publication date: Nov. 15, 2019

Conversation with The Cancer Letter

U.S. Nobel laureates tell us what they think about cancer research, moonshots, the dark side, funding, meritocracy, herd mentality, Trump, and joy

Kaelin_Lab-web

William G. Kaelin Jr.

Sidney Farber Professor of Medicine,

Dana-Farber Cancer Institute, Brigham & Women’s Hospital, Harvard Medical School

 

Semenza-web

Gregg L. Semenza

Professor of genetic medicine,

Director of the Vascular Program, Institute for Cell Engineering, Johns Hopkins Medicine

 

William Kaelin and Gregg Semenza have a message for young scientists: do science for its own sake—and enjoy it.

“What young trainees have to understand is that, at least for those of us who love science, getting to do science is a prize in and of itself,” Kaelin, Sidney Farber professor of medicine at Dana-Farber Cancer Institute, Brigham & Women’s Hospital, and Harvard Medical School, and a Howard Hughes Medical Institute investigator, said to The Cancer Letter. “If your goal in science is simply to get prizes and to get recognition, you may be doing it for the wrong reason, and you’ll probably, frankly, wind up being a miserable person, because there’s certainly some luck involved in winning prizes.

“I think you have to take some joy in the day-to-day life of a scientist and try to do science because you love it.”

Kaelin and Semenza—and Sir Peter Ratcliffe, director for the Target Discovery Institute within the Nuffield Department of Medicine at Oxford University—were awarded the 2019 Nobel Prize in Physiology or Medicine for their discoveries of how cells sense and adapt to oxygen availability (The Cancer Letter, Oct. 11).

“It’s so important to have a job that’s exciting,” said Semenza, professor of genetic medicine, and director of the Vascular Program in the Institute for Cell Engineering at Johns Hopkins Medicine. “And a lot of people in our field, they say, ‘When are you going to retire?’ Never. Why would I want to retire?

“Of course, the greatest luck of all is if we actually are able to take something that we’ve learned and have it impact public health—and that’s of course our ultimate goal. We may or may not be successful, but we at least feel that what we’ve learned might help other scientists get to that point.”

Kaelin, Semenza, and P. James Peebles, professor emeritus and Albert Einstein Professor of Science at Princeton University, a recipient of the 2019 Nobel Prize in Physics, were honored at the Swedish Embassy in Washington, D.C. Nov. 13. They will receive the prize Dec. 10 in Stockholm.

Kaelin and Semenza said they were worried about the diminution of science in Trump’s Washington.

“If I was a young person hearing some of the nonsense coming out of Washington, I would wonder, ‘Well, does my government still believe in science, and truth, and data-driven decision-making? Are scientists the good guys anymore, or are we now suddenly the bad guys, because we’re distrustful of expertise?’” Kaelin said.

“I worry sometimes that now we’ve flipped over to the dark side, where maybe some young people think, ‘Why would I follow this path if I’m hearing, at best, mixed messages from people who make very important decisions that are going to affect my life?’”

“The appearance of a segment of society that can completely ignore facts and science, is really disturbing. It’s really very disturbing,” Semenza said. “Certain elements of the government are fostering this attitude. I think it’s very dangerous and is a real threat to our society. Hopefully, that will be addressed in the next election.”

 

Semenza and Kaelin spoke with Matthew Ong, associate editor, and Alex Carolan, a reporter, at the House of Sweden in Washington.

 

Alex Carolan:

What is your advice to the young scientists that you train?

Gregg L. Semenza:

Well, first of all, I tell people the life of a research scientist is fantastic. Unfortunately trainees they may too often hear their mentors complaining about difficulty getting grants, and it can all sound very negative. But scientific research is just a fantastic profession, because you get to follow your ideas and curiosity, wherever they lead. You get to exercise tremendous creativity. No one tells you what to do or how to do it. You make friends all over the world who share your passion for science.

It’s fantastic, and I tell people, if you can have a job that takes advantage of something you’re good at, makes you happy, and people will pay you for it, you’ve got it made. So many people have a job they do solely to support their family. They want to be done with it. That’s most of your life—your working life.

It’s so important to have a job that’s exciting. And a lot of people in our field, they say, “When are you going to retire?” Never. Why would I want to retire?

This is too much fun. That’s what trainees really need to understand — what a fantastic profession it is, and how lucky we are. Of course, the greatest luck of all is if we actually are able to take something that we’ve learned and have it impact public health—and that’s of course our ultimate goal. We may or may not be successful, but we at least feel that what we’ve learned might help other scientists get to that point.

There’s great satisfaction about that, too.

William G. Kaelin:

Well, one piece of advice I give them is to first of all, not pay too much attention to scientific prizes.

I think scientific prizes are obviously wonderful when they happen, but I think what young trainees have to understand is that, at least for those of us who love science, getting to do science is a prize in and of itself. Most people come to work because they have to put food on their table and a roof over their head.

I think, if you’re the kind of person who enjoys science as I do—I would come to work even if I didn’t need the money, because most days it feels like I’m playing rather than working—then being a scientist is a gift. I think it’s a great privilege to come to work every day where you enjoy what you do, and it’s stimulating, and it’s fun.

I ask them to ask themselves whether they enjoy doing the science itself and whether they enjoy the small steps that you take, hopefully in succession, towards making meaningful breakthroughs and discoveries. I tell them to try to ask good questions and to be rigorous in the way they do their work and interpret their data, and to take some joy at the little successes along the way and, in particular, hopefully derive joy from understanding things that have never been understood before, because that’s another prize in and of itself.

When you understand something that’s never been understood before, especially when you look at the answer, and the answer strikes you as being beautiful, or elegant, or satisfying, that’s a prize. And then, if you’re really, really lucky and those discoveries generate new knowledge that touches patients, that again is a prize in and of itself.

I try to get them to think about doing science for the right reasons and not the wrong reasons. I warn them, if your goal in science is simply to get prizes and to get recognition, you may be doing it for the wrong reason and you’ll probably, frankly, wind up being a miserable person, because there’s certainly some luck involved in winning prizes.

I think you have to take some joy in the day-to-day life of a scientist and try to do science because you love it. As I said, if that’s already a prize and if you do your work well, you’re very lucky and the stars align, you may also occasionally win prizes.

I tell them, try to get good training so they understand the mechanics of doing science, so they have a good armamentarium of techniques that they’re comfortable with, but far more important than the techniques, which you can always learn, I think is starting to develop some scientific instincts and intuition in terms of where the next great discovery might lie. Secondly, to really learn how to think clearly, critically, logically, so that you can hopefully design powerful experiments and interpret them correctly.

 

Matthew Ong:

Could you describe how your work has affected the understanding of cancer?

GS:

I would say that we occupy a minority position in the world of cancer research, because as you know, the prevailing paradigm is centered on somatic mutations in cancer cells, and understanding cancer progression simply as a matter of accumulation of mutations. Our focus is not on the changes in the DNA, but changes in the tumor microenvironment.

Again, the prevailing paradigm is: if it’s not mutated, it’s not important. It’s not a bona fide therapeutic target. But what I would argue is that the most important targets cannot be mutated. Because when you mutate something, you lock it into a state, either on or off. And something like HIF-1 has to constantly be modulated.

Because you can go a hundred microns in a tumor, and you go from lots of oxygen to no oxygen. We know that this is really important, because cancer stem cells reside in the hypoxic niche. They can slowly divide and always give rise to another cancer stem cell, but also to a more differentiated cancer cell that can divide very rapidly, but only for a limited number of divisions.

All that cell has to do is migrate 100 microns from the hypoxic region to the well-oxygenated region around the blood vessel. It can divide like crazy. We think that most advanced cancers contain regions of intratumoral hypoxia for a reason. That is to say, it’s selected for. Because there are powerful selective forces and it would certainly select cancer cells to behave in a way that did not generate hypoxia.

This is really critical to the understanding of cancer pathogenesis and therapy, because all of the existing therapies are targeting dividing cells, which are well-oxygenated cells. It’s the hypoxic cells, that are particularly resistant to those therapies. They survive the therapy, and those are the cells with stem cell properties.

We’ve also been able to show most recently that those cells have also turned on a battery of genes that allows them to evade the immune system. These are the cells with the lethal phenotype—these are the cells that kill the patients—and there are no approved therapies targeting these cells.

And that’s our mission. As I say, we’ve been swimming uphill for a long time. But we continue, and we’re more convinced than ever. Now that there is a drug in clinical trials that targets HIF-2 in kidney cancer—hopefully soon we’ll have a proof of principle. Encouraging results from a phase I trial have been published, but it only involved 50 patients. Obviously, the next 50 could be the opposite.

But it’s encouraging to see that. We’re more convinced than ever that this is something that’s really important that will actually make a difference in the treatment of advanced cancers, because, as you know, there are not many effective treatments available for advanced solid cancers.

We think that adding HIF inhibitors to existing therapies will make many of the existing therapies work better.

WK:

Well, I’m a big believer in the power of genetics, including cancer genetics. We have the advantage now, of course, that in many cancers, we know the recurrent non-random mutations that contributed to those cancers.

Even as a postdoc, where I worked on retinoblastoma gene, I came to appreciate that a particularly powerful form of human cancer genetics is to use hereditary forms of cancer, because the definitive experiment, if you will, has already been done, right? Mutation in this gene does cause cancer.

That was one of the reasons why, when I started my own laboratory, I decided to work on the VHL gene, because it was pretty clear that germline mutations in the VHL gene cause specific forms of cancer and amongst those cancers was kidney cancer.

This was important to me, because back in the ‘80s, ‘90s, I would have said that many of the molecular advances and therapeutic advances were related to cancers that were interesting, but numerically not very common. It seemed to me, if we were going to make progress on cancer mortality, we had to start tackling the big bad common epithelial cancers.

Now, I will say, there was a time when people thought that solid tumors wouldn’t succumb to molecular analysis, that they were just going to be too complicated, too heterogeneous, but fortunately, when I was a resident at Johns Hopkins, I went to a seminar that a young Bert Vogelstein gave, where he was showing that you could begin to study colon cancer using modern molecular techniques.

That planted another seed in my mind. Again, when the VHL gene was cloned in 1993, there was clear genetic evidence that it played an important role in certain cancers, including kidney cancer. I now believed that you could study solid tumors using modern molecular techniques. Very quickly, it was shown, as you would predict, that in sporadic non-hereditary kidney cancers, the VHL gene also plays a role.

Fast forward, I think we now know that VHL is a negative regulator of HIF and HIF controls a number of genes, some of which almost certainly contribute to kidney carcinogenesis, including VEGF. We did the necessity and sufficiency experiments to show, that at least in the laboratory, kidney cancers lacking VHL were critically dependent on HIF and, specifically, HIF-2. Even in the ‘90s, when we showed that VHL regulated hypoxia-inducible genes like VEGF, we started arguing to our friends in the pharmaceutical industry that if the VEGF inhibitors they were developing were going to work anywhere, they were going to work in kidney cancer.

That’s turned out to be true. I think there are about seven approved VEGF inhibitors for the treatment of kidney cancer. Of course, they’re helpful in some other cancers as well, but I think their biggest benefit amongst the solid tumors is probably kidney cancer.

It’s been very gratifying to work with Peloton Therapeutics, which was recently acquired by Merck, that’s developing direct inhibitors of HIF-2, because I think you could argue that going after the master regulator would be more efficient than tackling any single downstream target of HIF-2. The HIF-2 inhibitor looks very promising, based on the phase II data. It’s about to undergo phase III testing. At least Merck thought so too, because they purchased Peloton; right?

Less appreciated is the fact that, to their credit, Peloton also agreed to treat 51 patients with VHL disease who have never been treated before with any form of cancer medication. These are patients who have multiple small tumors. Because they have VHL disease, they’re often put in surveillance programs to try to avoid doing multiple surgeries, and so, they’ll be put in careful surveillance programs. Fifty-one of these patients have now been treated with the HIF-2 inhibitor.

I don’t think the data had been publicly presented yet, but if you look at the Facebook posts of the patients on the trial, it looks like they’re responding. This is extremely gratifying.

 

AC:

Can we talk about science policy for a moment? What do you think about the current state of federal funding for cancer? What’s good? What’s bad?

GS:

Well, I’d say what’s good is that in terms of a piece of the pie (meaning total federal research funding), it’s a pretty big piece.

What’s bad is that we could make a lot more progress if there was more. From a public health point of view, this is obviously a wise investment. Even from an economic point of view, it’s a wise investment. We know that these innovations will lead to new companies and new products.

We hope that if we can effectively treat people with cancer, that cancer care is going to be much less expensive. Because on the back end of that, there’s a whole lot of expense.

If we can prevent patients from getting to that stage, that’s going to have a really big impact on public health and how we utilize limited resources to take care of people with chronic diseases, as the population ages.

That’s one benefit of the Nobel Prize. It provides an illustration to the public of how basic science can lead to new treatments, how that process works, and why they should support it.

Because ultimately, it’s taxpayer dollars that are funding NIH, NSF and other granting agencies of the federal government that are the major sources of research funding for scientists here in the U.S.

My own opinion is that the focus should be on basic research funding, because we don’t really know what discoveries will get us to new treatments for cancer. Likening cancer research to the Apollo Moon mission, I don’t think is helpful.

We already had one war on cancer in the 70s, and now we’re just repeating this same rubric. I don’t think it’s helpful.

WK:

I haven’t looked at the numbers recently, but it has certainly felt like it’s been flat for too long. I think that creates a lot of issues, because for example, I think study sections are pretty good at saying, “This grant is in the bottom 50% versus the top 50%,” and arguably, they’re okay at saying, “This grant is in the top 20 or 30% versus in the bottom 70 or 80%.”

I think where the system breaks down is when they’re asked to say, “Is this an 8th percentile grant versus a 14th percentile grant?” Because one is going to get funded and one isn’t. I think that just puts too much stress on the peer review system and it also tells you that there’s some very good grants that aren’t being funded. I think that’s problem one.

I think problem two is, I would say, the secret sauce in American biomedical research for most of my life was saying, “Let’s let the private sector, meaning mostly the companies, fund the late-stage research and the applied research, what some people call the translational research, but let’s let the public sector, largely the federal government, fund the early-stage basic science”—the fundamental science, the mechanistic science that gets done early, because companies don’t typically invest in that early stage work, because the timelines and deliverables are too unpredictable for them, and yet, over and over, they will say that’s the one thing they count on us to do in academia, right?

They rely on that information, and often that’s where the truly transformative discoveries come in the first place. I think having the public sector, again, largely the government, pump priming and investing in that early-stage work and letting the private sector be the harvesters or the beneficiaries of that new knowledge, that was a very powerful and useful formula.

But I think now, unfortunately, more and more investigators feel pressured to justify their work in terms of its potential clinical utility or impactfulness. I think that’s sort of distorted the whole ecosystem.

Again, I tell people the next big breakthrough for pancreatic cancer might come from someone studying pancreatic cancer, but it’s just as likely, if not more likely, to come from someone either studying another cancer altogether or, frankly, someone who didn’t even think they were studying cancer, but uncovered some new basic mechanism, maybe in some model organism, just trying to learn a new piece of biology, who could then come back and say, “This was the key piece of the puzzle we were looking for,” for say, pancreatic cancer.

So, I think it’s very shortsighted to hold people to, “What are you going to do with this knowledge in the next five years?” I think we have to maintain a longer view and understand that real progress comes by generating new knowledge, and you have to have scientists be free to follow their curiosity, and follow the road where it takes them, rather than just putting blinders on them and saying, “Well, you promised us in year five you were going to be working on this, and this was going to be your deliverable.” You know, that’s the language of engineering. That’s not the language of science.

 

MO:

So, where are we in cancer research, and what are the opportunities that scientists and lawmakers should be capitalizing on at this point?

GS:

Of course, the first step is prevention. There should be more funding for prevention, because that’s really where we can have tremendous impact. Stop smoking, prevent obesity, encourage exercise. These are major factors that impact on the likelihood of developing cancer. Prevention is critical.

Early detection is another revolution that’s going to have a big impact, because if we can identify tumors when they’re still contained within the organ of origin, the chances of cure are much greater. Now, with powerful sequencing, it’s become possible to identify a few cells in the blood that carry telltale mutations that say there’s a cancer growing in a particular organ.

That’s another critical area. There are companies now that are developing these new tests. Again, those need to be tested in a strict clinical way, and we have to be very careful about things being marketed that are not fact-based—making promises that that they can’t fulfill.

And then, as I mentioned, funding basic research is critical, but also funding translational work, because ironically, when you’re at the point when you think you know enough to develop a drug, it can be very hard to get research funding from the NIH because it’s not hypothesis driven. This idea that everything has to be hypothesis-driven is also not helpful.

WK:

So, I think we heard about the Big Bang. I really think the big bang in cancer was in 2000, when we had the first draft of the human genome. Because, of course, cancer to a first approximation is a disease of accumulated mutations in specific genes, and we didn’t, until 2000, have the complete list of genes and their sequences.

So, it’s truly remarkable, all the things that were discovered before the year 2000, but as you know, things have really accelerated since 2000, because first, the human genome became available, and secondly, there was a precipitous drop in the cost of sequencing.

So, now, I think, increasingly, we know the mutations that are responsible for specific forms of cancer. And as you know, there’s a first generation of targeted agents emerging that are based on those genetic mutations.

But I think where we must get now are, first of all, we have to get to combination therapy. I mean, this is axiomatic, but I think if we’re going to deal with the resistance problem, we have to stop using targeted agents as single agents. We have to get to combining drugs that have distinct mechanisms of action, and the hope is, because they have distinct mechanisms of action, they won’t be cross-resistant with one another and their toxicities will not overlap in a prohibitive way. So, we have to get, I think, to combination therapy.

And secondly, there are a lot of examples of cancer-causing mutations, where the protein product of those mutations is considered undruggable. So, we either have to come up with new ways to drug the undruggable, or we at least have to figure out the collateral vulnerabilities that are created by those mutations.

In some cases, we may not be able to directly target the genetic mutation, but at least we can target the vulnerabilities that are created by virtue of those mutations. And so, one paradigm for this, of course, is so-called synthetic lethality, where maybe mutation A makes you hyper-dependent on gene B. And so maybe the gene A mutation’s not druggable, but you can at least develop a drug against gene B. So, I think this is one area for the future.

I think the most important things for lawmakers to understand is, I would say that the goose that laid the golden egg for most of the 20th century in U.S. biomedical research was to have robust bipartisan support for basic investigator-initiated science, curiosity-driven science, and understand that you’re investing in the creation of new knowledge.

What’s exciting about that, and frustrating about that at the same time, is that you can’t always predict what the fruits of that work is going to be, what that knowledge will enable. But to just say we’re going to tie funding to short-term deliverables is incredibly short-sighted.

And so, they have to understand that I think what made American biomedical science great was we had like a pyramid, where we had very strong support at the bottom for investigator-initiated science. I think we should also judiciously support public big science projects, like the human genome, but not lose sight of curiosity-driven research.

But there’s a temptation, because once you get into big science, you sort of shift from letting a thousand flowers bloom to some centrally managed project, where you tell everyone to go in the same direction. It’s understandable that some people like that, because they like to manage the system.

But I think the analogy I would use is, if you had a thousand artists, I’d rather have them going in different directions doing great art rather than telling them, “Okay, you’ll get funded, but you all have to start painting pictures of a horse on top of a hill.”

And I think people who understand how science gets done will tell you it’s actually counterproductive to treat scientists like they’re engineers, precisely for that very same reason. When you’re still learning things, you don’t want to create herd mentality. You don’t want to tell everyone, “Okay, we’re all going to go in this direction and we’re all going to think in this particular way.”

That’s fine when you’re doing an engineering project, like putting a man on the moon, and you have to have a common objective. But when you’re doing science, it’s actually much more fruitful to let talented people follow their instincts and hope that some of them come back and tell you they actually discovered something, but understanding that they’re not all going to discover something, just like some artists aren’t going to produce things that you find attractive.

I think we have to have policymakers understand this.

And about every five years or so, it seems like someone writes a piece that says, “Cancer would be cured if you just worked in teams, and held hands, and exchanged information more readily,” and they don’t understand that this is still a scientific problem, largely, not an engineering problem.

Which is why I also think the moonshot metaphor is particularly unfortunate, because they’re really trying to conjure up the image of putting a man on the moon, which was of course an engineering project, which is why Kennedy could say it’s going to take approximately 10 years, because people like Newton and Galileo had come and gone.

But in cancer, we still need some science to be done here, and so you can’t completely pivot towards treating this like it’s now an engineering project. I think we have to help our policymakers understand that we need to believe in young, talented scientists.

Put another way, I’m often asked, “What do you think’s going to be the biggest scientific discovery in 10 years?” And I tell people, “If I could predict that, I’ll be really disappointed.” I hope the discovery in 10 years completely blows my mind, because I wouldn’t have been smart enough to think about it.

 

MO:

NCI is trying to cope with an influx of applications—the application rate at NCI is growing faster than NIH overall and at other institutes. What does this mean, and what should be done?

GS:

Well, of course, more funding is critical, because the rate of funding is so low. And at that level it’s very difficult to distinguish between applications. And, unfortunately, all it takes is one negative review by one reviewer to sink an application, because they all have to be outstanding. And that’s not good.

We know everybody has their own pet peeves, their own prejudices, their own way of looking at problems that may lead one reviewer—especially regarding a new idea—to have a negative opinion about something that could be really revolutionary. That’s not good.

WK:

Well, I think part of this problem is, frankly, sociological. For almost my entire life, we’ve had a model where the only way for principal investigators to be successful is to train multiple copies of themselves. And that’s obviously not sustainable.

And we’ve had this system where we have, for example, postdoctoral fellows arguably being underpaid, serving as almost indentured servants, but with the bargain being, “If I do this well, I get to have my own lab, and I get to be an R01 funded investigator.”

But if everyone’s training 10, 20, 50 copies of themselves over the course of their career, this is not sustainable. And every once in a while, when this has reached a crisis, either there had been a big increase in the NIH budget such as happened during the Clinton administration, or there was some big expansion in the biotech industry that absorbed some of these people.

But I think the problem is I don’t think either one of those things is actually happening now. And so, I think this is leading to the math problem where, yes, the denominator is growing faster than the numerator in terms of grant applications.

And so, I think we do need to think—and I’m not the first person to suggest this—in terms of how we fund and support laboratories, and should there be a bigger role for career scientists who maybe are very good working in the lab, like being in an academic environment, but maybe for any of a number of reasons, probably couldn’t or shouldn’t be writing for their own R01 grants.

I once spoke to George Yancopoulos at Regeneron, who said the beauty of biotech companies is he could pay people to do what they’re good at and not ask them to do the things they’re not good at, and in some cases, form sort of human complementation groups, where he could put together teams where people had complimentary skill sets.

And I think he correctly pointed out, we have a model in academia where, suddenly, you have to run your own lab. You have to be pretty good at multiple things. You have to be good at doing the science, but you have to be good at human resource management, and communication skills, public relations, budgetary management, et cetera, et cetera.

And a lot of scientists aren’t necessarily good at all those things, and you learn a lot of those things on the fly. So, maybe for some people, the right role would be to work in an academic lab as a research scientist—hopefully, you get paid much better than as a post doc—but you’re not going to be turning around writing an R01 proposal.

And what I’ve heard from people in the government is that, actually, it’s the academic institutions themselves who struggle more with this than, for example, the NIH. That Is largely because academic institutions haven’t known exactly what are we going to call these people. How will these people be treated academically?

Because we know how to deal with tenure-track people on their way to being a professor. You don’t want to have a two-caste system necessarily, but what do we call these people, and how do we treat them fairly, and how do we reward them fairly so that they find what they do is satisfying to them?

 

AC:

What are the challenges in the future for medical research? What about the next generation?

GS:

I’m an incrementalist, and I believe that science is built step-by-step on prior  discoveries. That process continues. Our tools are much more powerful now, so the rate at which we make progress is much greater now. That’s part of the excitement—we can determine the expression of every gene within individual cells of a cancer. It’s tremendous.

We can identify all of the mutations in the DNA of that cancer. We can measure the properties of the tumor microenvironment to understand their contribution. The prospects for the next generation of cancer researchers is tremendously exciting. For my PhD, I sequenced four kilobases of DNA at the beta-globin locus, in a family with beta thalassemia.

That’s ridiculous now—sequencing four kilobases, that took me a year. It takes a few minutes now. The scale of the power of our techniques is so much greater. Computing power is so much greater. And that keeps me going – it is a challenge to keep up with all of the novel technical and bioinformatics advances.

It’s a lot of fun to say “Wow, we have these new tools, we can do so much more to ask questions about the nature of cancer and how we might attack it.”

WK:

I think there are a couple challenges. One, we’ve already talked about, which is stable funding, and a balanced view in terms of early-stage science and late-stage science. I think we also have to make sure we have continued role models for these people.

And especially in my world, a physician-scientist, I think there are fewer and fewer institutions that have very robust support for young physician-scientists and a culture that still rewards and celebrates physician-scientists, because I think they have their own special challenges in terms of how you train them and get them to the point where they can be productive—an endangered species.

And then, I also think, stepping back to 40,000 feet, if I was a young person hearing some of the nonsense coming out of Washington, I would wonder, “Well, does my government still believe in science, and truth, and data-driven decision-making? Are scientists the good guys anymore, or are we now suddenly the bad guys, because we’re distrustful of expertise?”

So, I think all this incendiary language has potential unintended consequences. Because I’m sure, just as I’ve benefited from the celebration of science and engineering that I heard in the 60s and 70s, I worry sometimes that now we’ve flipped over to the dark side, where maybe some young people think, “Why would I follow this path if I’m hearing, at best, mixed messages from people who make very important decisions that are going to affect my life?”

 

MO:

Given the current state of funding for and rhetoric about science, how do we keep young people invested in cancer research?

GS:

Think about it: What other career are you going to take brilliant people and tell them the success rate is 15%, and they’re going to say, “Yeah, sign me up.” This is a big problem.

We’ve got to do something about the funding rate. We have young investigator programs, but I really wonder about the wisdom of that as an isolated approach. We fund people and say, “Okay, we’re going to give you an advantage for your first grant.” And then five years later the advantage is gone, and a lot of those people don’t get their grants renewed and leave the field, and then the investment was for nothing. That doesn’t really seem to be a good enough solution to the problem.

I’m not sure what the solution is other than just increasing funding in general. Bill Kaelin spoke about how in the Sputnik era there was all of this enthusiasm about science, and support for science. And we need to muster that energy today to advance cancer research. But unfortunately calling it a moonshot is not going to do the job. That’s not sufficient.

Also, this idea of “moonshots,” has become code for so-called big science. And I still believe there’s a role for small science in cancer research, and biomedical research in general. We need a mix of these different approaches.

 

WK:

So, that’s the glass half-empty. I think there is some good news. The one piece of good news is, there are many, many, many more private philanthropic sources, including, but not restricted to certain disease-oriented foundations, to help get support for your research, than when I was getting started. And so, I think that’s been very helpful.

If you’re doing anything that potentially touches a human disease, there may well be a foundation out there somewhere that cares about that particular disease.

So, I think, certainly, philanthropic sources of funding have improved. I also think, when I was young, there was this divide: there was academia, and if you were an academic you thought you wore the white hat, and if you were in industry—at least from the academic perspective—you wore the black hat. So, they didn’t mix very much.

Now, as you know, they mix much more. And there are more opportunities now to collaborate with companies and, in some cases, to get sponsored research agreements from companies. I think that’s another source of funding that’s gotten better over time.

The last thing I’ll say is, my view is always—maybe because I try to be an optimist—is that if I was really doing science well and had great preliminary data, somehow, I would parlay that into funding. Whereas, it wasn’t always clear to me if I started with funding that I would necessarily, for example, be able to turn that into great data.

So, I always tell my young people, “If you have a choice between having great data and funding, pick great data. Because eventually you’ll turn that into funding.” But I can’t always promise you you’ll turn your funding into great data.

 

AC:

What other policy changes need to happen to build on the momentum in oncology?

GS:

The other critical thing is we’ve got to support teachers better. I’m talking about elementary school teachers and high school teachers. We need to support the teaching profession much better, because these are the people that are the inspiration and the role models. Certainly, for me that was the case. It’s just too important of a profession to receive so little recognition and so little support.

We really have to start there. We know in terms of our standing in the world, that STEM education in the U.S. is nowhere near the top, and that’s not good. That’s not good for the future, and it’s really got to change.

WK:

I think partly because of this drive to do translational work, I think for my taste, there are too many people doing work that I would say is largely correlative, or descriptive. And I suspect, in many cases, it’s because they never had the opportunity or the desire to really get the training that’s necessary to go beyond correlative and descriptive to a deeper mechanistic type of work.

So, I think we want to make sure that young people are encouraged and supported to get the kind of training I think you need to do that kind of deeper, mechanistic work, and to understand it takes some time. It’s like everything else. I don’t think two years of working in a lab part-time gets you there.

And I used to think, or hope—maybe because I didn’t want to be elitist—that you could get good training almost anywhere. But that’s, frankly, not true. And we have to acknowledge that.

So, this is another point. I hear, occasionally, clamoring about, “Why is science funding concentrated in certain cities and certain states?” Well, I hope we recognize that science is supposed to be a meritocracy. And people, they vote with their feet, and go where they want to be. And you want to be at a place that has critical mass, and that has good mentors, and a really strong ecosystem.

So, I hope no one ever loses sight of that. I hope this doesn’t become something where we just decide we’re going to now suddenly distribute resources based on geographical considerations, and other considerations that would be totally silly.

I think this country’s always been about market forces and meritocracies, and at least in science, I think people have voted with their feet, and there are concentrations of places that are truly excellent. It’s not to say you can’t find great scientists in many places, but I do think there are certain places where now it’s almost become a little bit of a self-fulfilling prophecy that you have great institutions because they attract great young people. And they attract great young people because they’re great institutions.

Once you get that positive feedback loop happening, good things happen. And so, I don’t think we want to necessarily disrupt that.

 

MO:

Going forward, what worries you the most? And what excites you the most?

GS:

Climate change is an existential threat, and I think the appearance of a segment of society that can completely ignore facts and science, is really disturbing. It’s really very disturbing.

Certain elements of the government are fostering this attitude. I think it’s very dangerous and is a real threat to our society. Hopefully that will be addressed in the next election.

WK:

So, what excites me is I think we’ve never had a better understanding of the genetic alterations that are responsible for different cancers. And I think you could see the targeted drugs now coming, and, in some cases, you can even see the beginnings of some of the more effective combinations we talked about.

What we’ve learned over time from TB and AIDS, and even the curable cancers that we do cure, that sometimes, just combining drugs that have distinct mechanisms of actions is enough to get you there.

What worries me is that we lose sight of some of the things we talked about today. That we have to maintain robust funding—of course that’s mom and apple pie—but we’ve talked some different layers through that. And when I talked about robust funding I’m particularly concerned about robust funding for basic, mechanistic, curiosity-driven research.

And making sure we have an acknowledgement that there are certain places that have created these very special ecosystems that have the mentors and the culture to bring up the next generation. So, I hope we continue to support them.

 

AC:

Did we miss anything?

GS:

I don’t think so. Great questions!

WK:

I don’t think so. I think you did a good job.

Copyright (c) 2019 The Cancer Letter Inc.