“That’s it!” exclaims Dr. Richard Wilson, director of Washington University’s Genome Center and professor of genetics, jabbing his index finger at a piece of paper containing a strange pattern of dots.
Standing inside Wilson’s office, Dr. Timothy Ley (prounounced “lay”)—hematologist and Wash. U. professor of medicine and genetics—nods in agreement. The two believe a hunch has paid off—though they remain mum for the moment about what it all means.
This much they’ll admit: The breakthrough pertains to their much-lauded effort to sequence the genomes of cancer patients with acute myelogenous leukemia (AML). Last fall, after decoding a cancer patient’s entire DNA for the first time ever, their team published the groundbreaking study in Nature. Using a big-picture approach called whole-genome sequencing, they examined the patient’s entire genome, rather than looking at just one specific section as with previous research. What they found was remarkable: eight new mutations never foreseen.
The possibilities of whole-genome sequencing immediately set the scientific world abuzz. “It will result in a revolution in medicine that I believe will only be matched by the discovery of antibiotics,” Dr. Francis Collins, former director of the Washington, D.C.–based National Human Genome Research Institute, told the CBS Evening News.
Today, the tests continue as Wilson and Ley, along with a team of other St. Louis scientists, search for clues to the cancer’s origins.
When you started out, there was a lot of resistance to the idea of whole-genome sequencing, partly because it’s so costly and time-consuming.
Wilson: We feel that at the time we were grouped with such luminaries as Columbus and Marconi, before they made their discoveries. [They laugh.]
Ley: It was out there, let’s put it that way. People wanted us to prove it before they would give us money to do more. It took one man [Alvin J. Siteman] who had faith in us and in the idea.
Now it’s affecting the entire approach to cancer research.
Wilson: It’s changing the paradigm. We used to think about focusing on individual genes. It was relatively straightforward to study one gene in a large number of patients. But cancer is not a one-gene disease, so that’s never going to pan out. The conference call I was just on, we were talking about what several hundred cancer genomes we ought to sequence next year. Not only is the magnitude of this approach increasing with the number of people, but so is the value the community puts on using that approach.
Why start with AML?
Ley: There were many reasons. The clinical reason is because the tissue’s easily accessible, and we knew that we were looking for genetic classification tools for our patients. For many years, we’ve looked at AML patients’ chromosomes and cancer cells, and it has a huge impact on how we take care of them…It’s not that you see far, it’s that you stand on the shoulders of giants.
After studying the first AML patient, you found 10 mutations. Only two were previously known. What was your initial reaction?
Wilson: Did you hear what I said earlier? It was kind of like that. Scientists don’t really say, “Eureka!” They say, “Holy cow!”
Ley: We were relieved, I think, in one sense that there was such a low number. The greatest fear we all had was that there would be thousands of mutations and that figuring out what was important and what were bystander mutations would be an impossible task. That’s where the whole scientific community was kind of holding its breath. When we found such a small number, it was kind of vindication.
It appears that this is the tip of the iceberg. The disease seems to be incredibly individualized and genetically diverse. Is that discouraging?
Ley: The fact that [the mutations] are not more highly recurrent makes it more challenging. But if you think about the disease and the heterogeneity in the patients, it makes a lot of sense. There are a lot of recurrent mutations. What we’re looking at this morning is that a new recurrent mutation we just found is doing something important to the cell. We’re already finding new recurrent mutations in this disease that no one had previously suspected.
Wilson: It’s like asking a motocross rider if he’s concerned that there are hills on the course.
Does the disease spread sequentially, somehow knowing which cells to mutate next?
Ley: It doesn’t know. It experiments. We think these cancer cells are generating mutations… The hypothesis is that each occurs sequentially, giving the [cancer] cell a little more of an advantage... If the cell is still required, it sticks around, so you have evidence that mutation occurred sometime in the past. It’s almost like a fossil or a footprint.
So what’s the next step?
Wilson: The first thing is you learn about the disease, and that takes you a long way toward how to better treat the patients. The second thing is diagnostics. What we’re getting excited about here is a gene that appears to be mutated in some AML patients, that if you knew about it from the get-go, then it might tell us the best treatment path…Way down the road, it might give you insight as to what types of drugs you could design that would be most effective against specific targets, based on what you learn from the DNA.
What’s it going to take for us to understand the disease?
Wilson: We were just on a conference call where a staff member said, “How many cancer genomes do we need to sequence for each type of cancer?” And I said, “Well, you learn a hell of a lot from one. You’re certainly gonna learn a hell of a lot more by sequencing five.”
Ley: We don’t know… I think it will be a diagnostic test, just like getting your chromosomes looked at like cancer is now. When the cost reaches some level where it’s feasible to do it for everybody, I think it’s going to be what we do for everybody.
How has the time frame changed?
Wilson: New sequencing technology allows you to parallelize the way you read sequences. The way we sequenced the human genome the first time, you could look at about 100 pieces of DNA per run of the machine. With this new technology, you can look at about 100 million pieces. Because you have that parallelization, costs are reduced substantially, as well as the time.
What’s the current cost to map a single patient’s genome?
Wilson: It’s hard to say because it’s such a moving target, and it depends on how you do the calculations. For the first AML genome, we probably spent $1.5 million to $2 million. I’m guessing the second one is going to cost about half that, and the third one is going to cost half of that. Our goal is that a year from now, the analysis of one patient’s genome—this means sequencing both their tumor genome and normal genome—is going to be about $50,000. It will go down from there.
How will this research affect patients in the future?
Wilson: I think Tim’s right when he said eventually we’re going to sequence everyone’s genomes… Just like now, there’s a simple test on every newborn to test for phenylketonuria (PKU), and if you know that the child has the disease, then the parents are given instructions about the child’s diet; if it follows that diet, then the child lives a normal life. Otherwise, it develops mental retardation… You’d eventually like to think about genome-based approaches for that sort of thing. So if you have some sort of risk for developing colon cancer, then you’d have that information and say, “Guess what? You’re lucky you get to do colonoscopies two decades before where you would do it as part of the normal actuary phase.”
What’s it been like to watch the research evolve over the past two decades?
Wilson: If you go back to the late ’80s, when people in the research community started arguing about whether it was a good idea to sequence the human genome and what we would learn, the one thing we all agreed on is that we didn’t have the technology. It’s just like when we started arguing back in the early ’60s about going to the moon. There were mixed opinions, but we agreed that we certainly couldn’t get there—we had to figure out a way to do it. So we set an audacious goal for ourselves. Same thing for the Human Genome Project.
How rewarding is it to be on the cutting edge of such life-changing research?
Ley: As a hematologist, having studied patients with this disease for a long time, it’s tough to watch. We haven’t fundamentally changed the way we’ve done things since I was in medical school—just fine-tuning, but nothing major in terms of understanding most patients with this disease. It’s pretty exciting that we’re going to have the genetic rules of this disease figured out in our lifetime. I think a lot of other cancers will follow very quickly, and it will have a huge impact on what we do clinically.
This is the second of three “Healthy Living” features SLM will publish in 2009. Have feedback about this one or suggestions for future ones? If so, email us at feedback@stlmag.com.
