A decade ago, an international research team completed an ambitious effort to read the 3 billion letters of genetic information found in every human cell. The program, known as the Human Genome Project, provided the blueprint for human life, an achievement that has been compared to landing a man on the moon.
Dr. Eric D. Green was involved from the very beginning, refining some of the key technologies used in the project. At that time, he was a postdoctoral fellow and a resident in pathology at Washington University in St. Louis. He carved out his 5 percent of the genome, focusing on the mapping of the DNA of chromosome 7. Today, Green is the director of the National Human Genome Research Institute, which advances the understanding of the human genome through genomics research.
Let’s go back to the mid to late 1980s, when the idea for the Human Genome Project was first conceived. What was the motivation at the time?
It depends who you ask. Different people had different motivations. Keep in mind that the ’70s and early ’80s were the molecular biology revolution era. There were significant advances in methods that allowed us to isolate and study DNA in the laboratory.
In the U.S., for example, the Department of Energy got very interested in the notion of studying the genome because of interest in mutation, and the mutation process associated with some forms of energy, such as nuclear energy.
If you go to places like the National Institutes of Health, or you look at biomedical researchers and health-related researchers, they were very interested in being able to elucidate the genetic basis of disease. Among the many genetic diseases that were being considered, of course, was cancer.
A lot of other people across the biomedical research spectrum—even those working on model organisms, like flies and worms and yeast—recognized that if we could figure out how to comprehensively look at complex genomes, starting with flies and worms and yeast but then working our way up to humans, it would provide foundational information for understanding how the genome worked.
There was a coalescence of lots of different ideas that, with a backdrop of having incremental but important technological advances, made it seem that, while daunting, the problem of sequencing the human genome and determining the order of 3 billion letters was feasible.
Where did the material for the genome project come from? Whose genome was it?
When the genome project started, it was still pretty piecemeal. Different people were making different collections and DNA fragments called libraries, which are just pieces of DNA cloned. They would do it from anybody: Sometimes it would be the lab head, sometimes it would be the postdoctoral fellow or the grad student. They would just grab DNA back then when there were really no implications of that.
But then, when it finally came time to make the libraries that were going to be used for sequencing the human genome by the Human Genome Project, the person that was the best person for making those libraries was a scientist who worked at Roswell Park Cancer Institute in Buffalo, New York. [The team] got informed consent from about 10 or 20 anonymous blood donors, and then picked one of those at random, and that was the person. About 60 percent of the human genome sequence generated by the Human Genome Project was from one blood donor in Buffalo, New York.
But, you know what, it doesn’t matter. If you go across the human genome sequence generated by the Human Genome Project, it is like a mosaic. You may go for a hundred thousand letters and it may be that one person, from Buffalo. It might end up being that you’ll go the next hundred thousand and it will be somebody else. And the next hundred thousand, somebody else. All that served as was a reference. And since all humans are 99.9 percent identical at the sequence level, that first sequence doesn’t have to be a real person. It can just be a hypothetical reference of a person.
Of all that information, why did you choose to focus on chromosome 7 [the human genome has 23 chromosomes]?
It was somewhat arbitrary. We wanted to pick a chromosome that wasn’t too big. We didn’t want to pick one that was too small. We knew there was going to be a lot of work, so we picked a middle-sized chromosome.
We didn’t want to pick one that had a lot of people working on it already. At that point, the most famous gene on chromosome 7 was the cystic fibrosis gene, and that was discovered in 1989. And we had actually isolated some of that region and were doing some studies in a pilot fashion.
The truth is, we picked it because it wasn’t too big, wasn’t too small and wasn’t too crowded. That was an arbitrary way to start; by the time the genome project ended, most of the studies were being done genome-wide.
How did the work change over the project’s lifetime?
The whole story of genomics is one of technology development. If you trace where the huge advances were made, every one of them were associated with surges in technology. Early in the genome project, the surge came in that we had better ways of isolating big pieces of DNA.
Smithsonian.com
