Ludwig has a long history of pioneering cancer discoveries. Today, Ludwig scientists around the world are collaborating on new projects, and on ways to move breakthroughs toward the ultimate goal of patient benefit. These are some of the novel ways Ludwig researchers have teamed up to advance our understanding and control of cancer.
The pioneer: Q&A with Bert Vogelstein
Why don’t we all have cancer?
If we live long enough, we all will. It’s just a question of stochasticity. No single factor causes cancer—it’s a complex group of diseases with many possible origins. The first two that were recognized are heredity and environmental exposures such as cigarette smoke or radiation. These factors result in the mutations that drive the disease. Obesity has a very strong correlation with the development of cancer but the mechanisms are unknown. A third factor, one that actually causes most of the mutations in many cancers, is random errors during normal cell division. Every time a cell divides, approximately five new mutations occur. Most of those mutations are harmless but, occasionally, one will occur in a driver gene—a gene that can contribute to the development of cancer. It’s inexorable in the sense that our cells are dividing throughout our life so they are always making more mutations, no matter what we are exposed to, or how we live. For children, the incidence of cancer is fortunately very low, but it increases dramatically as we get older. If we live to an age of 300 years, most of us would have at least one cancer. So we’re all, in a sense, ticking time bombs.
You’ve been quoted as saying, “You should think like a science fiction writer.” What did you mean by this?
Science is about reality and understanding the universe we live in. If you ask a scientist to predict the future, they usually will not get it right. Scientists, including me, are very tethered to reality—what can be done now. We look at what seems feasible in the near future based on the technology that we know and understand. Science fiction writers, on the other hand, are not tethered to reality and are not limited to what we can do now but focus on what the future might be like. Young people who are in the formative years of their science careers can and should think like science fiction writers. I would counsel them not to think about what can be done now or the next month or even the next year or two. But to think about what might be possible several decades from now. It requires a good amount of judgment and wisdom to choose projects like this that are viable, but that’s where the real advances come from. Occasionally scientists make discoveries that were totally unanticipated and not even on the radar of most other scientists—those are the kinds of things that are worth working towards.
Why do you think early detection will change the tide of cancer research?
Early detection is a type of prevention. Primary prevention is preventing the disease from ever occurring—and in our case preventing cancers from ever occurring. Secondary prevention does not entail preventing their occurrence but rather detecting them and treating them early enough so that intervention is possible—while they are still curable. Now that we understand so much about the genetic basis of cancer, I’m optimistic we’ll make progress in early detection in the years to come. But I also think that we, as a community of those interested in cancer, need to readjust our efforts and spend more of our resources and intellectual energy on prevention and early detection.
Do you think these concepts of early detection and prevention are underappreciated by the pharmaceutical industry?
Yes. Right now, we spend an inordinate amount of our efforts developing drugs to fight metastatic disease. Such efforts are certainly critically important—because we will never prevent all cancers—but I’d like to see 40% to 50% of our efforts directed to early detection and prevention. Think about it—if cancers are detected earlier, then whatever drugs the pharmaceutical industry produces will work better on those cancers detected earlier than on those detected much later. And the duration of treatment will be longer. All societies are generally more reactive rather than proactive and our focus has been on curing cancers. There are a lot of reasons why. It’s much more dramatic to put a patient with an advanced cancer into remission than it is to prevent a cancer from ever occurring. And there are more economic incentives for developing new therapeutics than there are for developing new tests for earlier detection or new ways of prevention. The sooner we come to the realization that prevention is at least, if not more, important than therapy for reducing cancer morbidity and mortality, the sooner more advances in this area will occur.
There’s a famous story that during your internship you encountered a family with a four-year-old daughter who you diagnosed with leukemia. Why did that particular girl drive you to focus your research career on cancer?
That little girl was one of the first patients assigned to me when I was doing my internship in pediatrics. I remember very clearly when she came into the clinic on a late Friday afternoon. We did the usual diagnostic studies and it was obvious that she had leukemia from her blood smear. Her father was a mathematician and about my age. He asked me, “Why did this happen to my beautiful little girl?” I had no answer. Not only that, what he really wanted to know was, did he or his wife do anything that caused his little girl to have this horrible disease? I could not answer his question at all. At that moment, it seemed to me that answering this question would be a valuable thing to spend my life on. This was in 1974 and we knew nothing about cancer. It was like some strange beast that came from outer space and attacked people. We had no idea what the molecular underpinnings of it were. If we were to ever be able to prevent or treat cases like this in the future, so that little girls like his wouldn’t die from the disease or perhaps not even get it, then we needed to understand the disease.
Your scientific discoveries are legendary. Your group was the first to discover that P53 was a tumor suppressor. Your group found that mutations in APC underlie most colorectal cancers, created the concept of transciptomes, invented digital PCR that enabled liquid biopsies and many, many other things. What is your secret to accomplishing so much?
Part of my secret is not thinking I’ve accomplished so much. Which drives me to accomplish more. If I were satisfied with what I’ve accomplished, I probably would have accomplished less. But I’m still not satisfied because I look at the hospital right across the street from our research building and it’s still filled up with cancer patients, so I couldn’t have done that much. If I had, then that building would be devoted to patients with a different disease. The second thing is that my group, and particularly the trainees, has always been made up of careful, creative scientists who work extremely hard. The third thing is that I’ve always had a sign up on my wall that reads IT’S AMAZING HOW MUCH A PERSON CAN ACCOMPLISH IF HE OR SHE DOESN’T CARE WHO GETS THE CREDIT. Neither my research partner Ken (Kinzler) nor I really care about the credit. Not that credit is bad, but it’s less important than trying to do something important. Our end goal is not just publishing papers and making important discoveries. It’s about emptying out that hospital across the street. We’re continually trying to do new things that get us closer to that goal.
What is some advice you give to young scientists who want to join your lab?
Don’t do evolutionary research; try for revolutionary research that opens up new vistas. Evolutionary research is simply the very next obvious step. The vast majority of research today is evolutionary and that’s because it’s easier and because of all the pressures to get grants and publish. When I speak to incoming graduate students, one of the things I tell them is that you’re in graduate school because you want to set the world on fire. If you don’t want to set the world on fire, then go do something else, something easier, with less risk, that is more certain. As a scientist, you have the opportunity “to go where no one has ever gone before”.
Are you generally optimistic about the future of cancer biology—that we will be able to prevent life-threatening cancers?
Yes. Medicine shows that once you understand the disease, you’ll be able to do something about it. A deeper understanding about the genetic faults fueling tumors can lead to ways to detect them earlier. And spotting a cancer at an earlier stage means that treatment is more likely to be effective. Now it won’t come next year or maybe not even in the next decade but now that we understand so much about the genetic basis of cancer, I’m optimistic we’ll make continued progress in the years to come. There is a still huge amount to learn but we know enough so that we can begin to think about how to prevent it better and how to treat it better. So, in the long run, I am extremely optimistic.
If you were to change anything about your career, what would that be?
As you reach your 60s, you realize that you’re mortal and you don’t have an infinite amount of time left to reach your goals. Your time is limited. In terms of what I would have done differently—I would have focused more on what I consider the most important things I could accomplish. Some of the things we’ve done were important and they were successful to the extent that they were published in Nature or Science, but they weren’t necessarily the best way to spend my time. It can be very hard to focus on the one thing you can accomplish over the next decade or two. So often, you’re like that kid in the candy shop surrounded by so many wonderful flavors to choose from that it’s easier to say that one looks good, let me try that one today. The next day, you’re tempted to try a different one. I know I’ve engaged in some areas of research that were productive by metrics of publication but they probably distracted me from reaching my main goals, which are basically in prevention and developing novel therapeutics based on the genetic alterations in cancers. Now that I am getting older, virtually all my efforts are devoted to those goals.