December 20, 2010
Five Years In, Gauging Impact of Gates Grants
By DONALD G. McNEIL Jr.

SEATTLE — 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 $100,000 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 $100,000.”

Over all, he said: “On drawing attention to ways that lives might be saved through scientific advances, I’d give us an A.

“But I thought some would be saving lives by now, and it’ll be more like in 10 years from now.”

Several scientists at the conference noted that Mr. Gates comes from the software industry, where computing power constantly doubles. Biology, by comparison, moves glacially — and microbes are less cooperative than electrons.

Biology also has a greater tendency to create progress-hindering controversy. For example, doing clinical trials on illiterate subjects in poor countries, which was once cheap and fast but ethically dubious, has become time-consuming and expensive as ethical standards have improved.

Also, poor countries lacking regulatory authorities and highly educated political and scientific elites may be nervous about being misused by Western scientists and careful about accepting new technologies.

Despite discoveries on many fronts, up to two-thirds of the grants either did not get renewed or may not in the near future, Mr. Gates estimated. In some cases, it was because they were not succeeding, either scientifically or because of political obstacles, or someone else had found a better path. In others, the foundation changed the goal.

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.

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 thermostabilization 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 particles are in what Dr. Baker described as a “proprietary formulation of mayonnaise” based on soybean oil. The vaccine ends up inside the oil particles, which protect it from temperature changes and microbes. The immune system is “made to eat oil droplets,” Dr. Baker said, because it targets viruses, which are essentially time bombs of genetic instructions inside casings of fats. The “mayonnaise” is so safe, he said, that rats fed the equivalent of two quarts a day had only one side effect — weight gain. The emulsion by itself cures viral lesions like cold sores, he said; its surfactants harmlessly penetrate the skin but break up the herpes virus inside.

The second thermostabilized 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 percent 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.

“It would be a belt-and-braces approach,” he said. “We’d anticipate efficacy of over 80 percent.”

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. Some illnesses, like flu, left too few traces in the blood. Not every company whose patented test was to be miniaturized would cooperate. A big partner, Hewlett-Packard, dropped out; others were acquired.

“It was really challenging being the chief cheerleader for five research teams,” Dr. Yager said. “But the single toughest problem in the whole project was ‘low cost.’ ”

The prototype was as big as a toaster, weighed nine pounds, and cost $1,000.

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 color-changing reagents. The foundation gave him a grant two years ago to develop a liver-function test.

“He was right — paper was a good way to go,” Dr. Yager said. “An experiment we did 15 years ago with three $1,000 pumps and a $30,000 microscope you can do now with 5 cents worth of paper.”

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.

The Gates grant, he said “took me places I never would have gone, like a South African township. I have so many students I have to beat them back with a stick, and I’m left with a burning desire to accomplish the goals of the program.”

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 odors 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.

The ideal, Dr. Axel said, is a repellent harmless to humans that works at a fraction of the concentration of DEET.

But repellents aren’t the only way to outwit mosquitoes, he said. Triggering the hormone that tells a female she is already full of blood could work, as could one that sends her far from humans to lay her eggs.

‘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.

“You can’t continue a totally active T-cell response indefinitely,” Dr. Ahmed said. “You’d be sick or dead.”

In mice and monkeys, he has found molecules or antibodies that block those inhibitory receptors, perking up the cells again.

“It doesn’t result in a cure, but it’s quite promising,” he said.

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.

“Without Gates, we wouldn’t have been able to put together the team we did,” Dr. Ahmed said. “The money, and the fantastic vision of a grand challenge — that’s been one of the best things.”

A Better Banana

James Dale of the Queensland University of Technology in Australia successfully added Vitamin A to bananas and is working on adding iron. A new Gates grant will support field trials in Uganda.

Bananas are a staple for millions of people from Africa to Ecuador to India. “They’re also one of the best weaning foods for babies,” Dr. Dale said. “They come in a nice sterile package and don’t need to be cooked.”

The Ugandan government agreed to genetic modification as long as Ugandan scientists did the work on Ugandan bananas, he said. Dr. Dale finds the right bits of DNA in his lab and ships them to Uganda’s national agricultural laboratories for insertion — a team approach that the Gates Foundation praised.

He has had no problems doing field trials in Australian banana-growing areas.

“The growers there know bananas are sterile and can’t swap genes,” he said. (Bananas are propagated by shoots, not seeds.)

In Africa, Dr. Dale has kept a low profile since it may take another decade of testing before a banana is ready to be given to farmers.

Part of the Gates grant is for “feeding trials” to see if people will accept the new fruit, which has papaya-orange flesh from the vitamin precursor, beta-carotene.

“Everyone asks me what it tastes like,” Dr. Dale said. “And I don’t know.”

His licenses forbade testing them on humans before. But has he never succumbed to the temptation to take a bite?

“No. And I wouldn’t tell you if I did.”

And a Better Cassava

The $7 million grant to BioCassava Plus, a consortium led by Ohio State University, was increased to $12 million. While it, too, will take another 10 years, the project is meeting interim goals, said Richard T. Sayre, its principal investigator. They include decreasing the natural cyanide in the tubers, increasing the protein, iron, zinc and vitamins A and E, and engineering in resistance to new cassava diseases.

Cassava is a staple for 800 million people, but environmentalists like Greenpeace and Friends of the Earth have slowed the project by opposing field trials in Nigeria and Uganda.

Martin Fregene, a Nigerian geneticist who is BioCassava Plus’s product development manager, accused them of using scare tactics and prompting local journalists to issue warnings that “killer cassava” was on its way.

“These environmentalists are paternalistic,” he said. “They treat Africans as if we are kids and can’t make up our minds.”

“Middle-class newspaper readers in the capitals are under their influence,” he said. “But they are only 20 percent of the country. When we have meetings with the farmers, they say: ‘If you can assure us it’s safe, we’ll grow it. And you don’t have to worry about the politicians. We’ll take care of them.’ ”

Resistance to genetically modified crops, which was high five years ago in Africa, has begun fading country by country, said Claude M. Fauquet, another member of the cassava team. For example, when farmers in Mali and Nigeria saw the huge yields Burkina Faso farmers got from insect-resistant cotton, they agitated for the right to grow it, too.

Mosquitoes and Bacteria

The fastest-moving project is that of Scott O’Neill, a biologist at the University of Queensland, Australia.

Five years ago, Dr. O’Neill got $7 million to try to infect mosquitoes with a strain of wolbachia bacteria that didn’t kill mosquitoes outright, but made them die before they got old.

The advantage is that a female must be “middle-aged” — about 14 days — before she can pick up the dengue fever virus from one human, see it mature in her gut and then pass it on to another human. If she lives long enough to take one blood meal and lay eggs, she never transmits dengue, but the bacteria is under no Darwinian pressure to disappear from the mosquito population. Also, she passes it to her embryos, so they too lead shortened lives.

The wolbachia strain he started with killed mosquitoes too quickly, Dr. O’Neill said, but he found another that had an unexpected side effect: for unknown reasons, it blocks both the dengue virus and chikungunya, another tropical disease.

“That turned everything on its head for us,” he said. “It’s like a vaccine for mosquitoes — it protects them from picking up the virus.”

In Cairns, Australia, which has had repeated dengue outbreaks, his lab built 65-foot-long cages of fine mesh, filled them with Aedes egypti mosquitoes and introduced the wolbachia, which spread to all of them. In Vietnam, he let wolbachia-infected mosquitoes feed on the blood of people with dengue fever. “We got complete blocking,” he said. “No virus in the saliva.”

The next trial, just starting now, will release wolbachia-infected laboratory mosquitoes into the wild in Cairns to see if they infect others and curb the dengue problem.

Asked if he faced any popular backlash there, he said: “None at all. People are quite fearful of dengue, and really tired of having insecticide sprayed in their homes.”

The Gates Foundation is still supporting his work, and the Australian government is now contributing as well, he said. “And if the field trials are successful, worrying about financing isn’t going to keep me awake at night.”

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 reprogram 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.

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