Post by Bozur on Dec 12, 2005 20:08:12 GMT -5
Better Bananas, Nicer Mosquitoes
By DONALD G. McNEIL Jr.
Published: December 6, 2005
SEATTLE - Addressing 275 of the world's most brilliant scientists, Bill Gates cracked a joke:
"I've been applying my imagination to the synergies of this," he said. "We could have sorghum that cures latent tuberculosis. We could have mosquitoes that spread vitamin A. And most important, we could have bananas that never need to be kept cold."
They laughed. Perhaps that was to be expected when the world's richest man, who had just promised them $450 million, was delivering a punchline. But it was also germane, because they were gathered to celebrate some of the oddest-sounding projects in the history of science.
Reuters
THE CHALLENGE Bill Gates has pledged $450 million to long-shot research projects in global health.
Cassava Production
Disrupting the Mosquito's Sense of Smell
Without Refrigerators or Needles
Jean-Marc Bouju/Associated Press
Projects supported by the Gates Foundation include understanding immunity to H.I.V. among Kenyan prostitutes.
Nigel Cattlin/Photo Researchers, Inc.
The Gates Foundation supports building a better cassava.
Tony Cenicola/The New York Times
The foundation also supports making a hand-held diagnostic lab.
Their deadly serious proposals - answers to the Grand Challenges in Global Health that Mr. Gates posed in a 2003 speech in Davos, Switzerland - sounded much like his spoofs: laboratories around the world, some of them led by Nobel Prize winners, proposing to invent bananas and sorghum that make their own vitamin A; chemicals that render mosquitoes unable to smell humans; drugs that hunt down tuberculosis germs in people who do not even know they are infected; and vaccines that are mixed into spores or plastics or sugars and can be delivered in glasses of orange juice or modified goose calls.
What Mr. Gates had outlined at Davos were the greatest obstacles facing doctors in the tropics: Laboratories are few and far between. Vaccines spoil without refrigeration and require syringes, which can transmit AIDS. Mosquitoes develop resistance to all insecticides. Crops that survive in the jungle or desert often have little nutritive value. Infections outwit powerful drugs by lying dormant.
His offer - originally $200 million, raised to $450 million after 1,600 proposals came in - "was to make sure that innovation wasn't reserved just for big-ticket items like cancer and heart disease," said Dr. Carol A. Dahl, the foundation's director of global health technologies, who ran the conference.
The winning teams, which were named in June,came from as far away as Australia and China, withresearch partners all over Africa and Southeast Asia. Over three days in a Seattle hotel, the 43 team leaders delivered 10-minute summaries of their plans, quizzed foundation officials about details of the grants and discussed possible ethical quandaries with bioethicists from the University of Toronto.
(The most common questions were about the one ironclad rule: grantees may patent anything they discover, but must make it available cheaply to poor countries. An ethical concern common to many projects is that they will eventually require clinical trials on impoverished Africans or Asians with little understanding of informed consent.)
In the hallways and over cocktails and dinners - all paid for by the foundation - virologists and neurologists talked with plant biologists and nanoparticle physicists, sometimes finding ways to help one another. For example, a scientist with plans to improve vitamin-fortified "golden rice" asked the designer of a hand-held laboratory to test blood for pathogens whether it could be modified to test blood for iron and vitamins.
Mr. Gates, in an interview, sidestepped a request to name his favorite projects. "Oh, I love all my children," he said.
But he remained brutally realistic about where his "children" - and the money he lavishes on them - were likely to end up. "Eighty percent of these are likely to be dead ends," he said. "But even if we have a 10 percent hit rate, it will all have been worthwhile."
What follows is a selection of the winning projects.
Dried Vaccines
The only scientist to emit a goose honk during his presentation was Robert E. Sievers, who was illustrating inexpensive straws with useful vibrations.
Dr. Sievers, the chief executive of Aktiv-Dry, a Colorado company that turns liquids into superfine powders, is trying to develop a measles vaccine that can be stored dry and inhaled.
He proposed turning it into glassy particles around a matrix of trehalose, the sugar that allows brine shrimp cysts to survive dried out for years but hatch into wriggling creatures in seawater. (The shrimp are perhaps better known as the "amazing live sea monkeys" advertised in comic books.)
For the powder to reach the lungs instead of sticking to the straw or the throat, the particles must be dispersed evenly in the airstream. Vibration helps, and he tested oboe reeds, New Year's noisemakers and goose calls, trying to find something disposable that needs no power, even from batteries.
A longtime chemistry professor at the University of Colorado, Dr. Sievers, 70, had a second career running a company developing pollution-detection instruments when his son, a pediatrician, described how premature newborns were given surfactants to keep their lung sacs from sticking like Cling Wrap.
"They squirt a bolus of water down into the lungs, then they turn the baby over and pour it out," the elder Dr. Sievers said, shaking his head in disbelief. "There had to be a way to improve that."
In the 1990's, he turned his hand to inhalers for surfactants, then for asthma and now for vaccines. "Measles kills 2,000 children a day," he said, briefly tearing up, and then apologizing for it, as he described his new passion for the cause and what his $20 million grant will let him pursue. "That's like a World Trade Center disaster every day. This is what I want to do with the last stretch of my life."
Abraham L. Sonenshein of Tufts University, who received $5 million, wants to use bacterial spores, another form of nature that can survive desert heat or Arctic cold.
"Our ideal vaccine would be a packet of spores that could be emptied into a glass of juice and drunk down," he said
His chosen vehicle, bacillus subtilis, is found all over the world in dirt.
"Safety is a nonissue," he said. "A large fraction of the Japanese population eats it every day for breakfast." The bacteria are used to ferment soybeans for a dish called natto.
But rather than simply drying an existing vaccine, he wants to splice into the subtilis bacterium's DNA the ability to make the fragments of viral protein that provoke the immune reaction.
Dried bacterial spores could survive indefinitely - and then bloom in the gut and start assembling the proteins.
He has already inserted the genes for diphtheria and tetanus vaccines, and is working on adding whooping cough and rotavirus.
Ten years ago, he said, a Tufts colleague came back from a conference on children's diseases and excitedly described how hard it was to keep vaccines cold in villages without electricity.
Dr. Sonenshein, a bacteria expert, said he replied: "Why are you telling me this?"
But as soon as his colleague asked whether spores could help, he understood.
"We worked on it for two years, and then gave it up, because the traditional funding agencies thought it was too speculative," he said. "The project lay fallow for eight years, so I'm very grateful for the grant."
Mosquito Time Bomb
Scott L. O'Neill, a biologist at Australia's University of Queensland, had an inspiration based on two unrelated facts: mosquitoes must be "middle-aged" - about 14 days old - before they can transmit the dengue virus, and wolbachia bacteria kill fruit flies in midlife.
Since 1975, dengue fever has become a major cause of death for young children, especially in Southeast Asia, where Dr. O'Neill has done field work. "The mosquitoes were controlled in the 1960's," he said. "But they're invading new areas."
Wolbachia, parasitic bacteria, live in many insects, eventually killing some of them. But, in what Dr. O'Neill called a "sneaky and spiteful manipulation of their host," they assure their survival into the next generation by infecting embryos as well, and by rendering infertile any embryos that do not come from infected parents.
(They probably kill the hosts by growing prolifically on their nerve cells, and they may render embryos infertile by somehow preventing egg-sperm fusion, Dr. O'Neill said, but those mysteries are still unsolved.)
Most mosquitoes live about a month, but it takes about 14 days for the dengue virus, which the female picks up by biting an infected human, to mature in her gut and reach her salivary glands, ready to be injected into the next human.
Month-old females who have bitten several people are the most dangerous mosquitoes.
Dr. O'Neill, who received $7 million, hopes to find a life-shortening wolbachia strain in fruit flies or to create one by gene modification, and use it to infect mosquitoes, which now harbor benign strains.
If it works, a female will still live long enough to take a blood meal and lay one set of eggs, so there will be little evolutionary pressure on her to resist the bacteria.
But she will die before she can transmit dengue.
Prostitutes in Kenya
Since 1981, when he was a junior researcher at the University of Manitoba, Dr. Francis A. Plummer has studied thousands of prostitutes in Nairobi, Kenya - initially looking for chancroid and gonorrhea, and then, for the AIDS virus, once it was discovered.
Throughout that time, he said, about 5 percent of the women have remained uninfected by H.I.V., despite hundreds of exposures. That has been well known for years, and is also true of women in the business elsewhere, from Gambia to Thailand; what is not known is why.
With colleagues from several Canadian universities and Nairobi University, Dr. Plummer - who now directs Canada's equivalent of the Centers for Disease Control and Prevention - has found that the women have protective immune responses both in their white blood cells and in their vaginal walls.
Constant repeat exposures seem to boost those responses, but if the women stop working in the sex trade and then return, they often get infected, he said.
Many mysteries remain to unravel, and Dr. Plummer was awarded $8 million, which triples his research budget.
Resistance to H.I.V. clearly runs in families, he said, and he wants to analyze the genes of uninfected women and their relatives.
Also, uninfected women seem to have unusually slow immune systems, and he wants to infect some with mild flus to see how they react.
All attempts to make an AIDS vaccine have failed so far, and Dr. Plummer said his study might open up new approaches, like enhancing resistance genes or slowing immune responses.
Improved Cassavas
Cassava, a tuber practically unknown in the West, is the primary food for 250 million Africans - meaning that, in hard times, they eat nothing else for days.
The tuber's strongest point: it can survive for months in the ground as long as it is attached to its leaves. But it has many weak ones. It turns to mush within 48 hours of picking.
It has little protein. And it contains cyanide and slowly poisons those who eat it unless it is pounded and soaked repeatedly to leach the toxins out.
Dr. Richard T. Sayre said he developed his specialty decades ago when a Nigerian student asked for a job in his lab at Ohio State.
"He had been let go by his government and his department, and I hired him as a dishwasher," said Dr. Sayre, who was then studying photosynthesis.
The student, who was from the Biafra region of Nigeria and had nearly starved during the civil war and famine of the 1960's, asked if he could work on detoxifying cassava. He remembered his grandmother throwing ash in her cooking pot to release the cyanide as a gas.
The student later got a degree in soil science, but "we've been doing cassava for 20 years," Dr. Sayre said. Despite Rockefeller Foundation grants and some federal dollars, "it's always been a struggle." With $7.5 million from the foundation, he wants to genetically modify the tuber to store nitrogen as protein rather than as cyanogens, to produce more vitamin A and E and iron and zinc, and to better resist viral attacks.
The foundation is backing three other projects to improve rice, sorghum and bananas, and the scientists shared ideas at the meeting, as well as their common lament: not being taken seriously.
"It's difficult to get funding for banana research," said Dr. James Dale of the Queensland University of Technology, who is trying to improve Uganda's staple food. "Everyone thinks it's dessert."
Lab in a Box
"When I was in high school, the computer was a large machine that users brought data to," said Paul Yager, 51, a bioengineer from the University of Washington. "Now we have more computing power on our belts - in our cellphones - than existed when I was in high school."
Diagnostic laboratories, he said, have missed that change. Data - blood or urine - must still be shipped to them, a serious impediment to third world care.
Dr. Yager said he got interested in the field when he read about a mystery disease outbreak in a refugee camp that could not be treated correctly until blood samples reached Paris.
Dr. Yager's team received $15 million to develop a palm-size battery-powered lab.
His prototype, he said, will test a finger-stick drop of blood for flu, malaria, typhoid, dengue, measles, rickettsia, salmonella and other fever-causing infections - a tall order, because the infecting agents range from minuscule viruses to relatively immense parasites.
Ideally, the blood will be dripped into a well in a 30-layered piece of disposable plastic the size of a thick credit card, divided and sucked down 16 hair-narrow channels, mixing with reagents stored dry in tiny pits on the cards.
Enzymes will split the blood cells, discard the carbohydrates and leave only pathogen proteins or DNA, which will be amplified by the polymerase chain reaction. Fluorescent-tagged antibodies will be mixed in, and the fever diagnosed - all within 10 minutes.
"It's a stretch, but all the pieces are already done," Dr. Yager said, explaining that he was miniaturizing standard lab tests, "trying not to create any new science at all." (A movie of an instant blood-typing card developed by one of his partners, Micronics Inc., can be seen at micronics.net/products/blood.php.)
The biggest obstacles, he said, are keeping the blood cells from sticking in the microscopic channels and making sure there is enough pathogen to measure in each droplet.
"Engineers, being optimists, tell us that those are not drop-dead problems, but challenges," Dr. Yager said.
Legal challenges, he added, are another matter; many steps he must shrink are patented "by some very large players."
Mosquito 'Olfacticides'
Dr. Richard Axel of the Howard Hughes Medical Institute at Columbia University and Dr. Laurence J. Zwiebel of Vanderbilt University are both experts in insects' sense of smell. (Dr. Axel shared a 2004 Nobel Prize for working out how odors arouse the brain.)
Their complementary projects - Dr. Axel received $5 million and Dr. Zwiebel $8.5 million - have identified the genes that produce 79 odor receptors in mosquitoes.
Now they will seek to build what Dr. Zwiebel described as "a stand-alone mosquito-nose platform" - essentially, an antenna fragment in a petri dish - and to implant mosquito odor-receptor genes into fruit flies, which are easier to study.
Then they will test thousands of small molecules on these artificial or fly-borne "noses" to find chemicals that either block or overwhelm them.
Dr. Axel argued at the conference that blocking one receptor - the one that detects the carbon dioxide in human breath - might be enough to discourage biting.
Dr. Zwiebel argued that, since human sweat contains 150 different compounds, a cocktail of several blockers would be needed, both to encourage mosquitoes to bite other carbon dioxide-exhaling animals, like cows, and to make it harder for mosquitoes to evolve resistance to a single blocker.
One advantage of what Dr. Axel termed "olfacticides," which could be sprayed on the skin or soaked into mosquito nets, is that they are unlikely to be as toxic to humans as insecticides are.
A potential disadvantage is that odor-blockers could, for example, render pollinating insects like bees unable to smell plants.
It may also be possible, Dr. Zwiebel said, to find scents even more alluring than human sweat.
"Imagine," he said, "a village with a vat of DDT laced with compounds so attractive that it would become a mosquito motel: they'd check in, but they wouldn't check out."
Infecting Stem Cells
The most contrarian approach was that announced by Dr. David Baltimore, who shared a 1975 Nobel Prize for his work on tumor viruses and said he had been thinking since the 1980's about the frustrations of fighting AIDS.
Because the virus has thwarted every effort to make a vaccine, he said, "I decided there was potential in modifying the immune system so it would do what you want it to do instead of what it wants to do."
His project, for which he received $14 million, will require many steps: First, designing antibodies with two different "heads" that can bind the AIDS virus at two points. Second, genetically re-engineering a lentivirus to instruct white blood cells to produce those antibodies. Third, infecting stem cells with those lentiviruses, implanting them into patients and getting them to produce white blood cells that reproduce the antibodies.
To test each step, his team must create a mouse with a human immune system, something that three other teams getting Gates grants are also trying.
Although AIDS is his initial target, the approach, if it works, could theoretically be used against any infectious disease and someday render vaccination obsolete.
However, he acknowledged that there were still large problems to be solved, like the possibility that H.I.V. could mutate out of reach of his designed antibodies, and the fact that lentiviruses can cause cancer and must be rendered harmless before they are injected into a human immune system for life.
Vaginal Rings
Because some immune response to AIDS is at the site of infection, Dr. Robin John Shattock of the University of London is trying to develop vaccines that can be delivered in gels or a silicone ring that a woman can insert in her vagina, without a doctor's help, to deliver tiny daily doses.
The ring will be adapted from one already used for birth control and can adjust itself to menstrual cycles, which affect immune responses.
Ideally, he said, women will also get microbicides - virus-killing chemicals applied just before sex - through the same rings or gels, so the virus will get a one-two punch.
"We're trying to look at vaccination from a completely new viewpoint and set the bar really, really low," said Dr. Shattock, who received $20 million.
While conventional vaccine engineers try to invent one huge dose that provokes a strong immune reaction and gives lifelong immunity, he explained, he wants to deliver tiny doses conferring brief immunity without inflaming the vaginal wall, because inflammation there raises a woman's risk of infection.
By DONALD G. McNEIL Jr.
Published: December 6, 2005
SEATTLE - Addressing 275 of the world's most brilliant scientists, Bill Gates cracked a joke:
"I've been applying my imagination to the synergies of this," he said. "We could have sorghum that cures latent tuberculosis. We could have mosquitoes that spread vitamin A. And most important, we could have bananas that never need to be kept cold."
They laughed. Perhaps that was to be expected when the world's richest man, who had just promised them $450 million, was delivering a punchline. But it was also germane, because they were gathered to celebrate some of the oddest-sounding projects in the history of science.
Reuters
THE CHALLENGE Bill Gates has pledged $450 million to long-shot research projects in global health.
Cassava Production
Disrupting the Mosquito's Sense of Smell
Without Refrigerators or Needles
Jean-Marc Bouju/Associated Press
Projects supported by the Gates Foundation include understanding immunity to H.I.V. among Kenyan prostitutes.
Nigel Cattlin/Photo Researchers, Inc.
The Gates Foundation supports building a better cassava.
Tony Cenicola/The New York Times
The foundation also supports making a hand-held diagnostic lab.
Their deadly serious proposals - answers to the Grand Challenges in Global Health that Mr. Gates posed in a 2003 speech in Davos, Switzerland - sounded much like his spoofs: laboratories around the world, some of them led by Nobel Prize winners, proposing to invent bananas and sorghum that make their own vitamin A; chemicals that render mosquitoes unable to smell humans; drugs that hunt down tuberculosis germs in people who do not even know they are infected; and vaccines that are mixed into spores or plastics or sugars and can be delivered in glasses of orange juice or modified goose calls.
What Mr. Gates had outlined at Davos were the greatest obstacles facing doctors in the tropics: Laboratories are few and far between. Vaccines spoil without refrigeration and require syringes, which can transmit AIDS. Mosquitoes develop resistance to all insecticides. Crops that survive in the jungle or desert often have little nutritive value. Infections outwit powerful drugs by lying dormant.
His offer - originally $200 million, raised to $450 million after 1,600 proposals came in - "was to make sure that innovation wasn't reserved just for big-ticket items like cancer and heart disease," said Dr. Carol A. Dahl, the foundation's director of global health technologies, who ran the conference.
The winning teams, which were named in June,came from as far away as Australia and China, withresearch partners all over Africa and Southeast Asia. Over three days in a Seattle hotel, the 43 team leaders delivered 10-minute summaries of their plans, quizzed foundation officials about details of the grants and discussed possible ethical quandaries with bioethicists from the University of Toronto.
(The most common questions were about the one ironclad rule: grantees may patent anything they discover, but must make it available cheaply to poor countries. An ethical concern common to many projects is that they will eventually require clinical trials on impoverished Africans or Asians with little understanding of informed consent.)
In the hallways and over cocktails and dinners - all paid for by the foundation - virologists and neurologists talked with plant biologists and nanoparticle physicists, sometimes finding ways to help one another. For example, a scientist with plans to improve vitamin-fortified "golden rice" asked the designer of a hand-held laboratory to test blood for pathogens whether it could be modified to test blood for iron and vitamins.
Mr. Gates, in an interview, sidestepped a request to name his favorite projects. "Oh, I love all my children," he said.
But he remained brutally realistic about where his "children" - and the money he lavishes on them - were likely to end up. "Eighty percent of these are likely to be dead ends," he said. "But even if we have a 10 percent hit rate, it will all have been worthwhile."
What follows is a selection of the winning projects.
Dried Vaccines
The only scientist to emit a goose honk during his presentation was Robert E. Sievers, who was illustrating inexpensive straws with useful vibrations.
Dr. Sievers, the chief executive of Aktiv-Dry, a Colorado company that turns liquids into superfine powders, is trying to develop a measles vaccine that can be stored dry and inhaled.
He proposed turning it into glassy particles around a matrix of trehalose, the sugar that allows brine shrimp cysts to survive dried out for years but hatch into wriggling creatures in seawater. (The shrimp are perhaps better known as the "amazing live sea monkeys" advertised in comic books.)
For the powder to reach the lungs instead of sticking to the straw or the throat, the particles must be dispersed evenly in the airstream. Vibration helps, and he tested oboe reeds, New Year's noisemakers and goose calls, trying to find something disposable that needs no power, even from batteries.
A longtime chemistry professor at the University of Colorado, Dr. Sievers, 70, had a second career running a company developing pollution-detection instruments when his son, a pediatrician, described how premature newborns were given surfactants to keep their lung sacs from sticking like Cling Wrap.
"They squirt a bolus of water down into the lungs, then they turn the baby over and pour it out," the elder Dr. Sievers said, shaking his head in disbelief. "There had to be a way to improve that."
In the 1990's, he turned his hand to inhalers for surfactants, then for asthma and now for vaccines. "Measles kills 2,000 children a day," he said, briefly tearing up, and then apologizing for it, as he described his new passion for the cause and what his $20 million grant will let him pursue. "That's like a World Trade Center disaster every day. This is what I want to do with the last stretch of my life."
Abraham L. Sonenshein of Tufts University, who received $5 million, wants to use bacterial spores, another form of nature that can survive desert heat or Arctic cold.
"Our ideal vaccine would be a packet of spores that could be emptied into a glass of juice and drunk down," he said
His chosen vehicle, bacillus subtilis, is found all over the world in dirt.
"Safety is a nonissue," he said. "A large fraction of the Japanese population eats it every day for breakfast." The bacteria are used to ferment soybeans for a dish called natto.
But rather than simply drying an existing vaccine, he wants to splice into the subtilis bacterium's DNA the ability to make the fragments of viral protein that provoke the immune reaction.
Dried bacterial spores could survive indefinitely - and then bloom in the gut and start assembling the proteins.
He has already inserted the genes for diphtheria and tetanus vaccines, and is working on adding whooping cough and rotavirus.
Ten years ago, he said, a Tufts colleague came back from a conference on children's diseases and excitedly described how hard it was to keep vaccines cold in villages without electricity.
Dr. Sonenshein, a bacteria expert, said he replied: "Why are you telling me this?"
But as soon as his colleague asked whether spores could help, he understood.
"We worked on it for two years, and then gave it up, because the traditional funding agencies thought it was too speculative," he said. "The project lay fallow for eight years, so I'm very grateful for the grant."
Mosquito Time Bomb
Scott L. O'Neill, a biologist at Australia's University of Queensland, had an inspiration based on two unrelated facts: mosquitoes must be "middle-aged" - about 14 days old - before they can transmit the dengue virus, and wolbachia bacteria kill fruit flies in midlife.
Since 1975, dengue fever has become a major cause of death for young children, especially in Southeast Asia, where Dr. O'Neill has done field work. "The mosquitoes were controlled in the 1960's," he said. "But they're invading new areas."
Wolbachia, parasitic bacteria, live in many insects, eventually killing some of them. But, in what Dr. O'Neill called a "sneaky and spiteful manipulation of their host," they assure their survival into the next generation by infecting embryos as well, and by rendering infertile any embryos that do not come from infected parents.
(They probably kill the hosts by growing prolifically on their nerve cells, and they may render embryos infertile by somehow preventing egg-sperm fusion, Dr. O'Neill said, but those mysteries are still unsolved.)
Most mosquitoes live about a month, but it takes about 14 days for the dengue virus, which the female picks up by biting an infected human, to mature in her gut and reach her salivary glands, ready to be injected into the next human.
Month-old females who have bitten several people are the most dangerous mosquitoes.
Dr. O'Neill, who received $7 million, hopes to find a life-shortening wolbachia strain in fruit flies or to create one by gene modification, and use it to infect mosquitoes, which now harbor benign strains.
If it works, a female will still live long enough to take a blood meal and lay one set of eggs, so there will be little evolutionary pressure on her to resist the bacteria.
But she will die before she can transmit dengue.
Prostitutes in Kenya
Since 1981, when he was a junior researcher at the University of Manitoba, Dr. Francis A. Plummer has studied thousands of prostitutes in Nairobi, Kenya - initially looking for chancroid and gonorrhea, and then, for the AIDS virus, once it was discovered.
Throughout that time, he said, about 5 percent of the women have remained uninfected by H.I.V., despite hundreds of exposures. That has been well known for years, and is also true of women in the business elsewhere, from Gambia to Thailand; what is not known is why.
With colleagues from several Canadian universities and Nairobi University, Dr. Plummer - who now directs Canada's equivalent of the Centers for Disease Control and Prevention - has found that the women have protective immune responses both in their white blood cells and in their vaginal walls.
Constant repeat exposures seem to boost those responses, but if the women stop working in the sex trade and then return, they often get infected, he said.
Many mysteries remain to unravel, and Dr. Plummer was awarded $8 million, which triples his research budget.
Resistance to H.I.V. clearly runs in families, he said, and he wants to analyze the genes of uninfected women and their relatives.
Also, uninfected women seem to have unusually slow immune systems, and he wants to infect some with mild flus to see how they react.
All attempts to make an AIDS vaccine have failed so far, and Dr. Plummer said his study might open up new approaches, like enhancing resistance genes or slowing immune responses.
Improved Cassavas
Cassava, a tuber practically unknown in the West, is the primary food for 250 million Africans - meaning that, in hard times, they eat nothing else for days.
The tuber's strongest point: it can survive for months in the ground as long as it is attached to its leaves. But it has many weak ones. It turns to mush within 48 hours of picking.
It has little protein. And it contains cyanide and slowly poisons those who eat it unless it is pounded and soaked repeatedly to leach the toxins out.
Dr. Richard T. Sayre said he developed his specialty decades ago when a Nigerian student asked for a job in his lab at Ohio State.
"He had been let go by his government and his department, and I hired him as a dishwasher," said Dr. Sayre, who was then studying photosynthesis.
The student, who was from the Biafra region of Nigeria and had nearly starved during the civil war and famine of the 1960's, asked if he could work on detoxifying cassava. He remembered his grandmother throwing ash in her cooking pot to release the cyanide as a gas.
The student later got a degree in soil science, but "we've been doing cassava for 20 years," Dr. Sayre said. Despite Rockefeller Foundation grants and some federal dollars, "it's always been a struggle." With $7.5 million from the foundation, he wants to genetically modify the tuber to store nitrogen as protein rather than as cyanogens, to produce more vitamin A and E and iron and zinc, and to better resist viral attacks.
The foundation is backing three other projects to improve rice, sorghum and bananas, and the scientists shared ideas at the meeting, as well as their common lament: not being taken seriously.
"It's difficult to get funding for banana research," said Dr. James Dale of the Queensland University of Technology, who is trying to improve Uganda's staple food. "Everyone thinks it's dessert."
Lab in a Box
"When I was in high school, the computer was a large machine that users brought data to," said Paul Yager, 51, a bioengineer from the University of Washington. "Now we have more computing power on our belts - in our cellphones - than existed when I was in high school."
Diagnostic laboratories, he said, have missed that change. Data - blood or urine - must still be shipped to them, a serious impediment to third world care.
Dr. Yager said he got interested in the field when he read about a mystery disease outbreak in a refugee camp that could not be treated correctly until blood samples reached Paris.
Dr. Yager's team received $15 million to develop a palm-size battery-powered lab.
His prototype, he said, will test a finger-stick drop of blood for flu, malaria, typhoid, dengue, measles, rickettsia, salmonella and other fever-causing infections - a tall order, because the infecting agents range from minuscule viruses to relatively immense parasites.
Ideally, the blood will be dripped into a well in a 30-layered piece of disposable plastic the size of a thick credit card, divided and sucked down 16 hair-narrow channels, mixing with reagents stored dry in tiny pits on the cards.
Enzymes will split the blood cells, discard the carbohydrates and leave only pathogen proteins or DNA, which will be amplified by the polymerase chain reaction. Fluorescent-tagged antibodies will be mixed in, and the fever diagnosed - all within 10 minutes.
"It's a stretch, but all the pieces are already done," Dr. Yager said, explaining that he was miniaturizing standard lab tests, "trying not to create any new science at all." (A movie of an instant blood-typing card developed by one of his partners, Micronics Inc., can be seen at micronics.net/products/blood.php.)
The biggest obstacles, he said, are keeping the blood cells from sticking in the microscopic channels and making sure there is enough pathogen to measure in each droplet.
"Engineers, being optimists, tell us that those are not drop-dead problems, but challenges," Dr. Yager said.
Legal challenges, he added, are another matter; many steps he must shrink are patented "by some very large players."
Mosquito 'Olfacticides'
Dr. Richard Axel of the Howard Hughes Medical Institute at Columbia University and Dr. Laurence J. Zwiebel of Vanderbilt University are both experts in insects' sense of smell. (Dr. Axel shared a 2004 Nobel Prize for working out how odors arouse the brain.)
Their complementary projects - Dr. Axel received $5 million and Dr. Zwiebel $8.5 million - have identified the genes that produce 79 odor receptors in mosquitoes.
Now they will seek to build what Dr. Zwiebel described as "a stand-alone mosquito-nose platform" - essentially, an antenna fragment in a petri dish - and to implant mosquito odor-receptor genes into fruit flies, which are easier to study.
Then they will test thousands of small molecules on these artificial or fly-borne "noses" to find chemicals that either block or overwhelm them.
Dr. Axel argued at the conference that blocking one receptor - the one that detects the carbon dioxide in human breath - might be enough to discourage biting.
Dr. Zwiebel argued that, since human sweat contains 150 different compounds, a cocktail of several blockers would be needed, both to encourage mosquitoes to bite other carbon dioxide-exhaling animals, like cows, and to make it harder for mosquitoes to evolve resistance to a single blocker.
One advantage of what Dr. Axel termed "olfacticides," which could be sprayed on the skin or soaked into mosquito nets, is that they are unlikely to be as toxic to humans as insecticides are.
A potential disadvantage is that odor-blockers could, for example, render pollinating insects like bees unable to smell plants.
It may also be possible, Dr. Zwiebel said, to find scents even more alluring than human sweat.
"Imagine," he said, "a village with a vat of DDT laced with compounds so attractive that it would become a mosquito motel: they'd check in, but they wouldn't check out."
Infecting Stem Cells
The most contrarian approach was that announced by Dr. David Baltimore, who shared a 1975 Nobel Prize for his work on tumor viruses and said he had been thinking since the 1980's about the frustrations of fighting AIDS.
Because the virus has thwarted every effort to make a vaccine, he said, "I decided there was potential in modifying the immune system so it would do what you want it to do instead of what it wants to do."
His project, for which he received $14 million, will require many steps: First, designing antibodies with two different "heads" that can bind the AIDS virus at two points. Second, genetically re-engineering a lentivirus to instruct white blood cells to produce those antibodies. Third, infecting stem cells with those lentiviruses, implanting them into patients and getting them to produce white blood cells that reproduce the antibodies.
To test each step, his team must create a mouse with a human immune system, something that three other teams getting Gates grants are also trying.
Although AIDS is his initial target, the approach, if it works, could theoretically be used against any infectious disease and someday render vaccination obsolete.
However, he acknowledged that there were still large problems to be solved, like the possibility that H.I.V. could mutate out of reach of his designed antibodies, and the fact that lentiviruses can cause cancer and must be rendered harmless before they are injected into a human immune system for life.
Vaginal Rings
Because some immune response to AIDS is at the site of infection, Dr. Robin John Shattock of the University of London is trying to develop vaccines that can be delivered in gels or a silicone ring that a woman can insert in her vagina, without a doctor's help, to deliver tiny daily doses.
The ring will be adapted from one already used for birth control and can adjust itself to menstrual cycles, which affect immune responses.
Ideally, he said, women will also get microbicides - virus-killing chemicals applied just before sex - through the same rings or gels, so the virus will get a one-two punch.
"We're trying to look at vaccination from a completely new viewpoint and set the bar really, really low," said Dr. Shattock, who received $20 million.
While conventional vaccine engineers try to invent one huge dose that provokes a strong immune reaction and gives lifelong immunity, he explained, he wants to deliver tiny doses conferring brief immunity without inflaming the vaginal wall, because inflammation there raises a woman's risk of infection.