Interview with Executive director oF Bill-Melinda Foundation

Tadataka Yamada, the executive director of the Bill and Melinda Gates Foundation, is the former chairman of research and development at the pharmaceutical giant GlaxoSmithKline and was a gastroenterologist for much of his early career.

Yamada is responsible for the foundation's grant-making in global health. He spoke to Katherine Nightingale, at a media briefing, about the philosophy behind the foundation's Grand Challenges Explorations programme (see US$100 million awarded for innovation in health research). The US$100 million programme, launched in 2008, provides investigators with unorthodox ideas US$100,000 grants to take their ideas to proof of principle stage — with the potential for further funding.

What is Grand Challenges all about?
Health solutions for the developing world are hard to create, so we believe that true innovation is needed. Some areas require a revolution in thinking — not just an evolution in thinking. If you think about HIV vaccines, everything that's been tried so far has not gone well, and part of the problem is that we are locked in an orthodoxy of thinking about the problem that prevents us from thinking in novel creative ways.

We have many different mechanisms for funding innovation but the one that we started last year was really focused on creating true innovation, ways to imagine solutions to problems that have existed for some time but really challenge orthodoxy.

Is it hard to apply for a grant?

You need a two-page application at the start with no preliminary data required. If you have a 20-page application where you dot the "i"s and cross the "t"s, you're not going to get those new ideas.

Have you been deluged with applications?

We've had 7,000 applications. The first round we funded about 105 and the second round about 75–80 new grants. Over five years I'm thinking we'll have signed off 1,000 grants. The whole point is that we're willing to take risks. My guess is that maybe one or two are real charlatans but that happens.


Can people submit any idea?

We pick the subjects. We say: here are the stumbling blocks, here are the roadblocks. So there is a variety of topics that are specifically interesting to us: new ways to protect against HIV; new ways to think about TB latency; new ways to prevent against infection in general.

And are the proposed subjects always a direct response to problems "on the ground"?

Yes. Let me give you an example. This is one that we haven't announced yet. Reproductive health is one of the major problems. High fertility rate is a big problem but one of the biggest problems is the early onset of the first pregnancy, and maternal death and child death is greatly enhanced if the mother is young.

One of the major concerns — though hard to prove — is that hormone-based contraceptives close epiphysis of bone early [preventing bones from reaching its full height]. It hasn't been proven yet but that's one of the fears and there's been some evidence that that might happen. So you can't use these hormone-based pills for pre-adolescent girls and one of the big questions is what kinds of non-hormonal contraceptives are there? Zero. Why? Because there's no market for them, because in the developed world 13-year-olds don't have babies by and large.

So I said what if we created a Grand Challenges Explorations category: new ways to prevent pregnancies that are not hormone based. I hope we get a thousand ideas on this of which we can pick 20 or 30 and fund them and see how far they go.

How does the foundation choose between the applicants?

The critical piece is the review. The NIH established a "pioneer" award in the US, but the reviewers were peers. Peer review innovation because by definition innovators have no peers. That's really critical because I think people who are experts in their field are locked in an orthodoxy of thinking that makes it difficult for them to accept the most novel ideas. As long as you've got smart people looking at the application that aren't experts in the field they'll recognise innovation. We had many outstanding scientists and entrepreneurs on the panel.

The reviewers in each cycle get to pick one winner for certain, that's their 'gold'. Then they get to pick two 'silvers' to be considered. Most of them have never had that opportunity before, they're usually part of a review panel and they state an opinion but don't actually pick. Some very smart people — Nobel prize winners — found this very hard, it made them very nervous.


And what's your own approach?

Good incremental science, the kind of thing you would get in an NIH or MRC application, I throw in the wastebasket — the MRC should be funding that; the NIH should be funding it. It's the stuff that NIH would never fund that I put into my 'good' pile. I love those ideas. And none of them are completely original, they've been around but no one's actually funded them.

Are Bill and Melinda Gates heavily involved in the vetting and ideas process?

Definitely. We always run our new ideas by Bill to make sure he knows about them. Bill was one of the reviewers. Here's a guy who's a bright person, an innovator — why shouldn't he be able to tell the difference between something that's good and not?


Can you give some examples of grant-winners?

In the first round we had approaches whereby acrylamide nanoparticles would be incubated with HIV virions [virus particles] and as they solidified the virions would be washed off. So there would be particles with pockets that exactly fit HIV virions — a little bit like a synthetic antibody. The idea is that you would inject the particles, the particles would mop up the virions in the way an antibody would.

That one got funded in the first round and it's been six months or so and I haven't heard back from the scientist in Singapore.

Another one involved expressing malaria antigens in the salivary glands of a mosquito so that every time a mosquito bit you it was basically inoculating you. That might not work but these are novel concepts.

There's another one that involves a magneto-optical approach to diagnosing malaria. Malaria parasites make from human haemoglobin a pigment called haemozoin which has iron in it. Using a certain kind of magnetic field you can orient those iron particles in a certain direction that is different from the way that particles of, let's say, human blood orient. And then you can use an optical mechanism to make the diagnosis. That's one that's just been submitted. That's exciting. I love reading these proposals.



And what's the deal for the winners?

You get funding of US$100,000 within three months of submitting your proposal . But we're prepared to fund the ones that work with US$1 million in the second round and more if necessary as it succeeds. It's potentially a US$200 million investment.

Does Grand Challenges attract developing world scientists?

Roughly 10–11 per cent of applications came from the developing world and 10–11 per cent of the funded applications came from the developing world — they did as well as people from the developed world.

We had a scientist in the last round from Kenya who was working with a group from Canada who had come to Kenya to try to understand why some sex workers were highly exposed to HIV but didn't get HIV. When they stopped having frequent sex they got exposed again so it wasn't quite clear what causes their resistance. He couldn't get funding in Kenya and went to Canada to get some training. He'd gone back to Kenya and pored through the data and made the link between potential — or a propensity to — diabetes and resistance to HIV so he's pursuing that.

Have you ever funded very simple ideas?

There was one from someone in Africa in the first round who was going to use the house as a means of baiting and trapping mosquitoes. That was very basic. They did get funded though.



Are you interested in funding projects through to application?

The idea is that we get these ideas, we fund them, we de-risk them. Once they get to the point where there's a proof of concept, then other organisations are interested. One of the things we've been looking at is how we can help countries and other agencies invest in what we're doing.

Are you going to patent these ideas?

No. We don't own the patents.The investigator could patent it or sell the idea to somebody else. The only thing we ask for is a global access agreement, which basically says that if something happens to make this a viable product then the product will be made available at an affordable cost for poor people.

Do you get any really nutty ideas?

Yes, some of them are absolutely crazy.

Aren't you scared that all these wacky ideas will fail?

That's one of the things I asked Bill. I said: "There's a risk that we'll do this and nothing will happen". I think our conclusion was: billions have already been thrown at [these problems] by the Wellcome Trust, the NIH and the MRC and nothing's happened — the standard approaches haven't been successful.

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