BREAKING THE CODE

December 2, 1999
		Today, scientists announced the completion of a major step in breaking the human genetic code. The Health Unit is a partnership with the Henry J. Kaiser Family Foundation.

Focus: Internet Rx Nov. 30, 1999: Medical Errors Nov. 11, 1999: Hope for the Heart Nov. 9, 1999: What the Doctor Ordered Nov. 1, 1999: Patient Privacy Browse the NewsHour's coverage of health.   Nature University of Oklahoma National Institutes of Health	SUSAN DENTZER: For nearly a decade, scientists have been attempting to decipher the so-called book of life, the sequence of billions of molecules of DNA that constitute humans' genetic makeup. Yesterday, researchers yesterday, researchers involved in the international human genome project announced that one chapter of the book was now essentially complete. Dr. Harold Varmus, director of the National Institutes of Health, described the accomplishment. DR. HAROLD VARMUS: As this chart indicates, there are, of the 24 volumes of the human encyclopedia that we mentioned earlier, chromosome 22, volume 22, is now filled in. In each of these volumes there are many chapters that tell us profound information about essentially the entire human body plan and the diseases that affect all those organs.
	A tour de force
	SUSAN DENTZER: Scientists said they had succeeded in deciphering the basic chemical structure of one human chromosome. That's the collection of strands of DNA that is a basic genetic building block. Until they finished chromosome 22, it wasn't entirely clear that the makeup of almost an entire human chromosome could actually be decoded in this way -- the fact that it can reinforces scientists' belief that the entire book of life, the whole human genome, will be fully sequenced by 2003. Mark Patterson is a scientist and an editor of the British journal "Nature." MARK PATTERSON, Journal "Nature": The determination of a DNA Sequence of a whole human chromosome is a tour de force. It provides the first view of a complete chromosome from a completely new vantage point. It's like seeing the surface or the landscape of a new planet for the first time. SUSAN DENTZER: Human beings have 22 pairs of chromosomes and two sex chromosomes. Identical copies of these reside in almost all of the body's trillions of cells. Along these chromosomes are arranged an estimated 80,000 to 90,000 different genes. Each gene in turn is made up of particular arrangements of four chemical bases, or sub-units of DNA, commonly known by the letters "A," "C," "G," and "T." Determining how these sub-units are arranged in effect unlocks the secrets of life, since the patterns can control the formation of proteins that carry out innumerable body functions. Scientists selected chromosome number 22 for decoding in part because it is one of the smallest human chromosomes. As a result, they reasoned, its genetic sequences would be comparatively easy to decipher with the aid of the latest in gene-sequencing technology. But that still meant locating nearly 34 million different pieces of a huge jigsaw puzzle. That was roughly the number of chemical building blocks that made up the chromosome's genes. Then they had to figure out precisely how all these pieces fit together. There were important medical reasons, too, to unlock the secrets of chromosome 22. Potential defects in the genes along this chromosome are also believed to be at least partly responsible for as many as 35 different human diseases. These range from schizophrenia to leukemia. Knowing the normal structure of these genes was thus crucial to understanding where and why abnormalities occur. Other researchers looking into these diseases will now have access to all the human genome project's data about chromosome 22, which has been posted on the Internet.
	A wonderful new tool
	JIM LEHRER: And to Ray Suarez. RAY SUAREZ: One of the lead scientists on the new research joins us. Bruce Roe is professor of chemistry and biochemistry at the University of Oklahoma. Also with us is Dr. Francis Collins, who directs the National Human Genome Research Institute, part of the National Institutes of Health. Well, Dr. Collins, as the leader of the project, when you hit a milestone like this, do you stop, catch your breath, take stock or do you start on chromosome number 23 or 21? DR. FRANCIS COLLINS: Well, it's hard not to take a moment at least to experience this milestone because it is a pretty historic moment. Never before have we seen laid out in front of us the entire landscape of a human chromosome, or any mammalian chromosome, for that matter. And it does give one pause to stare at this. I have to tell you, when I looked at this entire sequence, it gave me chills. It was really a moment where you realize how far we have come, this whole sequence in front of us. Now, we have a lot of work to do. It was one of the smallest one. We want to get all of the rest of them done in the next two and a half years, maybe less, so we'd better not celebrate too long, we have to get back in the lab and keep the job going. RAY SUAREZ: Professor Roe, I know I'm supposed to be excited about this but I'm not sure why. Maybe you could break it down for us and tell us what this wonderful new tool can help us do. BRUCE ROE: Well, this wonderful new tool actually tells us the location of roughly 700 or 800 genes on the chromosome and it tells us some of the landmark features of the chromosome -- the regions that are involved this deleting segment segments of the chromosome that cause genetic diseases, the regions that map for cancer genes, that regions that have various genes for mental retardation. Now that we know what the structure of the complete chromosome is, we can go about pinpointing many, many more of the genes that are involved with diseases. It's interesting that there are almost 40 different genetic diseases that have been found on human chromosome 22 or related to chromosome 22, and of those, we only know about two-thirds of what -- the actual point on the chromosome that's altered during that genetic disease. We know that many diseases map within a million units of one gene or another that cause a disease, but now that we have this complete blueprint, the complete sequence in front of us, those scientists that are interested in these diseases in determining what the features are that cause those disease can then go and look directly at those genes that are on the chromosome. RAY SUAREZ: But don't you have about a billion of those letters, those C, G, A, and T's. There's an awful lot of chaff there, isn't there, along with the diseases and the clues that could help you find the things you're looking for? BRUCE ROE: But the chaff is that, that you want to call it, is, to me, the most intriguing and interesting thing. That's what creates for us our individual differences, those regions of the genome that people think of are junk DNA or something like that are really not junk but those are what allow genes to get expressed at different levels and the differences between humans, our genes are actually pretty much identical but how those genes are expressed and at what level they're expressed, that's what gives us our individual differences. RAY SUAREZ: Dr. Collins, even if you had been able to use the techniques that you've used to do this tracking, would this work have been possible before supercomputers were available? DR. FRANCIS COLLINS: Computers have been enormously helpful to this project. It's rather fortunate that the computer revolution and the genetics revolution are occurring in a nice dovetailed fashion, or we'd be having some trouble. But I will say for the real computer experts, they don't see our problems so far as all that demanding or challenging; even though it's a lot of information, it is fairly straightforward compared to, say, satellite photos that you're trying to determine the significance of. But we'll get there soon because here we have a whole human chromosome. Soon we'll have the entire human instruction book, all of the chromosomes and the genomes of other organisms as well, the mouse, for instance, the zebra fish, the fruit fly, the round worm. And doing those comparisons where you're trying to mine through this complex data set and figure out what are the nuggets of information, that will require substantial computing power and a lot of smart people as well to know how to program those computers.
	The detective story
	RAY SUAREZ: Because I'm trying to imagine three billion variables. It's like the answer that you're looking for being on one page in a million-book library. You know it's on a page, but where do you begin? DR. FRANCIS COLLINS: Well, that is part of the detective story that is modern genetics. We have this instruction book. If you printed out the whole human genome on pages-- and I don't know if we'll ever do that-- but if you did and bound it into volumes and piled them on top of each other this would be the height of the Washington Monument and one letter misspelled on one page is sufficient to cause the terrible diseases -- things like cystic fibrosis, sickle cell anemia or diabetes. And the detective work we have in front of us is to figure out how to find the misspellings that matter and figure out which of them don't matter. That is the challenge of the next few years. RAY SUAREZ: Professor Roe, this gives us what we need to know to start inquiring about making modifications but it doesn't bring us closer to being able to know what to do yet, does it? BRUCE ROE: No. I think that what this gives us is this gives us the ability to, besides discover what the actual genes are that cause some genetic diseases, it also gives us the ability to detect these genetic diseases earlier. This will help us with earlier detection of cancer and earlier detection of different forms of mental retardation and then to classify them so that we can know how to treat them and how to make life a higher quality for people who are afflicted with various genetic diseases. I don't see down the road these kinds of genetic manipulations in the very near future. I'm sure that somehow that will happen, but I think that for the present time, we're really looking for the positive aspects of early detection of diseases and then more directed treatments for those genetic-based diseases that right now many of them are intractable to treatment. DR. FRANCIS COLLINS: Let me jump in there because I think, in fact, that's what everybody's question is. Okay, so you've got this instruction book, what are you going to do with it? The things that come out of genetic research fall in a certain predictable pattern as far as the time line. As soon as you've identified a gene that's involved in a particular disorder, you then have the opportunity to figure out who's at risk, to develop a diagnostic test. In many instances, that alone can be very useful -- colon cancer, for instance. If I know I'm at risk for that because there's a glitch in my DNA in a particular gene, then I'm going to be motivated to go through that medical surveillance to pick up that first evidence, that little polyp in the colon while it's still possible to remove. And that's a curative therapy. Even though it's a diagnostic and a surveillance strategy, it works. Over the longer term, though, the real excitement and the reasons that every pharmaceutical company now has a genomics division is the absolute confidence that these gene discoveries give you a window into the inner-most workings of disease in a way that we've never had before. The blockbuster drugs of the future are all going to be built on the genome project and the insights that come out of that. RAY SUAREZ: Well, I'm glad you mentioned those pharmaceutical companies because not more than a couple of miles from here is a place called Solera Genomics which is, in effect, racing your team to complete the handbook and would like to start patenting your discoveries, while you're taking the approach that this is something that should be given to humankind over the Net and through other sources. DR. FRANCIS COLLINS: So this is a complex issue. Genomics will not reach its benefit without a vigorous partnership between universities and the private sector. We want the pharmaceutical companies and the biotechnology industry to be plunging into genomics and they are, that's great, because that's how products get developed. Where it gets more complicated is at what point along this pathway from very basic science to a product that you're going to offer to the public is it appropriate to begin to attach intellectual property constraints. The publicly funded Genome Project believes that the fundamental information about the human genome, the shared inheritance of humankind, if you will, is so basic and for the most part not very well understood that we ought to put it out there. So we do. Every 24 hours it goes up on the Internet and any scientist that wants to work with it can do so. If they get a good idea, they can run with it, and there's nothing getting in their way. On the other hand, as that gets moved into a circumstance where these discoveries turn into ideas that look like they would be pharmaceuticals, something the public needs but where patents are often important to provide an incentive to a company to do the kind of investment it takes, hundreds of millions of dollars to bring a drug to the market, then we have no problem at all with intellectual property kicking in. The argument sort of falls down to at what point along that road to discovery should you start to put up the toll booths? We believe they ought to be reserved for a fairly late step in that pathway but there are understand business plans out there and I understand the marketplace and maybe it's good we have competition here. We'll see how it turns out. The publicly funded effort aims to, by next spring, have 90 percent of the sequence in the public domain and once it's there, it's there. RAY SUAREZ: Quickly, Professor Roe, are you ready to get back to work? BRUCE ROE: I was in the lab today. It was really quite exciting. Everyone was at the bench and we collected another million bases today. Things are moving forward, and we're moving forward with new vigor because this is one of the most important projects that's ever been done in the public sector, and we need to get this data out there, as Dr. Collins said, a lot of pharmaceutical houses are anxiously awaiting our data and a lot of scientists at other universities are awaiting it. So, yes, we're back in the lab full steam ahead. RAY SUAREZ: Professor Bruce Roe, Dr. Francis Collins, thanks a lot. BRUCE ROE: Thank you. DR. FRANCIS COLLINS: Thank you.