In the early 1980s, scientists began to wonder whether, with existing technology, we could determine the sequence of the human genome, that is, the sequences in the DNA that we pass on to our children. And would we be able to interpret the language of the Genome?
As it turns out, says David Botstein, that our estimates of the cost and the duration were just about right. And so, he pondered at the February 17 Lunch ‘n Learn seminar, just what did we get for the $3B spent to determine the sequence of the human genome?
We got not only the sequence of the human but also of 1000’s of other organisms, from yeast (12 megabases) and worms (100 megabases) through humans (3,300 megabases). The sequence of the human genome, the primary goal of the Human Genome Project, was achieved just a few years ago. Because our genomes are a string of 3 billion sequences of four chemical letters in the DNA polymer, the ability to obtain genomic sequences depended on revolutionary progress not just in DNA chemistry but also on the equally revolutionary advances in speed, capacity and versatility of digital computers.
One of the original intentions was to examine the similarity among the organisms to estimate the rate of evolution. Botstein emphasized that by far the most prominent result of the determination of the sequences of many hundreds of diverse organisms is the unambiguous reality that all these organisms are related to each other by descent, as predicted by Darwin. We now have a quantitative way of depicting evolution, which Botstein argues is remarkably similar to what Darwin drew in 1837.
The intellectual impact on biology has also been immense. “Once we understand the biology of E. coli, we will understand the biology of the elephant” postulated Nobel laureate Jacques Monod, around 1960. We now know that he was correct. The top level result shows that the basic cellular functions of all of these organisms are carried out by proteins and RNAs whose structure and function have basically not changed significantly over evolutionary time. You can replace a yeast gene with a human gene without killing the yeast. Just three decades ago, discoveries about yeast would be seen as having no bearing on humans.
Says Botstein, such findings provide us with a “grand unification” of biology: Despite the obvious diversity, all the functional parts of all living things are related by lineage and the fundamental biological mechanisms must also ultimately be related.
For humans, we can use the new techniques to follow the function all the way back to the common ancestor of all living organisms, many millions of years ago. The clear conclusion is that the human species is extremely young in evolutionary terms, and originated in Africa before radiating out of Africa into the rest of the world.
Among the many more practical benefits to society provided by our knowledge of genomic sequences has been in the realms of forensics. Having settled upon a standard set of markers, the FBI today performs a huge number of DNA tests.
Says Botstein, we are also able to understand diseases that had been impenetrable, and to begin the development of effective treatments. Probably the most important medical results are the identification, through their inheritance in families, of thousands of genes that cause inherited diseases such as Retinoblastoma, Huntington’s Disease, and Amyotrophic Lateral Sclerosis. And because we have found the actual protein, says Botstein, you can find the actual mutations, and then, in another species or sometime in the human, you can figure things out.
Scientists are now able to identify genes that cause inherited predispositions to breast cancer, colon cancer, and kidney cancer. Study of how these genes cause relatively rare forms of cancer has informed our understanding of cancer generally. Another benefit of the genomic sequences is that they permit us, for the first time, to study the activities of all the genes simultaneously, using once again a combination of new DNA chemistry and computational methods.
With these methods it has become possible to study, at a comprehensive (genome-wide) level, the differences in gene activity that accompany the transformation of tissues from normal to cancerous, and to classify different subtypes of cancers by their “molecular signatures”. We now can distinguish several kinds of breast cancer, some of which are more aggressive and lethal than others, and some of which are uniquely sensitive to new classes of unusually effective drugs directed specifically at these subtypes.
One of Botstein’s colleagues, Mike Eisen, has pioneered the use of color as an effective mechanism to view masses of genome data. Colors are based on the relationship of numbers to the median. The result is the quick ability to find genes with similar functions.
The sequencing of the human genome, says Botstein, gets us a list of all the moving parts, at least if they are proteins or RNAs. The challenge for the future is to understand not just mechanisms at the individual process level (the individual moving parts), but also the interactions among all the processes and their mechanisms.
The near future, he expects, holds the promise of far better diagnoses, earlier detection of disease in blood tests, and New therapeutic targets. “All of these things are no longer speculative. They will happen.”
David Botstein is a renowned geneticist and educator and director of the Lewis-Sigler Institute for Integrative Genomics, at Princeton University. His fundamental contributions to modern genetics include the development of genetic methods for understanding biological functions and the discovery of the functions of many yeast and bacterial genes. In 1980, Botstein and three colleagues proposed a method for mapping human genes that laid the groundwork for the Human Genome Project. In the 1990s Botstein collaborated with P.O. Brown in exploiting DNA microarrays to study genome-wide gene expression patterns in yeast and in human cancers. A graduate of Harvard College who earned his doctorate from the University of Michigan, Botstein taught at the Massachusetts Institute of Technology and the Stanford University School of Medicine and was vice president for science at the Genentech prior to joining the Princeton faculty in 2003.
A podcast and the presentation are available.
