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October 25, 2000:

Of Genetics, race, and evolution
What the director of Princeton's new institute for genomics has to say

One of the newest and most important initiatives at Princeton is a new genomics center, where new scientific approaches to biology are going to happen, according to Shirley M. Tilghman, the director of the Lewis-Sigler Institute for Integrative Genomics.

"Biology is going to make a transition from being a data-poor science to being a data-rich science," Tilghman said. "We can now ask questions about living systems that we could never ask before because we just didn't have enough information." She added that biologists have been functioning for the last 25 years by taking things apart and studying each of the parts individually. "And now we sort of have a sense that we are at the brink of being able to put the pieces back together."

Tilghman, who has been at Princeton 14 years, said that the center has been up and running for 18 months, and a new building, designed by Rafael Viñoly (who also designed Princeton Stadium) is in the works.

In addition to research activities at the institute, new undergraduate courses will be offered.

"There should be a major impact on the curriculum as a result of the activities in this institute. And not just in biology, but in physics, in chemistry, and in computer science, because all of these sciences are going to impinge on the way in which we go about answering the question of how all the pieces we've been studying individually work together," Tilghman says.

Another thrust of the institute will be various symposia. Last year bioinformatics was the focus of one such gathering - taking a look at the intersection between biology and computer science. This fall, another took place that looked at the question of how chemists are coming at the problems in biology. Another one, called from Physics to Biology, did the same for physicists.

With the symposia, Tilghman said, "we're trying to create the discussions and the dialogues and the interfaces that will become reality once the building is completed in two years. The other thing I'm very happy to say is that we have forged alliances with the Center for Human Values, and in particular with Peter Singer."

This alliance with Singer yielded another gathering. Two speakers came to campus the beginning of October to talk about the genetics of violent behavior, an interesting issue from a scientific perspective but one which also has major bioethical implications, said Tilghman.

Human genome project

The latest big news in the field of genomics was splashed across all the newspapers across the country a few months ago: the decoding of the human genome.

When asked how Princeton fits in with the human genome project, Tilghman, who for the last several years has chaired the External Advisory Committee at the National Institutes of Health that has overseen both mouse and human genome sequences, smiled. "I actually spend a lot of my time thinking about how the federal project is going. The sequencing is being done in highly specialized centers, at five large institutions across the world as well as in the few smaller centers. But we always made it clear as we thought about the Institute here at Princeton that the Institute was not going to actually sequence. What the Institute was going to do was to essentially take advantage of the sequence and to move forward at how do we use this sequence to understand new things about biology."

Now that pretty much all the parts of the human genome have been identified, the next step is what is called annotation, or figuring out what the parts do. Tilghman keeps a ready metaphor for the nonscientist.

"Think of it as a kid with a radio. What biologists have been doing is what the kid does when he or she takes a radio apart. The genome project has identified all the parts. We can say with some confidence that yeast has 6,000 genes, in other words, there are 6,000 products that go into making a yeast cell a yeast cell. The number for human is still being hotly debated. It could be as small as 40,000, it could be as large as a 100,000. Someplace in that range. Now what the genome project has done has at least given us a chemical identity of those parts. But that's different than knowing what each part does.

"So it's just like the kid who has all the parts on the table, and the kid's looking at this and saying 'Well, this part you know looks like a screw, and I guess it is a screw. But this part, I've never seen anything that looks like this part. What does this part do?' And that's where we are today in the year 2000. We have all these parts on the table. Some of them we know a great deal about because we've been studying them for 25 years. But actually a shocking percentage of them we don't know anything about what they do. We just know they're there."

Figuring out what the parts do will be one of the thrusts of the research at the Institute. One way to go about it is to make a mutation in the gene and then see what goes wrong when that gene isn't working. Scientists then deduce what the function of that gene is.

"Genetics is a great tool, but not a perfect tool," Tilghman said. For instance, in the mouse genome, which is her particular area of research, she studies a gene that if mutated completely deletes the gene. "Nothing bad happens to the mouse. Now that is a conundrum because this gene is in all mammals. It is highly conserved. Evolution wants that gene there. And yet when we take it away nothing happens. It could be that it so important that there's another gene that will compensate. It's a back-up. So that's why genetics isn't a perfect tool."

Another tool is biochemistry, where scientists can purify the product of the gene and then try and understand what it's biochemical property is.

But Tilghman hopes that at the Institute, some of the research will be broader. One of the newest researchers at the institute is Saeed Tavazoie, who approaches the annotation in this way. As Tilghman explains, " The idea is to say, 'Let's see if we can take all of the genes and figure out what they do, what each one does, but do it in a sort of multiplexed way. So that we can actually get the answers to a lot of genes at once instead of one gene at a time.'"

But the Institute is really going to go further. "We're going to try and pretend that all that annotation has happened. And we're going to say, 'Now that all the parts have labels and all the labels are meaningful, how can we use that information to know the logic behind a cell responds to its environment. We know that a cell has to respond to many, many signals in its environment, and we study them by studying them one at a time. But we've never asked in totality how does the cell respond to them all at once. Because that's what happens in real life. So we're trying to actually jump beyond where the science is right now and anticipate what the key problems are going to be in five years.'"

Once the genome is understood, it is absolutely irrefutable that it will lead to practical, clinical, and disease prevention discoveries, said Tilghman.

Racial differences on the genetic level

Another realization coming from the genome project might have a profound effect on social understanding. "From a scientific perspective," Tilghman said, "there is no such thing as race. You cannot scientifically distinguish a race of people genetically from a different race of people. Now you can find a gene that affects skin color, and you can show that this gene has one form in people of African descent and is different form of people, let's say , of Danish descent. But that's just one little change. That doesn't make them a race. If you look at all the other things in their DNA that determine all the ways in which we're the same, in fact the two DNAs are indistinguishable.

So it seems that there is only one race: the human race. "There are variants," Tilghman said, "and the variants we pay more attention to are the variants that are visible to us. But in fact the variants that probably matter much more than whether your skin is black or your skin is white are variants that predispose you to breast cancer. And those occur in all populations; variants that predispose you to heart disease; variants that predispose you to Alzheimer's disease. And those do not track by race. So the important ones are not the visible ones."

And where does that leave evolution?

Another area in which scientists find confirmation on the genetic level is the area of evolution. When asked if Tilghman believes in the theory of evolution. She smiled again and nodded emphatically. "Oh yeah. I'm a scientist, so I spend my life evaluating information and asking whether that information supports or doesn't support various models. If one looks at the question of evolution, in my opinion, the evidence is overwhelming. Most people who've looked at it objectively believe that that's the case.

And how does a scientist answer the question of how did life start? Tilghman said, "Well, I'm an atheist. So I look for scientific explanations, and I think that we don't have a definitive answer to that question as scientists . What we have is now I think a reasonable idea of what the conditions on earth were at the time when the first biological molecules were arising, were appearing. We don't know the order in which those molecules appeared, and in fact that's a very contentious field right now in early evolution. There are people who favor the idea that the first molecules were RNA-like. There are people who believe the first molecules were protein-like. Both can sort of show you experiments that would argue in favor of their particular idea. How it really happened we don't yet I think have a clear idea, and yet I think the fact that we can create these molecules in test tubes that mimic those conditions tells us it's plausible that that in fact is how life evolved. It's a fascinating problem."

By Lolly O'Brien

For more information: http://www.genomics.princeton.edu