalist. Knowing a lot about biology and instrumentation, he has had to learn about computers, about the ethical issues involved in genetic engineering, and about the organization and management of the businesses that now sell the instruments he is designing. And that, he says, has brought him to the edge of the three great problems in molecular biology that will be resolved over the next two decades. The first, he says, is to unravel the human genome, ``so that we have a book that has all the information that's responsible for constructing a man. That's going to take 15 years to do.''

The second, he says, is the ``enormous intellectual challenge'' of understanding what this book is saying. ``It's like being given a book on atomic physics: You can read through it, you can understand a few words here and there, but you don't know what that paragraph means, you don't know what the chapter is trying to say. In a sense, the hardware for making a man is 23 pairs of chromosomes. But what's the nature of the software that actually takes that material and constructs a man? How do you go from a single fertilized egg to the 1014th [ this number is ten to the fourteenth power ] cells that construct you? It's perhaps the most fundamental problem in modern biology.''

The third ``global issue'' in biology, he says, has to do with the way proteins are made. A protein, he explains, is a linear string made up of 20 different subunits. ``It folds into a three-dimensional machine,'' he says, ``and each machine does a different kind of thing. What are the rules for folding up a particular sequence of these subunits to get a three-dimensional structure? In fact, of the 100,000 proteins you can make, we don't fully understand how one of them works at this point.''

Beyond that, says Hood, lie some issues that range far beyond molecular biology into ``broader questions of interaction and communication.'' Scientists have found, for example, that the nervous system can cause a secretion of hormones that interfere with the immune system. ``So worry and stress quite clearly can make the immune system less effective,'' he says. ``One of the real challenges is to understand all of these linkages.''

What's not on the table - at least not now - is the creation of life in the lab. ``The idea of being able to build something that's living is so far in the future that we can't even imagine it. The human qualities of intelligence and emotional stability and physical attractiveness - these are multigenic traits, and we haven't got the faintest idea how they are all put together.''

But what will happen in the next 15 to 20 years, says Hood, is the ability to determine ``just exactly what your probabilities are for any one of a number of diseases'' - along with the ability to remove the cells that cause the problems. ``So the whole focus of medicine is going to change from contemporary medicine - where you get sick and we make you better, hopefully - to a medicine that keeps you well all the time. We'll design preventive medicine that will never let you get sick.'' It won't, however, keep people from aging, which is so complex an issue that it will be ``the last of the problems solved.''

So what would Hood say about a career in science to young students today? ``That's a really complicated question,'' he muses. ``Science is a tough discipline these days, because of the funding and the competition. So the first thing I generally advise students is, `You have to be good, and you have to have a real confidence in yourself. And you have to have a real vision that somehow this is what you want to do.'

``Part of being good is having the drive, part is the intellect, part is the vision - and people have them in different dimensions. I think the most important thing is intellectual curiosity. You have to be fundamentally excited about solving problems.

``Now, if you've got those things, then it's an opportunity like no other you can imagine. I really do my work as an avocation. I work as hard as anyone in the lab, and I don't begrudge the long hours, because in all its different dimensions it's always exciting, and you're learning things, and it's changing. I'm as excited about things I'm doing now as I was when I was a graduate student.''

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