Klausner spoke with Paul Goldberg, editor and publisher of The Cancer Letter.
Paul Goldberg: How is this grant different from all the other grants?
Richard Klausner: Well, all the other grants you can do sitting up, or lying down, but this grant you have to do while reclining … No …
Okay.
RK: I have to say, nothing has given me more pleasure in the grant world, then this whole approach of grand challenges. You may know, we started the first of this, interest in grand challenges when I was with Bill Gates. We set up the Grand Challenge in Global Health.
It was not only productive, it was inspiring. The reason is, and you know this, that largely, the grant systems around the world have become atomized.
The best model is the R01, which is into funding projects—and that’s fine. I’m not criticizing them, but what we’re trying to do with the [CRUK] Grand Challenge is to fund the solutions of problems.
There are several reasons why it’s so exciting, but I think, most importantly, it gets at actually why people want to go into science. No one goes into science because they want to do a series of projects. They want to take on big problems; right? They want to take big problems that seem important, that seem on the edge of doable, pushing the envelope of being doable, and really a stretch, but not unrealistic.
It’s not just a wish like, “Let’s cure cancer.” It has a specificity to it, but it’s about attempting to solve a problem. The responses you get to these Grand Challenge articulations are fabulous. This is the second round for the CRUK Grand Challenges.
And everyone involved—I feel I can speak for them—felt that all the work was justified by the quality of the proposals we got. Not all of them, but certainly the ones that were awarded last year, I will say, Paul, were among the most inspiring and beautiful grants I have ever read.
And you read them and you say, “Ah-ha, if they achieve what they’re trying to achieve in this aspect of cancer, we will be able to look at before this grant and after this grant, and think that their field has changed.”
And that’s the goal here.
And this is another 100 million dollars over five years; right?
RK: Or more. So, let me just say, it could be more, and the reason I say that is that as we did last time, once we got all these proposals and we ranked them, we then—and we’re doing this now—went out to a variety of funders and invited them.
And so, there is philanthropic money to add to the CRUK money, and we’re going to try to do that again.
CRUK has set aside a certain amount of money that it’s able to do for this. And it’s really wonderful. I have to say I can’t give them enough credit for their vision, their openness—and remember this is the first time that this UK cancer research entity is opening this up to the world.
You don’t have to be British, and it’s for anyone in the world that would want to come together to convince this review group, which is the same group that struggled to articulate the grand challenges, to convince us that this is a worthwhile attempt.
I think that’s really important that here is a major grant that is totally internationalized. And so that’s what’s exciting about it. The panel—and you can see who is on the panel—has spent a lot of time together, but articulating grand challenges is really hard.
I can imagine.
RK: It’s really hard to do, which is one of the reasons it’s so interesting. And do we know that we get it right?
No.
In the end, getting it right is probably only determined by the quality and the nature of the proposals we end up getting. And everyone that gets funded may be against one grand challenge or multiple grand challenges. It really depends upon whether the group really feels that what comes together is a really interesting, exciting and novel shot.
When we get applications that look like the same old people doing the same old things, just looking for a £20 million grant, they don’t make it very far.
Fascinating.
RK: It’s really about challenging the community to solve problems. This gets at an issue that I think gets lost, and that is the relationship between what we as a research community do and the public. And that is, it’s really hard to articulate, and communicate that as, “Ah-ha, this is what you people do.”
But when you make an attempt to articulate the solving of a problem, and in that you can articulate if you solved this, what will change about our approach to cancer, I think it’s so much more understandable to the public and, again, I really think that in our times of skepticism about science, it’s extremely important that we as a scientific and biomedical scientific community are capable not of justifying, but communicating and explaining that the reason we do all this is to solve their problems.
You’ve mentioned how these grants are different from RO1s. How are they different, say, from Stand Up to Cancer as an approach, philosophically?
RK: I love Stand Up to Cancer, and I think Stand Up to Cancer is another wonderful alternative. It’s much more about a very specific translation. And that’s terrific, and it links together scientists and clinicians to do a very specific translation.
This is basically to solve overarching problems in cancer, like what is the difference between a lethal and nonlethal cancer? Last year, we funded something that’s never been done, and that is to create a Google map of a tumor.
How do we think about actually mapping at every dimension, cellular, molecular, genetics, interaction, all the components of the organ we call a tumor?
If you think about it, there’s never been a picture of that.
And the solutions that have been proposed by several groups that were funded are quite remarkable. And again, once we have that picture, we really think we’ll think about tumors differently than we currently do. That’s very different than the type of very directed, let’s try something in the clinical approach of Stand Up to Cancer.
There’s no one type of grant that should define grant-making.
How is it different from Harold Varmus’s Provocative Questions?
RK: I happen to think that Provocative Questions are a close cousin to this. Remember Harold was one of the co-chairs that I invited into the Grand Challenge in Global Health, and I view the Provocative Questions as very much a close kin of that experience that Harold had.
So, there’s some similarities, but the way they’re formulated is different. In other words, they’re formulated as, here’s a set of really wonderfully provocative questions, which I love, I think it’s fantastic that that was done.
What we try to do with the [CRUK] Grand Challenge is take it one step further and basically talk about a multi-pronged approach to identifying the very specific bottlenecks that exist that get us from the lack of understanding to an understanding that would create impact on cancer.
There’s just more structure to the Grand Challenges. But, as I say, I think they’re closely related.
This may be a provocative question, but how does it differ from, say, the industry, what the industry can do?
RK: Well, industry, honestly, isn’t in any way set up to step back and attempt to answer big fundamental questions.
Even though there are some challenges that sound like applied research, such as challenging how we look at as
treatment regiments vis a vis a science of both resistance and toxicity, we’re looking for things that will change the framework of how industry thinks about cancer and how it sees opportunities for interventions.
These are not really about building the interventions. These are about making the breakthroughs to demonstrate how you would create a new set of interventions. Like the tumor vaccinology challenge, which is laid out very specifically, and that is, we think we have an understanding of why checkpoint therapy works, but we have no idea why it only works in the fraction of patients that it works in.
We are not asking for a biomarker of response. Industry is doing that. We rather mean this as a deeper intellectual question.
The fact is, it’s not that there’s no underlying immune response in patients who fail to respond, so what really are the controlling processes? If you understood that, you would then understand what it is that determines the 10, or 20 or 30% that respond and what you would do to increase that.
What industry does is try to find biomarkers that say you won’t respond, or you will respond. That’s not the same as solving the mechanistic problem.
Underlying another of this year’s challenges is the fact that we’ve known since the beginning of finding tumor genes and tumor suppressors, that there’s this totally mysterious question of tissue specificity. VHL is in every cell of the body, and it’s only associated renal cell carcinoma. Why?
What is that specificity telling us about the actual mechanism of tumor development and survival? To go from these actual universal pathways to a specific tumor, and does that create interesting sensitivities and points of intervention, and it’s amazing, but what we want is not an example. We want to solve the problem.
That’s the challenge here of what could possibly be determining tissue specificity of uniformly expressed tumor suppressor genes, for example.
Who came up with the idea of the grand challenge? Was it you, or Gates, or Harold, or somebody else?
RK: No, I invited Harold and [then NIH Director] Elias [Zerhouni] after Bill and I conceptualized the Grand Challenges in Global Health. The whole idea of the Grand Challenge [in Global Health] happened one evening in Bill Gates’s office.
He and I were just spending the evening together at his Microsoft office, and we were literally in an argument about the value of funding research. I was positive, he was negative.
I hadn’t been at the foundation very long, we were just developing our strategy. We were doing that together.
I kept pushing, and he was skeptical. And then, somehow, in the conversation Bill asked whether I knew or had ever read about the grand challenges in mathematics, formulated in 1900, by [German mathematician David Hilbert].
He excitedly, and very knowledgeably, started talking about those mathematical grand challenges, and how for a hundred years, that formulation defined the most critical, important questions to be answered in mathematics. Amazing how long they’d been there.
We started discussing that remarkable piece of science history, and what it meant and how, because Bill was able to see, “Ah-ha, there’s an example of how one can articulate big problems.”
Whereas he felt if we were just going to get into supporting research, it was just supporting an endless amount of projects. And he was right.
And so, as that night went on, we basically agreed together, I said to him, “Why don’t we do grand challenges in global health?”
And he just lit up. And we started going back and forth, what would this mean, what would this look like? And it was done. That’s how it started.
So how does Harold fit in, because he came in with the idea of calling them Provocative Questions?
RK: And they were, yeah. So what happened is that because at the Gates Foundation I wanted to bring NIH further into this world of global health with the Gates Foundation, I went to Elias, and told him about this idea of grand challenges, and said, “Is there a way to do this together?”
And it turned out there was no real way. It was just too difficult. But what we did to was to give a grant to the FNIH, and then enabled the FNIH to grow their ability to manage these things, and they helped us manage the grand challenge process, and then I asked Harold, who was developing, post-NIH, an increasing interest in global health, I asked Harold and Elias to join me, so I chaired it, and they were the two co-chairs. The three of us were the triumvirate that sort of managed over the program.
In addition, we had a big scientific advisory board and we had review committees and an amazing staff both at the Foundation and the FNIH.
But the three of us really were the intellectual managers. And I think Harold loved it. In fact, it’s all described in his book. And there’s no question, because when Harold told me he was going to become NCI director, I said, “Let’s do grand challenges in oncology.”
It’s interesting, because I covered this. I had no idea. I mean, I knew about all the pieces that you’re describing, but I didn’t quite put them together.
RK: Anyway, that’s exactly the story.
That’s very helpful to know.
RK: Actually, Paul, I think this issue of grand challenges and how we think about inspiring, not just funding, but inspiring and motivating the community, the whole process of this, to me, is really fascinating. It will be great, actually, to take even more time, because I think there’s a lot of interesting issues that are raised by the whole process.
Let’s do that.
RK: And I can’t imagine someone covering this better than you.
Let’s totally get back to that. Is Cancer Research UK playing a greater role or planning to play a greater role in the U.S.?
RK: You know, this is their first foray into doing something that’s not limited to the UK. And all I can say is all of us on the board, from all different parts in the world, just keep applauding them. We think that’s fantastic.
So, it’s really that. It’s not so much that they want to fund in the U.S., but they’re basically saying that if this is a process where a community or a subset of a community has said these are worthy challenges, they understand that if it’s worthy, wherever the potential solutions come from ought to be funded. I really applaud them for that.
How did you get involved in Cancer Research UK?
RK: Well, actually I’ve had a long relationship with them. You know, I helped peripherally with the formation of CRUK. You probably remember that in the 90s, there were two cancer research charities in the UK, the Cancer Research Campaign and the Imperial Cancer Research Fund.
When we get applications that look like the same old people doing the same old things, just looking for a £20 million grant, they don’t make it very far.
And I got very involved in the discussions with the heads of both as they began thinking about whether should they merge.
In fact, while I was NCI director I was also a member of the board of ICRF, the scientific board. Actually with Harold, we were both members.
So, I had this long relationship with the both the Cancer Research Campaign and the Imperial Cancer Research Fund, and with CRUK, which was the merger of these two.
And I just remain friendly and close to them, had no formal relationship, and their CEO, Harapal Kumar called me about two and a half years ago about this idea of doing grand challenges in oncology, and would I help them and chair it. And so that’s the origin.
One of the challenges is in health services research. Or certainly the question of overtreatment. It’s nice to see that.
RK: Yes, well, honestly, the Grand Challenge most relevant to this question of overtreatment is determining what distinguishes lethal versus nonlethal cancers, in other words, what are cancers we should ignore.
Many of us believe that there’s a lot more of these nonlethal early cancers than what one would conclude based on treatment patterns of early cancer. And that is Grand Challenge No. 5. Grand Challenge No. 6 is about using artificial intelligence machine learning to look at all sorts of medical and health systems aspects of a new way to think about early detection.
That said, we did not choose to try to do grand challenges in health systems per se. We just felt that was not cancer-specific. It’s an interesting question. We came up with this at the Gates Foundation, where we realized that you could say, let’s do a Grand Challenge to get rid of poverty.
And that would take care of a lot. Unfortunately, that doesn’t have the mechanistic specificity that’s required to fit our definition of a fundable Grand Challenge.
