Gauging the impact of the Gates grants

Donald G. McNeil Jr.

Five years ago, Bill Gates made an extraordinary offer: he invited the world's scientists to submit ideas for tackling the biggest problems in global health, including the lack of vaccines for AIDS and malaria, the fact that most vaccines must be kept refrigerated and be delivered by needles, the fact that many tropical crops like cassavas and bananas had little nutrition, and so on.

No idea was too radical, he said, and what he called the Grand Challenges in Global Health would pursue paths that the National Institutes of Health and other grant makers could not.

About 1,600 proposals came in, and the top 43 were so promising that the Bill & Melinda Gates Foundation made $450 million in five-year grants — more than double what he originally planned to give.

Now the five years are up, and the foundation recently brought all the scientists to Seattle to assess the results and decide who will get further funding.

In an interview, Mr. Gates sounded somewhat chastened, saying several times, “We were naïve when we began.”

As an example, he cited the pursuit of vaccines that do not need refrigeration. “Back then, I thought: ‘Wow — we'll have a bunch of thermostable vaccines by 2010.' But we're not even close to that. I'd be surprised if we have even one by 2015.”

He underestimated, he said, how long it takes to get a new product from the lab to clinical trials to low-cost manufacturing to acceptance in third-world countries.

In 2007, instead of making more multimillion-dollar grants, he started making hundreds of $1,00,000 ones.

“Now,” he said, only half-kidding, “you get a hundred grand if you even pretend you can cure AIDS.”

That little won't buy a breakthrough, but it lets scientists “moonlight” by adding new goals to their existing grants, which saves the foundation a lot of winnowing. “And,” he added, “a scientist in a developing country can do a lot with $1,00,000.” Over all, he said: “On drawing attention to ways that lives might be saved through scientific advances, I'd give us an A.

What follows is a sample of the progress of a few grants.

Dried vaccines

The hardest-hit inventors were those working on thermostable vaccines. Several techniques worked, but paying for all to go ahead made little sense. Billions of dollars — including hundreds of millions from the Gates Foundation — have been poured into improving the distribution of a dozen existing refrigerated vaccines, and having one or two heat-stable ones doesn't help if rural clinics still need refrigerators and electricity for the rest.

Abraham L. Sonenshein of Tufts University succeeded in splicing tetanus vaccine proteins into a bacterial spore that survives heat or cold and can be sprayed into the nose. But his grant ended before he could add diphtheria or whooping cough vaccines or start human trials.

Dr. Sonenshein said he was grateful to the Gates Foundation for the seed money and now might switch to veterinary vaccines. “A lot of farmers would like to be able to vaccinate their own cows and pigs instead of calling the vet every time,” he said.

India angle

Robert E. Sievers, a University of Colorado chemist, also reached his chief goal — attaching a measles vaccine to a sugar matrix that can be stored dry and then sprayed into a child's lungs.

His first sugar — based on the one that protects the “amazing sea monkeys” seen in comic books (actually dried brine shrimp) — did not work, so he found another. In his speech five years ago at a gathering of grant winners, he blew a goose call as an example of a device that vibrates air to send particles into the lungs. That didn't work either, so he designed a puffer that lofts the sugar in a tiny plastic bag, creating a sweet cloud that a child inhales.

While Dr. Sievers's Gates grant is not being renewed, he is partnering with the Serum Institute of India — the world's biggest vaccine maker — to test it there.

The foundation is still supporting two thermostabilisation techniques.

The first attaches vaccines to nanoparticles that can be absorbed by the skin inside the nostrils. Dr. James R. Baker Jr., director of the University of Michigan's nanotechnology institute, said it works with hepatitis B and flu vaccine. He won a new grant to test the respiratory syncytial virus, which causes pneumonia.

The second thermostabilised vaccine the foundation is still backing is a complex one against malaria. It fuses the genes for parasite proteins onto a “genetic backbone” from vaccines against smallpox and a chimpanzee virus.

Rather than being bottled, the vaccine can be dried onto a bit of filter paper.

No malaria vaccine comes close to working 100 per cent of the time. Dr. Adrian Hill, of the University of Oxford, said his is the “the No. 2 most effective in the world.” He has proposed combining it with its chief rival, made by GlaxoSmithKline, since his attacks the malaria parasite in the liver, while Glaxo's attacks it in the blood.

Lab in a box

Another grant that was not renewed was $15 million for several teams collaborating on a hand-held battery-powered diagnostic laboratory. The plan was to have it split a single drop of blood into a dozen fractions to test for flu, malaria, typhoid, dengue, measles, rickettsia, salmonella and other infections, all within 30 minutes.

Many advances were made, said Paul Yager, a bioengineer from the University of Washington. The blood drop went into a plastic card with 23 layers of microchannels, pumps and bladders.

But obstacles kept cropping up.

And while the project had no competition when it began, two types of rivals emerged. Big companies developed boxes that cost up to $70,000 but could do more. And George M. Whitesides, a Harvard chemist, got intrigued by the same challenge and began work on a revolutionary variant: skip all the plastic and let the fluids instead be wicked through paper the size of a postage stamp infused with colour-changing reagents. The foundation gave him a grant two years ago to develop a liver-function test.

He is now moving on to other projects, like writing code and developing chemicals that will turn cellphone cameras and inkjet printers into diagnostic devices.

Mosquito ‘olfacticides'

As the inventors of “a cell line that behaves like a mosquito antenna, recreating mosquito smellers in a dish,” Leslie B. Vosshall of Rockefeller University and Dr. Richard Axel, a Howard Hughes Medical Institute investigator at Columbia University, got $5 million to hunt for molecules that could block mosquitoes' ability to detect people. Dr. Axel shared a 2004 Nobel Prize in Medicine for cloning insects' olfactory receptors.

“When you puff human odours over the cells, they get excited just like mosquitoes would,” Dr. Vosshall explained. In this case, they turn fluorescent green.

They tested 91,000 compounds in Rockefeller University's chemical library and found five that jammed the antennae. Their Gates grant is renewed for two years, but they now have a contract with Bayer CropSciences to screen its two million compounds — the same smell mechanism is used by corn borers, apple maggot flies and other farm pests.

‘Exhausted' immune cells

Another grant is ending because it attracted so much commercial backing. Rafi Ahmed, an Emory University immunologist, studies why the immune system's T-cells get “exhausted” during a long battle against some viruses like H.I.V. or hepatitis C. Eventually, he discovered, the cells start growing “inhibitory receptors” on their surfaces as a self-protection measure. He hopes to find a way to revive exhausted cells in humans with AIDS and let them take breaks from the toxic drugs. Because T-cells fight many diseases, including cancer, Genentech, Bristol-Myers Squibb and the National Institutes of Health are all offering him money.

Stem cells to muscles

The most radical project announced in 2005 was that of Dr. David Baltimore, who shared a 1975 Nobel Prize in Medicine and now teaches at Caltech. Dr. Baltimore envisioned removing stem cells destined to be white blood cells from people and infecting them with a slow-acting virus containing genes to reprogramme their internal machinery to produce double-headed antibodies to attack H.I.V. at two different points.

“This original high-risk, high-reward approach proved too difficult,” said a foundation document describing the grant's history. Slow-acting viruses have cancer risks, and harvesting bone marrow from rural Africans “wasn't really practical,” said Dr. Christopher B. Wilson, the foundation's director of global health discovery.

Meanwhile, other scientists cloned new anti-H.I.V. antibodies found in the blood of infected people, so the grant was “repurposed” with a different goal: to inject genes that code for these new antibodies into muscle cells. The hope is that this could become a simpler form of prevention than current H.I.V. vaccine efforts.— © New York Times News Service