Complicated Path Toward A Healthier World*

WASHINGTON - About 1,600 proposals came in, and the top 43 were so promising that the Bill & Melinda Gates Foundation gave $450 million in fiveyear grants. Now the five years are up, and the foundation recently brought all the scientists to seattle to assess the results.

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."

In 2007, instead of making more multimillion-dollar grants, he started making hundreds of $100,000 ones. That little won't buy a breakthrough, but it lets scientists "moonlight" by adding goals to their existing grants. "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."

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. 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 in Massachusetts 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.

Eobert 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.

Dr. Sievers's Gates grant is not being renewed, but he is partnering with the serum institute of India.

The foundation is still supporting two thermostabilization techniques. The first attaches vaccines to nanoparticles that can be absorbed in 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. The second thermostabilized vaccine works against malaria. Rather than being bottled, the vaccine can be dried onto a bit of filter paper.

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 in New York and Dr. Richard Axel, a Howard Hughes Medical institute investigator at Columbia University in New York, got $5 million to hunt for molecules that could block mosquitoes' ability to detect people. Their Gates grant is renewed for two years.

‘Exhausted' Immune Cells

Another grant is ending because it attracted so much commercial backing. Rafi Ahmed, an immunologist at Emory University in Atlanta, studies why the immune system's T-cells get "exhausted" during a long battle against some viruses like H.I.V. or hepatitis C. He discovered the cells grew "inhibitory receptors."

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

"It doesn't result in a cure, but it's quite promising," said Dr. Ahmed, who 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.

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.

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, betacarotene.

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 will take another 10 years, the project is meeting interim goals, said Richard T. Sayre, its principal investigator. They include decreasing natural cyanide in the tubers, increasing protein, iron, zinc and vitamins A and E, and engineering in resistance to 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.

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 stays in the mosquito population. The wolbachia strain Dr. O'Neill used had an unexpected side effect: it also blocked chikungunya, another 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."

The Gates Foundation is stil l supporting his work.

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. 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. 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.