publication date: Nov. 15, 2019

William G. Kaelin Jr.

Sidney Farber Professor of Medicine,

Dana-Farber Cancer Institute, Brigham & Womens Hospital, Harvard Medical School

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 sakeand 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 & Womens 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 youll probably, frankly, wind up being a miserable person, because theres 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 Semenzaand Sir Peter Ratcliffe, director for the Target Discovery Institute within the Nuffield Department of Medicine at Oxford Universitywere 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).

Its so important to have a job thats 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 weve learned and have it impact public healthand thats of course our ultimate goal. We may or may not be successful, but we at least feel that what weve 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 Trumps 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 were distrustful of expertise? Kaelin said.

I worry sometimes that now weve flipped over to the dark side, where maybe some young people think, Why would I follow this path if Im 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. Its really very disturbing, Semenza said. Certain elements of the government are fostering this attitude. I think its 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.

Its fantastic, and I tell people, if you can have a job that takes advantage of something youre good at, makes you happy, and people will pay you for it, youve got it made. So many people have a job they do solely to support their family. They want to be done with it. Thats most of your lifeyour working life.

Its so important to have a job thats 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. Thats 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 weve learned and have it impact public healthand thats of course our ultimate goal. We may or may not be successful, but we at least feel that what weve learned might help other scientists get to that point.

Theres 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 youre the kind of person who enjoys science as I doI would come to work even if I didnt need the money, because most days it feels like Im playing rather than workingthen being a scientist is a gift. I think its a great privilege to come to work every day where you enjoy what you do, and its stimulating, and its 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 thats another prize in and of itself.

When you understand something thats never been understood before, especially when you look at the answer, and the answer strikes you as being beautiful, or elegant, or satisfying, thats a prize. And then, if youre 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 youll probably, frankly, wind up being a miserable person, because theres 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 thats already a prize and if you do your work well, youre 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 theyre 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 its not mutated, its not important. Its 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, its 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. Its the hypoxic cells, that are particularly resistant to those therapies. They survive the therapy, and those are the cells with stem cell properties.

Weve 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 phenotypethese are the cells that kill the patientsand there are no approved therapies targeting these cells.

And thats our mission. As I say, weve been swimming uphill for a long time. But we continue, and were more convinced than ever. Now that there is a drug in clinical trials that targets HIF-2 in kidney cancerhopefully soon well 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 its encouraging to see that. Were more convinced than ever that this is something thats 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, Im 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 wouldnt 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.

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

Its been very gratifying to work with Peloton Therapeutics, which was recently acquired by Merck, thats 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. Its 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, theyre often put in surveillance programs to try to avoid doing multiple surgeries, and so, theyll be put in careful surveillance programs. Fifty-one of these patients have now been treated with the HIF-2 inhibitor.

I dont 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 theyre 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? Whats good? Whats bad?

GS:

Well, Id say whats good is that in terms of a piece of the pie (meaning total federal research funding), its a pretty big piece.

Whats 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, its 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, theres a whole lot of expense.

If we can prevent patients from getting to that stage, thats 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.

Thats 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, its 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 dont really know what discoveries will get us to new treatments for cancer. Likening cancer research to the Apollo Moon mission, I dont think is helpful.

We already had one war on cancer in the 70s, and now were just repeating this same rubric. I dont think its helpful.

WK:

I havent looked at the numbers recently, but it has certainly felt like its 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, theyre 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 theyre asked to say, Is this an 8th percentile grant versus a 14th percentile grant? Because one is going to get funded and one isnt. I think that just puts too much stress on the peer review system and it also tells you that theres some very good grants that arent being funded. I think thats problem one.

I think problem two is, I would say, the secret sauce in American biomedical research for most of my life was saying, Lets 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 lets let the public sector, largely the federal government, fund the early-stage basic sciencethe fundamental science, the mechanistic science that gets done early, because companies dont 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 thats the one thing they count on us to do in academia, right?

They rely on that information, and often thats 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 thats 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 its just as likely, if not more likely, to come from someone either studying another cancer altogether or, frankly, someone who didnt 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 its 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, thats the language of engineering. Thats 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 thats 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 thats going to have a big impact, because if we can identify tumors when theyre still contained within the organ of origin, the chances of cure are much greater. Now, with powerful sequencing, its become possible to identify a few cells in the blood that carry telltale mutations that say theres a cancer growing in a particular organ.

Thats 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-basedmaking promises that that they cant fulfill.

And then, as I mentioned, funding basic research is critical, but also funding translational work, because ironically, when youre 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 its 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 didnt, until 2000, have the complete list of genes and their sequences.

So, its 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, theres 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 were 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 wont 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 mutations not druggable, but you can at least develop a drug against gene B. So, I think this is one area for the future.

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