Dr. Richard K. Wilson, executive director of the Institute for Genomic Medicine at Nationwide Children’s Hospital in Columbus, Ohio, has helped drive genomic discoveries and medicine since the 1980s. He reflects on advances in molecular medicine and how interpreting genomic findings will increasingly inform diagnosis and treatment decisions.
Q. Rapid progress in genomic science has changed the way we look at the human body, health and disease. Dr. Wilson, you have been a hands-on participant, so where do you see the future going?
A. If I look at where we are now, with next-generation sequencing and other technologies, I think back to when I was sitting in a lab at Caltech in about 1988 or ’89 talking to Jim Watson. We all thought ‘How the heck are we ever going to sequence the human genome, or even bacterial genomes, when the technology isn’t there?’ It took two days just to sequence 16 samples. But we had this idea where sequencing could eventually go – it was just a question of pushing the technology. Flash forward to today: we’ve seen wave after wave of improvements, greatly reducing the cost and expanding what sequencing can do. That progress makes it easier to envision the future. These changes will have a tremendous impact on medicine and patients.
Q. For example?
A. So I have this iPhone in my hand. I can envision some sort of device, about the size of my thumb, that plugs into the port on my iPhone that basically could take a drop of blood and sequence a human genome in relatively quick order, connect to a server and give me not only an analysis but an interpretation. It might tell us about a mutation in a particular gene and, based on the literature, we would know that the disease phenotype is likely going to be this, so a great course of treatment would be that. When we have that kind of incredibly fast, comprehensive and inexpensive technology, we’ll be able to sequence the genomes of newborns routinely, and we’ll be able to predict diseases on a relative schedule. As children mature into adults, physicians will know better how to care for each individual.
Q. Do you think we’re moving toward sequencing the genome of every newborn?
A. I see no reason why that can’t happen, short of simply not presently having available funds to develop the technology. Today, when every child is born they get a little “heel stick.” The hospital takes a little blood from their heel, and a small bevy of tests is run on those newborns. If the tests indicate a disorder, the pediatrician gives the parents special instructions to prevent or deal with that disorder. More and more, these are not simple biochemical tests but also look at DNA – we check for maybe 50 different heritable disorders. Once the cost goes down and we have the ability to interpret the information and pass it to physicians in an understandable manner, you could envision whole genome sequencing for every child.
Q. When do you think this will come about?
A. I think we’re still years from sequencing newborns in a widespread manner, but the technology is in hand. It’s a question of how to lower the cost and improve our ability to scale it up. Right now at Nationwide Children’s, we perform exome sequencing on selected patients and both parents. It takes a couple of months to get the interpretation – that’s too slow. It also costs about $8,000 per family. So we need to improve the technology, but we can do that. The tougher question that’s going to limit how quickly this becomes routine is the healthcare funding picture.
Q. So do you think everyone, ultimately, should have their genome sequenced?
A. At this point, I feel strongly that the only good reason for a healthy adult to be sequenced is cancer – if I had a cancer diagnosis, I would definitely have my genome sequenced. But right now, sequencing isn’t going to tell a healthy adult all that much they can use in their personal healthcare management. It would be a different story for newborns. When we have comprehensive newborn sequencing, we would pick up clues from the genome that will provide advance warnings, some of which would be actionable. For patients who won’t show symptoms until years later, these early clues could enable an intervention before a disease develops. I think we’ll get there at some point.
Q. How would you explain the potential of genomic information to a lay person?
A. I think of our genomes as sort of a human operating system, and a gene as a bit of code within that system, which might be specific to a function in a cell or a disease. You and I use computers to write, check email, read the news – and we never think about the program code that underlies what we do with Windows or Mac OS. Our genome sequence is similar to the operating system that allows us to use a computer, and when it’s bug-free, it allows us to be well. If something goes wrong, if there’s a bug in the code, we may develop a disease. The cool thing is that, both for the computer and the genome, there are ways to de-bug. Once you’ve found the root of an error, which is what genome sequencing allows, quite often you can address it. Of course, it does take an experienced person with special skills to do that.
Q. Are doctors ready? How do you see the use of genomic information evolving in healthcare?
A. Clearly, as the role of genomics is growing, so too the training of doctors in molecular medicine. Many oncologists already understand that genomic testing provides one more very useful insight into a patient’s disease. To diagnose a cancer patient, often there is a biopsy and cells are examined under the microscope. Examination determines the patient’s physical condition, if they’re relatively healthy and strong, or older with a lot of complications. Beyond these standard tests and examinations, genetic test results are seen by the physician as an additional piece of information to help determine the best treatment. A mutation in a particular gene can indicate that the patient is a good candidate for a targeted therapy. In the future, interpretation of genomic findings will increasingly inform diagnosis and decision-making on treatments.
Q. Cancer seems to be where many applications are now. Why is that?
A. Cancer has been the low-hanging fruit for a couple of reasons. The first is that every cancer patient is essentially their own built-in control experiment. Starting with their biopsy sample, we extract DNA from tumor cells. We also extract some DNA from their normal body cells, maybe from blood. Then we sequence and compare both tumor and normal genomes. You look for the differences – mutations – that occurred in the tumor genome. And boom, maybe you’ve found the tumor’s Achille’s heel. This has become relatively straightforward. The other thing is that, you know, it’s cancer. If the standard of care treatments haven’t worked for a patient and they are likely to have a very poor outcome, it often makes sense to pull out all the stops and see what you can come up with to treat them. So we have seen a lot of discovery and applications in cancer, and work continues on using this information to get better and better in decision-making on treatment.
Q. What’s next in drug development based on genomic information?
A. When we first started sequencing cancer patients, I naively thought we were going to find mutations in certain cancer-causing genes, many of which would be new targets for drug development. Then we would wait 10 or 15 years for new drugs to be developed, brought through clinical trials and regulatory approvals before patients received the drugs. And this is clearly happening, which is terrific. What I didn’t realize at the time is that discoveries in cancer genomics would also teach us how to better use drugs that were already approved and simply in need of finding the right patients. That was and continues to be a big role for genomics. For example, when Iressa was first tested, it wasn’t very effective for most lung cancer patients. But a fraction of those patients experienced an amazing response – their tumors virtually melted away. About this time, we sequenced several patients who happened to be enrolled in a clinical trial for Iressa. In nearly every patient who responded to the treatment, we found an EGFR mutation. So the answer was in their genomes – if you’re a patient with that particular mutation, this is the drug for you. That was eye-opening. People started thinking about how we might be able to use the mutational profile of cancer genomes to better treat patients.
Q. And now people are looking for genetic mutations across all kinds of cancer?
A. Yes. And a big lesson of cancer genomics studies is that it doesn’t matter so much what organ in the body a tumor arises from, but what its genetic profile is. For example,
we had an adult acute leukemia patient who had been through a bone marrow transplant, had two relapses and was in pretty bad shape, so we sequenced his genome. We found a mutation in a gene called FLT3, for which there was a drug that probably was a good candidate for him to try. Unfortunately, the drug was only approved for use in kidney cancer. His insurance company wouldn’t pay for treatment, and the manufacturer wouldn’t give him the drug on compassionate use. Friends collected donations, over $10,000, so he could have treatment. His cancer quickly went into remission, and it’s been almost six years now that the patient has been cancer-free. So a powerful application that genome sequencing brings to the table is knowing how to better use drugs we currently have, and that will continue to expand.
Q. How does a doctor use sequencing data? What does the doctor need to help a patient?
A. Interpretation is the key. Most physicians are not going to know what to do with a result where you say, “Hey, your cancer patient has a P53 mutation, but no mutation in RAS.” There are physicians who do know what to do when they hear something like that, but what most would prefer to hear is, “Your patient has an EGFR mutation, and there are studies that show Drug X and Drug Y are good candidates for treating patients with those types of mutations. Also, the patient did not have a RAS mutation, so there’s not any sort of contraindication to treating with an EGFR inhibitor.” In other words, most of them want to get a genomics report that’s similar to what they get in a histopathology report – the findings, what they mean based on the literature, and a recommendation on how to turn this finding into treatment. Faster and better interpretation is an area where we really need to focus.
Q. What’s next in healthcare applications of sequencing?
A. Many diseases have genetic influences, either inherited or developed during life. There are as many potential applications as we have disorders. What we’ve started doing at Nationwide Children’s is sequencing kids who have some sort of unexplained condition or disease, because these are difficult to treat without a better understanding. If you can find a potential causative variant in a gene, or multiple variants, you begin to take away the unexplained, and you may be able to treat that condition or at least provide helpful counseling to the family.
Q. You have contributed to many milestones. Do you have a philosophy about what enables us to achieve breakthroughs?
A. I’m not sure I can put my finger on it. I’ve been fortunate because I’ve been in the right place, the right situation, a bunch of times and that’s worked out really well. Now, I do feel I had a prepared mind and, as Pasteur said, “Fortune favors a prepared mind.” I was fortunate to meet the right people on several occasions – Bruce Roe who had just spent his sabbatical in Fred Sanger’s lab and brought back those sequencing methods, Lee Hood at Caltech who developed so many new technologies, Jim Watson and others. You have to be in the right place at the right time, but you also need to have some vision and a pretty good idea of how to take the first steps. That combination leads to breakthroughs .
Q. What about funding for research? Are we about where we should be?
A. We’re not anywhere near where we should be. Right now we’re in a terrifying situation in the United States with regard to the level of federal research funding, and we haven’t been where we need to be for years. There was a period during the Clinton years in which a bipartisan decision was made to double the NIH [National Institutes of Health] budget. And that allowed an explosion of research, including much of the work in cancer genomics that has taken us so far down the road to better treatments. The reason we completed the Human Genome Project in the 2000s and applied genomic technologies to many diseases was because of the research budget that funded so much fundamental work. That budget has declined in recent years and, as a result, discoveries have started to fall off now. There is a lot of amazing stuff we can do – so much that will translate into better outcomes for patients. To not be doing the kind of research we could be doing, and making discoveries for patients, it’s just wrong.
Q. And as sequencing for clinical diagnosis expands, is funding available?
A. Right now it’s difficult to get insurance companies to reimburse for sequencing-based assays. Test costs are relatively high – though not as expensive as an MRI, for example – and insurance companies have a lot of competing costs. I would argue that if you sequence the genome of a leukemia patient, for example, the cost of sequencing pales in comparison to the cost of a bone marrow transplant, hospitalization, and potential lifelong treatment to manage immune response. If you had sequenced that patient, you may have found that they likely would have responded to a targeted therapy, and that a costly and dangerous transplant was not really indicated. We need to develop a better understanding of the value of testing relative to treatment so that insurers might realize the benefits of genome-based testing.
Q. In your career in genomics, is there a single most gratifying project you worked on?
A. I feel like our original work on AML, acute myeloid leukemia, was particularly important because it showed very clearly how genomics represented a powerful new approach to understanding the biology of a deadly disease. That work started to make a difference in how everyone looked at the application of genomics to cancer. So that’s pretty satisfying. And then being able to move a lot of that work into the clinic. These days, the most exciting thing for me is not just to publish another paper or get a grant, but to be able to say, “Hey, here’s another story about a patient whose genome we sequenced, and they’re alive now and probably wouldn’t have been if we hadn’t been able to do that.” That’s a game-changer. It’s hard to not feel fulfilled.
July 2017
