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Sequencing the Human Genome: Transcript Part 4
Future Plans for Human Genome Sequencing:
We are now going further because we want to understand the genetic variations in the genes and regulatory genes, so we recently announced a major program to take us beyond the 5 diverse individuals that we sequenced. We are going to sequence all the genes and all the regulatory regions in 40 individuals over this next year. It is a massive program, so we are making PCR primers for every single exon and the upstream 5KB region so we will understand regulation, and the initial set is in 40 people.
This is going to give us a tremendous set where we can actually understand in a broader population, those changes in the genetic code that might have a biological function. But what I am most excited about a year from now is that we will have the tools to sequence any one of your complete gene sets in less than a week. That is a big change from the 15 to 20 year multibillion dollar program. It is a big change from the 1 year 100 million dollar program, to where we will be able to sequence all the genes in an individual.
We are getting this baseline and then we are building out with a large number of diseases on top of that. where we will be doing the entire genome scans of individuals. As the technology changes, we hope this will come down first to days, then hours and come down orders of magnitude and cost. Ten years from now...easily 10 years from now...anybody could get their genome sequenced for probably less than 10,000 dollars. That is how rapidly things are changing. A lot of people are afraid of this because of the genetic determinist out there who say well if you have this change, you will get breast cancer. It is bunk, except in the rarest cases of Mendelian genetics.
There are some exciting changes that are associated with disease susceptibility. For example with HIV, there are a number of single changes that delay the onset of AIDS, and there are others that are associated with very rapid progression and early death. One of these--in the CCR5 gene--is pretty fascinating to me because it leads to very significant resistance to HIV infection in roughly 9% of Caucasians, but only a tenth of a percent of blacks.
What does that tell us? It tells us it was a very recent evolutionary event. Some scientists at the NCI have postulated that this event was 700 years ago, because apparently this same variation in the same CCR5 gene provides resistance to yersinia pestis infections. So you can see selection at work. If you had this [variation] you would survive the plague. If you didn't have it, you would be part of the millions that died off. You can understand how something that could be a relatively rare allele at the beginning, could grow to be very abundant in the population over a relatively short period of human history. So, understanding the genetic cause and susceptibility to disease, I think, gives a wonderful opportunity to do something in unique ways about those diseases.
Several years ago out of the EST program we found, in collaboration with Burt Vogelstein, three new mismatched DNA repair enzymes. Vogelstein's lab linked these to non-polyposis colon cancer. There are no clinical assays you can get, to find out whether you have these changes that diminish the activity of your DNA repair. That won't tell you whether you will get colon cancer or not. In fact, I had to have Burt explain it to me. I said, "You know if these genes are defective in all the cells...why do you get colon cancer? Why don't you get brain cancer or liver cancer?"
He explained that colon cancer is actually an environmental disease, it is not a genetic disease. It is toxins in the colon that damage the DNA in the colon epithelial cells. Even if you have a normal repair enzyme, you can still get colon cancer from that cumulative damage. But if you can't repair the DNA as well, your chance of getting colon cancer goes up. So is that genetic or is that environmental? It is similar for most human traits and most human conditions. You know, we are not pre-programmed. We have to take into account the environment and all these other factors.
The Next Step-Characterizing Proteins:
I will close quickly by just talking about what we are doing in the protein world as understanding the next orders of magnitude of expansion. As we go to DNA to RNA to proteins, we go up probably an order of magnitude at least numerically. In terms of complexity and information it is impossible for us to estimate how many orders of magnitude it is, but it is substantial. It goes up more...We have 100 trillion cells in each of our bodies. So, to understand the possible variants you would have to take 250,000 to the 100 trillionth power to understand at least the range of possibilities of different combinations. That tells me this is not a deterministic set of information back here.
There are now new ways to measure these proteins, in fact because we have the human sequence now. We use mass spectrometry to break down and sequence proteins but earlier, before the genome, when you compared the peptides back to databases, most of them didn't match anything and you couldn't interpret the data.
We have exciting new tools now that allow us to measure these proteins very dramatically. This is the new Time of Flight mass spectrometer, developed by our sister company Applied Biosystems. We don't have a single 2D gel apparatus. We have developed all new cell and protein fractionation tools. We have one of the world's fastest cell sorters. When we get a tumor tissue in we break it down in individual cells. We then fractionate those cells. We have unique methods for isolating just the plasma membrane. We can deal with complex mixtures of 300 or so proteins at once. We don't have to have pure proteins anymore.
And so we are rapidly characterizing protein profiles with disease. We started with pancreatic cancer and lung cancer but we also have programs for colon and breast underway, where we are first taking the blood and looking for proteins that might exist in the serum that could be early diagnostic markers for those cancers.
And there are some potential candidates that we are already looking at. We also break down the tissues, as I talked about, into single cells, and characterize the protein fractions in those, both with primary tumors and in the metastases, and we already have a protein and pancreatic cancer that we are beginning to approach with a T cell vaccine approach.
But with the therapeutic company we just bought, Axis Pharmaceutical, they also have a protease inhibitor that works against that protein. We think these approaches are going to lead to much more rapid advances. Whether they [will] lead to the kind of detections and treatments we are hoping for, it is still unclear, but at least we have dramatic new information to work from.
So since 1995 we have gone from genomes, first with the microbial genomes then with insects and now with the human and mammalian genomes. Now we are characterizing the protein world because we think that is the key link between the genetic code and understanding biology and disease. We are combining all these together to try and use the same kind of automation we developed for sequencing the genome...and now the protein world...to see if we can come up with new therapies and new diagnostics much more rapidly out of this information.
Thank you very much for this honor and this attention.
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