Beija-Flor, Brazil- It took a four-wheel-drive vehicle a kidney-jarring hour to traverse five miles of rutted, rocky road leading to the one-room church serving the agricultural settlement. Once inside, immunologist Jeff Bethony of George Washington University (GWU) and physician David Diemert of Washington, DC-based Sabin Vaccine Institute, pushed aside the wooden benches to set up a scale, an examination space, and a makeshift interview room.

The researchers were at a critical juncture. Today, they were going to register the first volunteers for a clinical trial that would test the safety of a hookworm vaccine in people routinely exposed to the parasite, Necator americanus.

The researchers hovered nervously nearby as a local physician and several assistants interviewed the first three candidates. Azizo Alves Dos Santos, 36, one of the first to arrive, was eager to volunteer. He previously had several serious hookworm infections, which sapped his strength and kept him away from the hillside fields where he grew beans and manioc, the local staples. An active member of the local agricultural laborers association, Santos was familiar with the toll that the disease took on farm workers like him. When they can't work, they don't get enough to eat. "This vaccine will benefit this region, Brazil, and all the world," Santos says through a Portuguese translator.

Unlike developing world pandemics such as HIV/AIDS and malaria, mortality among the 500 million people worldwide infected with hookworms is not so high - an estimated 65,000 people a year. Studies have shown, however, that hookworm infestations reduce agricultural productivity by 40% and lead to a 25% reduction in childhood educational performance among those chronically infected. An estimated 44 million hookworm-infected women give birth each year. They deliver low-weight babies, have impaired milk production, and have higher-than-expected infant and maternal mortality.

Infection requires only a few dozen larvae migrating from the lungs to the bronchial tract, where they are coughed up and swallowed. The surviving larvae eventually latch onto the intestinal wall where they grow to maturity while sucking the victim's blood. They also mate, with the females' eggs exiting the host in feces. After hatching in the surrounding environment, the larvae can live as long as a year in warm, wet climates before infecting other people, thus completing the cycle.

Though a three-day course of benzimidazoles (albendazole or mebendazole are most commonly used) effectively eliminates the worms, in poorer precincts where clean water and sanitary facilities are rare, reinfection within less than a year is common. Even in areas with annual deworming campaigns - the World Health Organization's Partners in Parasite Control program estimates that 55.6 million children were dewormed in 2005 - infection rates remain above 50% of the local population. In this section of Brazil, for instance, the infection rate is above 60%.

Even in relatively prosperous Brazil, deworming campaigns can pay only sporadic visits to isolated rural communities. It would take four years to get to every pocket of the Texas-sized state of Minas Gerais, where hookworm is endemic, according to Rodrigo Corrêa Oliveira, chief of the immunology laboratory at René Rachou FIOCRUZ, the Ministry of Health's research arm in Belo Horizonte. "The Gates Foundation is funding a massive deworming program in Africa for which we're producing the drugs," he says, "but it is not sustainable."

The extent to which a person gets sick is directly proportional to the number of worms inhabiting his or her intestinal tract. Reducing that number can substantially reduce the overall disease burden, which argues for a vaccine. The principal developer of the vaccine, Peter Hotez of GWU, knows that creating a vaccine that would make an individual totally immune to hookworm infection is not possible. "The goal," he says, "is to elicit an antibody response that reduces the number of larvae that will migrate and become adult hookworms."

Vaccines against multicellular parasites such as N. americanus, however, have proven almost impossible to produce. That's because most vaccines work by mobilizing the immune system to generate a massive response to the presence of a pathogen, usually a bacteria or a virus. This sterilizing immunity kills off the pathogen shortly after exposure. The natural immune reaction to the presence of a large and complex organism simply isn't adequate to provide protection.

This inadequacy occurs in part because hookworms, which can grow to one centimeter in length once they lodge in the intestines, have their own immune systems. After larvae enter humans through the skin, the worms deploy defenses that may cloak their presence in the blood stream during their early stages of life. Moreover, its extensive genome - the Sanger Institute estimates 25,000-plus genes - produces many proteins that interact in complex ways. So even when the human immune system produces antibodies, it is usually only in minute quantities and often aimed at the wrong targets. The ineffective reaction may kill off some larvae, but it allows others to escape.

So while a successful vaccine would help, "the likelihood of success is not very high," says Oliveira. "This is a complex parasite that has evolved over a million years." Unlike water-borne schistosomiasis, he explains, to which people build up immunity after repeated exposures, many people's immune systems never learn how to resist hookworm. For some, the older they get, the worse the infections become. "We have to show that the immune response generated by a vaccine is quite distinct from the immune response of the actual infection," he says. "We're hoping it will be."

It took decades for the Sabin research team to reach a point at which it had a vaccine worth trying in Beija-Flor. Hotez, who received his medical and biochemistry training at Rockefeller University, began his parasitology studies in 1980. Short in stature but long in optimism, Hotez wears bow ties and round, gold-framed glasses. His brown curly hair has only a hint of gray and his perpetual smile is infectious. He stumbled onto his life's calling after reading a 1962 paper by Norman Stoll, the pathbreaking Rockefeller parasitologist who called hookworms "the great infection of mankind."

In 1989, Hotez moved to Yale University, where he conducted most of the early scientific work aimed at identifying a vaccine target. His early epidemiologic studies in China had revealed a wide variation in the number of worms among people who were routinely exposed to the parasite. He also knew from his early days as a graduate student that an attenuated larvae vaccine for canine hookworm had been developed in the 1960s and 1970s. Its manufacturer discontinued making it in 1975 after only a few years on the market, citing poor sales. Veterinarians, it turned out, made more money from routine deworming than from a one-time vaccine. Plus, some pet owners complained because they still saw worm eggs in their dogs' feces. To Hotez, though, the partial response suggested that some naturally occurring antibody, albeit stronger in some hosts than in others, was offering partial immunity.

Hotez began hunting for the antigen that was generating the response. If reproduced in large quantities through recombinant engineering and administered as a vaccine, he hypothesized, the body might build up a large store of the immune system's memory cells that could generate an overwhelming antibody response against future invaders.

Working with canine hookworm, Hotez ran experiments to isolate potential antigens from the larvae that could form the basis of a recombinant vaccine. Using a method that a postdoc, John Hawdon, had established for getting larvae to resume development, the two men were stymied initially by the activated larvae's failure to produce proteins that might be potential vaccine targets. "There were no secretions," Hotez recalled. "You had to trick them to think they were in the host."

So Hotez and colleagues placed the larvae in media containing either host blood serum, glutathione, or both, and they managed to identify three major proteins emitted from the invading larvae. Two were Ancyclostoma-secreted proteins (ASP-1 and ASP-2), which belong to a family of signaling proteins that all animals and some plants secrete in the presence of pathogens; the third was MTP-?1, which also plays a role in the worm's own immune system.2 The next steps, however, required serious funding, which Hotez set out to procure.

Moises Gonzales de Chagas, a 54-year-old agricultural laborer, is typical of the rural populations around the world that would benefit from a hookworm vaccine. The day in early May that I visited his small, cinderblock home, he told me he had begun feeling ill last December. As the months went by, he grew gradually weaker. Diemert, the project's lead field physician, later speculated the man had probably harbored some worms for years - they can live up to five years in the intestines. It was only when the population of blood-sucking visitors reached a critical mass (between 40 and 120 worms) that he developed iron-deficiency anemia, the primary symptom of the disease.

Emerging from the shadows of his three-room house, Gonzales' eyes slowly adjust to the late afternoon sunlight. He sticks out his dry tongue to reveal white spots. Two days earlier, he had walked to a government-run traveling clinic where he was treated with albendazole, a deworming drug whose three-day course kills the parasites to provide temporary relief. When he returns to his job, however, the moist fields where he works will be filled with hookworm larvae, deposited there in human waste. He will probably get infected again, since humans do not naturally develop immunity, even with repeated exposures.

An effective vaccine would be a godsend to the estimated half billion people around the globe who are infected with hookworms. Although the parasite usually doesn't kill, chronic hookworm infections sap the strength and productivity of adults. "Before I was sick, I worked on the farm," Gonzales says. "Now I don't work."

Chronic infection also retards the mental and physical development of children - perhaps its most pernicious and socially debilitating effect. At the cabin next door, a farmworker cradles his son in his arms. For months, 6-year-old Renilson dos Santos had been tired and listless, doing poorly in school and not wanting to play football with his friends. After being treated by the traveling clinic (it comes by only around twice a year), his mother Maria notices the difference. "He plays. He has more energy now," she says.

By the 1990s, foundations were becoming interested in helping Renilson Santos and others in similar straits. In 1998, shortly after hearing about the Bill and Melinda Gates Foundation from Jeffrey Sachs at Harvard University, whose growing interest in the issue of global poverty had led him to the hookworm project, Hotez applied for and received one of the first Gates grants for research in neglected diseases. The Sabin Institute has received $54 million since 1999.

"I always say, be careful what you wish for," Hotez says. He moved his operation to GWU in 2000 to be near the vaccine development infrastructure that surrounds the nation's capital. "I had to set up a biotech company," he says. "We recruited an extraordinary bunch of PhD scientists who were interested in becoming vaccine manufacturers."

The researchers needed to isolate and identify the human hookworm equivalents of the protein targets they had identified in canine hookworm, clone those proteins, combine them with an adjuvant, and begin injecting experimental animals to determine the protein that generated the best immune response. They developed a scoring system based on measurements of adult worm reduction, host blood loss, and eggs per gram of feces. The animal tests all pointed to ASP-2 as the best lead candidate.

Bethony's crackerjack epidemiologic field work supplemented these animal experiments. The immunologist, who spends most of his time in Brazil, created a blood test to check for antibodies. He discovered that 15% of the population had measurable levels of antibodies to ASP-2. "We found that (those) people ... did not have heavy infections, so we deduced they were at lower risk," Bethony says.

At this point, an academic researcher with a lead candidate will usually license his or her discovery to a pharmaceutical company to begin scaling up production for clinical trials. But no company was interested in developing a vaccine for a disease that affects only the globe's poorest citizens.

Maria Elena Bottazzi, the newly hired product development officer at the Hookorm Vaccine Initiative, instead turned to the Walter Reed Army Institute of Research (WRAIR) for help in setting up a small facility to produce large quantities of the protein for an experimental vaccine. WRAIR used recipes that Bottazzi's team had developed in a pilot plant on the GWU campus. Next, a trial in 36 healthy US volunteers showed that the injection was safe and generated a substantial immunologic response, at least in people who had never been exposed to the parasite.

The same technology is now being transferred to the government-run Butantan Institute in Sao Paolo, Brazil, which will eventually produce the vaccine for the large trials needed to prove efficacy. The Butantan Institute, Sao Paolo's public health research arm, is best known for its research into antivenoms and antitoxins for rabies, diphtheria, and botulina. It also houses one of the world's largest vaccine manufacturing complexes, producing nearly 200 million vaccine doses per year, including tetanus, pertussis, hepatitis B, and the latest influenza strain.

Using money from the Gates Foundation, Butantan recently purchased the equipment needed to produce a sufficient number of vaccine doses for the final efficacy trials, which should be underway by the end of the decade. The plant, which uses a 60-liter fermenter, may be large enough to supply the entire country once ANVISA (Agencia Nacional Vigilancia Sanitario), the Brazilian equivalent of the US Food and Drug Administration, approves the vaccine. "Our bottom line is the right to produce it here for Brazil," says 80-year-old Isaias Raw, president of Butantan. "We would like to provide it if possible to organizations like UNICEF and the Pan American Health Organization."

Raw, whose excellent English skills date from his time in exile teaching at City College in New York, says his experience at government-run Butantan defies the conventional wisdom that "governments are incompetent and companies are competent. Our problem is that whatever doesn't make profit isn't their concern. You're never going to vaccinate unless the price is low. If you show up with a vaccine that costs even $50 a person, in a country like ours, it might as well not exist," he says.

The Sabin Institute's Hotez, who holds the patent to the hookworm vaccine, follows an intellectual property model adopted by most nonprofits that the Gates Foundation funds. It has agreed to transfer the cell line, the manufacturing technology, and a royalty-free license to any country able and willing to produce it at standards set by the FDA and other regulatory agencies. It is already exploring partnerships with India, China, Indonesia, and Cuba, in addition to Brazil. "We will send it to anyone," says Hotez.

"I feel like I'm the conductor of a symphony orchestra," Hotez says. "I'm organizing the labs, the science, the production for delivery to the field - all to solve a common problem among the world's poorest people."

The night before the team registered their first patients, Bethony and Diemert described the difficulties of adhering to "good clinical practices" while conducting clinical trials in developing countries. They have built a small, three-bedroom house in nearby Americaninhas where the research team bunks four to a room. A long picnic table fills the dining area of the communal kitchen. Their work shed, complete with a small microscopy lab, has satellite-driven Internet access to the outside world, that is, when surges or outages don't crash the computers.

The logistic challenges of conducting a clinical trial in this resource-poor setting are extraordinary. The three-shot vaccine has to be administered over three months since the goal is to build a large store of immune-system memory cells that will produce a high volume of anti-ASP-?2 antibodies when the person is exposed to hookworm larvae. Each dose has to be maintained between 3°C and 9°C while being transported from the United States, and the temperature must be monitored and documented every step of the way.

Moreover, while stool samples collected in the field can be analyzed in the local microscopy lab for their hookworm egg count (a primary measure of efficacy, but a secondary endpoint in this safety trial), the blood samples for measuring antibody response must be sent to a more sophisticated lab in the regional capital, 12 hours away by car. Detailed case report forms must be filled out for every patient. "A properly designed study will be a failure if the data are not collected in a fashion that can be verified, which in turn compromises the ethics of conducting such a trial, because participants will have been exposed to risk needlessly," Diemert and Bethony wrote recently in response to an editorial questioning the applicability of First World regulatory standards in tropical disease trials.

The forests that once blanketed the hills in this equatorial climate have long since been stripped away for cattle grazing and subsistence farming of sugar cane, corn, beans, and manioc. The people who eke out a subsistence living from this rugged terrain understand perfectly well how hookworms and the other infectious parasites such as water-borne schistosomiasis are ruining their lives and robbing their children's future. Bethony, Diemert, and their colleagues must explain to these volunteers that the vaccine is only an early safety test and that there are risks with no guarantee that it will work. "You don't want them [to participate] because they think they're going to get something in return," Bethony says. "You want them to understand the benefits and risks. That's the challenge."

Most of the people in the area are illiterate, Bethony says. "So many of our participants have witnesses appointed by the community to make sure they've heard the whole consent form and presentation, and that they comprehend." Long before today's final interview, social scientists working on Sabin's Hookworm Vaccine Initiative had traveled throughout the region showing a video to educate the public about the life cycle of the disease and the purpose of the experimental vaccine program. Potential volunteers, before signing up, had to attend community lectures.

Now that sign-up day has finally arrived, the volunteers, accompanied by a community ombudsman who serves as their advocate, must take a final test showing that they understand the risks associated with being among the first people living in an endemic setting to receive the vaccine. Institutional review boards at both the state and national levels in Brazil approved both the experimental protocol and the informed consent process.

Erleide Pereira Viana, a 27-year-old mother with one preschool child, shows up early, her red cap turned jauntily backwards. She looks on pensively as project officials tally her responses to a test of whether she understands the risks of the trial. Told she has passed, she smiles. "It's good for the health of the people," she says.

Even as this trial gets underway, the Sabin team is laying the groundwork for the next phase of the project: identifying a second target in mature hookworms that may escape the initial immune system onslaught. "You want to hit them a second time after they become adults," Hotez says. With Alex Loukas of Australia's Queensland Institute of Medical Research in the lead, the Sabin team, again working with canine hookworm, identified an aspartic protease (APR-1) in the worm that is key to digesting hemoglobin once the parasite is in the intestines. A vaccine using a recombinant version of APR-1 significantly reduced hookworm burdens in dogs.

However, the protein is proving very costly and difficult to manufacture in bulk. The search is now on for a second candidate. "If you can't make it cheaply, you might as well not make it at all," Hotez said. "We have to build into our design process the ability to deliver this vaccine at less than $1 a dose."

Even if they finally do come up with a vaccine that can be made cheaply, it will be of little use unless it can be delivered to the world's poor. Hotez and the Sabin Vaccine Institute recently launched Global Network for Neglected Tropical Disease Control, whose partners include the World Health Organization and nonprofits fighting schistosomiasis, trachoma, and the soil-transmitted worms known as helminths (hookworm, ascaris, and trichuris). The partnership's goal is to set up healthcare delivery systems, especially in sub-Saharan Africa where the need is greatest, for rapidly delivering low-cost drugs that are effective in treating these diseases. The same networks will later be able to administer vaccines if they become available.

That's still a big if. If the safety trial that started in June is successful, the efficacy trials that will be needed for regulatory approval will take at least another half decade, maybe longer. The entire process will then have to be repeated for a vaccine that includes the second antigen attacking adult hookworms that escape the initial immune system reaction.

"A lot of academics think that if you isolate a protein in a lab, you've done your job," Hotez says. "Then all you have to do is turn it over to a manufacturer and it appears in a bottle. This takes a long time. Vaccine development takes a lifetime of refining."

Lucimar Medina de Souza Gomes, a 29-year-old mother whose young child clings to her skirt, is hopeful as she inks her thumbprint to the consent form. "It will help develop a vaccine that will put an end to the worm."

One morning in August, a 24-year-old Karen tribeswoman living in a remote village in northeast Myanmar woke with a rapidly mounting fever. Though five months into her fourth pregnancy, she walked two hours to the rain-swollen Moei River, the poorly patrolled border with Thailand. After paying a boatman five baht (about 15 cents) to make the dangerous crossing, she arrived at a clinic in Mae Kon Ken, Thailand.

A physician's assistant at the clinic, which is operated by the Shoklo Malaria Research Unit (SMRU) of the Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Program, immediately diagnosed malaria and gave her one of the most powerful weapons in the global armamentarium for fighting the disease: an artemisinin-derivative called artesunate. Because the fast-acting antimalarial - which Chinese scientists first derived in the early 1970s from qinghaosu, the sweet wormwood bush (Artemisia annua) - is cleared from the body in a matter of hours, the physicians in charge of her care contemplated giving her another antimalarial to prevent a recurrence of the disease.

Such combination therapy is crucial to preventing the emergence of artemisinin resistance. While the drug is the most efficient malaria parasite killer ever discovered, it's short half-life requires another, longer-lasting drug that can kill any parasites that survive the initial onslaught or emerge later in the parasite's life cycle. "What am I to do with this pregnant woman?" wonders François Nosten, as local volunteers scrambled to find a suitable blood donor to combat the woman's lingering anemia, even as the artesunate began rapidly clearing most of the parasites and saved the woman's life. "The other drugs are toxic," says Nosten, who founded SMRU 20 years ago after several years as a young volunteer for Medicine Without Frontiers and built it into one of the most innovative and productive malaria research outposts in the world.

"There have been 13 papers since the 1960s on how to treat pregnant women with malaria, and we have done nine of them," Nosten says.(1) Yet there is still little understanding of how artemisinin-based derivatives and the other drugs used in combination might affect a pregnant mother or the developing fetus. Indeed, there is an unfinished research agenda on how the many different artemisinin-based combinations now being tested affect various subpopulations such as small children or people with co-infections (combinations either in use or being tested around the world add lumefantrine, mefloquine, piperaquine, amodiaquine, proguanil, or atovaquone to an artemisinin derivative such as artesunate or artemether). "We have to do studies on what are the risks and benefits of ACT [artemisinin-based combination therapy] in pregnancy."

THE PROOF: IT WORKS

If a research team led by Nosten and his mentor, Nicholas White of Mahidol University in Bangkok (whom many consider the world's leading malariologist), lead the way to better protocols for treating pregnant women and others with ACT, it won't be the first time that the duo has used the tools of clinical science to teach the world new methods for combating this age-old scourge. In 2001, the World Health Organization (WHO) declared ACT the preferred method for treating malaria, especially the most deadly form of the parasite, Plasmodium falciparum, which in most parts of the world has evolved resistance to older drugs such as chloroquine. WHO's 2001 decision was based largely on clinical trials that SMRU had conducted during the early 1990s.(2)

This breakthrough came despite the fact that artemisinin's mechanism is poorly understood. When the parasite invades a red blood cell to reproduce, it destroys the hemoglobin and frees up iron. In the presence of artemisinin, this free iron forms highly reactive oxygen radicals that some scientists believe inhibit the parasite's ability to digest more hemoglobin, thus breaking the chain in its lifecycle.(3) By contrast some older drugs such as chloroquine disrupt membrane function, thus disabling the invaded blood cell's ability to disgorge the newly formed parasites.

Not knowing the chemistry hasn't stopped the drug's deployment in the field, though. Early in this decade, SMRU spearheaded a joint public health program with the Thai government that trained rural health workers, most of them recruited from local villages, to use test kits to diagnose malaria and then administer ACT. The campaign also attacked the Anopheles mosquito that spreads the disease by conducting indoor home spraying with deltamethrin, a pyrethroid ester insecticide considered one of the safest in the world. (DDT, recently resuscitated by WHO, was banned in Thailand in 1997.) Distribution of insecticide-treated bed nets was also part of the campaign.

The result? Malaria in mountainous Tak province was reduced by 34% and mortality was cut in half.(4) Though the program was cut short when the Thai government's funds were depleted, it proved that even in remote areas, where people live exposed to the elements and have no formal healthcare system, it is possible to roll back malaria.

That's the goal of the campaign that world health officials launched in 1998 to cut the incidence of malaria in half by 2010. The campaign has so far fallen woefully short of expectations. This year will see an estimated 500 million cases of malaria, two-thirds more than the 300 million cases estimated in 1999. Somewhere between one and two million people will die of the disease, most of them children under the age of five in sub-Saharan Africa.

To Nosten, who has devoted his life to fighting the resurgence of drug-resistant malaria, it's inexplicable that global health officials and policymakers haven't moved faster to deploy the knowledge and tools that he helped to create - especially the three-day regimen of ACT. (Two combinations tested by Nosten and colleagues included artemether-lumefantrine and mefloquine-artesunate, both of which proved more than 96% effective against P. falciparum.(5) "The death toll is enormous. It's like five jumbo jets filled with children crashing every day," he says. "By 2010, there could be twice as much malaria. That, to me, is a failure."

THE ECONOMICS OF ANTIMALARIALS

Part of the problem is availability. Presently only Novartis, the Switzerland-based pharmaceutical giant, sells a two-drug ACT in a single-pill formulation called Coartem, which combines the artemisinin derivative artemether with lumefantrine. Health officials prefer the two-in-one pill because it improves patient compliance, which is crucial if artemisinin is to avoid the fate of chloroquine, which has become virtually useless against most strains of P. falciparum because of drug resistance.

A Coartem pill, however, costs $2.40 for the three-day treatment. While the company says it earns no money at that price, it is still far more than most of the world's malaria victims can afford, which could explain why chloroquine, at 10 cents per dose, is still in widespread use in Africa and South Asia. Moreover, the profit markups and graft that plague the supply chain in many parts of Africa make Coartem all but unaffordable except through aid-financed programs. Surveys of local clinics and pharmacies report that Coartem often sells for eight dollars and more in the private market.

Since these new artemisinin combinations are still months if not years away from regulatory approval, demand for Coartem is skyrocketing. Novartis expects to ship 58 million treatments this year from its production facility in Suffern, NY, nearly double the 2005 level. The plant has the capacity to produce more. In September Novartis began subsidizing ACT deployment by reducing the average price to one dollar per dose. "We have the capacity to make 100 million doses but don't have that many orders so price is clearly an issue," explains Robert Laverty, a spokesman for Novartis' malaria initiative. "We wanted to improve access to what is clearly the most effective treatment out there."

Lower-priced options should be arriving soon. Medicine Without Frontiers' Drugs for Neglected Diseases Initiative (DNDi) plans to introduce two new, single-pill artemisinin combinations by the end of this year. Its artesunate-amodiaquine combination, besides reducing the number of pills swallowed daily from eight to two, will sell for just one dollar for an adult treatment and half that for a child. The industrial partner, Sanofi-Aventis, is managing the manufacturing and registration of the combination pill, and has promised to offer the technology for free to any manufacturer that can produce the drug at world standards for less. DNDi's second combination, which Brazil's Far-Manguinhos produces, combines artesunate with mefloquine to combat the strains of drug-resistant malaria that are endemic in southeast Asia and parts of Latin America.

TESTING NEW COMBINATIONS

Physicians led by Nosten and White conducted the final registration trial of the artesunate-mefloquine combination at SMRU during the first half of 2005. This year, a team of physicians led by the duo is collaborating with the nonprofit Medicines for Malaria Venture (MMV) in a 2,550-patient trial across two continents that should, if all goes well, lead to the registration of a dihydroartemisinin-piperaquine combination. (Dihydroartemisinin is the active metabolite of the other forms of artemisinin: artemether, arteether, and artesunate.) This one will be the first manufactured by an independent Chinese company - Chongqing Holley Holding - that meets global standards for good manufacturing practices (GMP). Another industrial partner, the Italian drug firm Sigma Tau, is managing the registration of the single-tablet combination, which should sell for about one dollar for a three-day treatment.

While the need for cheaper alternatives is compelling, Nosten has mixed feelings about the dihydroartemisinin-piperaquine trial, which is focused only on proving efficacy to register the drug, something he's done numerous times before for other artemisinin-based combinations. "Registration trials are a pain in the neck; it's a lot of bureaucracy," he says while driving a Toyota 4WD along the rutted road that leads to the clinic on the Thai-Myanmar border. The 49-year-old physician-researcher is wearing blue jeans, a khaki vest, and a pair of old sneakers, crushed in the back so he can slip them on and off easily (the local custom) when entering one of his clinics.

"We have already studied this treatment in thousands of people," says Nosten. "We know its pharmacokinetics and pharmacodynamics. You have drugs that have been studied by us and the Chinese for decades. I accepted to do this new study because I thought it would be useful to get this drug more quickly to African children." He pauses for a moment, as if pondering how what he was about to say might be interpreted by his funders in Geneva. "It is not that interesting," he says. "My main thing in life is to learn new things."

FROM CHINA TO THAILAND

Artemisinin was a relatively new thing in 1983 when White, then 32, and his colleagues met Li Guoqian, who was the first to use the drug (see "The first 13-year-old patient"), on a trip to Guangzhou, China. "He gave us some ampoules (of artesunate) and said, 'this stuff is really good,'" recalls White, who had been studying malaria resistance since moving to the Mahidol University faculty from Oxford in 1980. White was thrilled to have an alternative to chloroquine, which was quickly becoming useless against resistant strains, and the almost new mefloquine, which had been touted as a miracle drug but was already beginning to lose its effectiveness.

White, soon joined by Nosten, moved a Chinese version of the drug into a series of clinical trials. Because patients cleared the artemisinin derivative so quickly, initial regimens needed to last seven days to hit every phase of the parasite's life cycle. Patient compliance was terrible. To shorten the regimen, they began experimenting with various combinations that included longer-lasting drugs. "We were forced by events; we've always been, in a way," White says.

Combination therapy was already common in other parts of the world where infectious diseases were being treated. It was first used against resistant strains of tuberculosis. Then in the early 1990s, researchers on the front lines of HIV/AIDS research were turning to combination therapy. But malaria drugs? Physicians had always used them sequentially. White realized that this was the field's fatal mistake.

"Nick White deserves credit for the theme of using antimalarial drugs in combination, and he was relentless in pursuing it," says Thomas Brewer, a former military researcher of anti-infectious disease drugs. He now runs the malaria program at the Bill and Melinda Gates Foundation. "For a long time, people were resistant to that, like any paradigm shift in medicine."

In an interview in his cramped Bangkok office, White, whom one colleague described as equally at home on the cricket patch as he is in a research lab, attributes his insights to his willingness to delve into the math behind the drug's activity. "I could see what was happening to the drug levels in the blood - which is opaque to most physicians, they avoid it - and what that was doing to the parasite," he says. He calculated that if patients faithfully followed a two-drug combination that included artemisinin, the odds of a mutant parasite emerging that was resistant to both drugs was a once-in-a-century event.

Even White's critics, including Harald Noedl of Medical University of Vienna, admit that "artemisinin resistance is still extremely rare or even nonexistent." Noedl believes it is only a matter of time, however, before resistance emerges, because some people won't follow the combination regimen as it comes into more widespread use.(6)

ARTEMISININ TAKES THE GLOBAL STAGE

After publishing his analysis in Antimicrobial Agents and Chemotherapy in 1997 (7), White began organizing the world's leading malaria clinicians to press WHO for a dramatic change in its recommended policy for treating malaria. "To treat tuberculosis or AIDS with a single drug is no longer regarded as ethical," wrote White, Nosten, and 15 colleagues in "Averting a malaria disaster," a June 5, 1999, Lancet viewpoint. "We believe the same principle should apply to the treatment of malaria."

The wheels of the global health bureaucracy moved slowly, however. It took two more years before WHO endorsed ACT, and even then, few nations placed orders with Novartis, which had the only GMP-qualified combination on the market, a artemether-lumefantrine combination called Coartem. Though the company offered to supply the drug at cost, its relatively high price kept it beyond the reach of most African nations until international aid began flowing. Then, in 2004, when nations finally began placing substantial orders, supply bottlenecks emerged.

Not surprisingly, non-GMP-made artemisinin tablets began infiltrating the market, creating the potential for a public health disaster. In January 2006, WHO malaria chief Arata Kochi issued a stern rebuke to the 18 firms manufacturing the tablets in eight countries. The fear is that parasites exposed to artemisinin alone will quickly develop resistance, just as they have to all the other drugs. "In some countries, 60 to 70 percent of the people get their treatments directly from pharmacies, where they have access to monotherapy," says Awa Marie Coll-Seck, the former Senegalese health minister who is now executive secretary of the Roll Back Malaria (RBM) partnership. "We're saying, no, no, no, you must follow the WHO policy."

Coll-Seck's own experience in Senegal, a nation of 11 million people on the West African coast, reveals the difficulties in forcing adherence to the new approach. She was among the first group of African health ministers to adopt ACT as the preferred treatment, in 2002, but it didn't become widely available in her country until last year. "It takes one year to change policy, one to find money, and one year to change the (local health) plan," she says. "You have to train the nurses and the physicians to ensure that the new treatment will be properly used."

Since 2001, 34 countries have adopted ACT as the first-line defense against malaria, but only 17 are currently deploying it. Even so, RBM projected global demand at 60 million treatments last year. Novartis expanded production, but the orders didn't appear. Since artemisinin has a relatively short shelf life of 18 months, some of that production had to be destroyed. This year, things have gone more smoothly: 50 million courses were shipped through the end of June, and 80 million courses are projected for the entire year.

While more nations are committed to switching to ACT, global donors have not yet solved the core economic problem. Even at one dollar for a three-day regimen of the new products about to come on line, chloroquine at a fraction of the price is still widely available in the private networks of most African and South Asian countries.

In 2004, an Institute of Medicine committee, which was chaired by Nobel Prize-winning economist Kenneth Arrow and included White, recommended that global donors pool their resources into a single agency that could buy ACT at market prices and make it universally available at a competitive 10 cents a treatment. The World Bank, whose antimalaria efforts have been revamped after widespread criticism, is designing the subsidy program.

"We're consulting with a number of partners to develop an arrangement for this subsidy. How will it work in practice?" asks Olusoji Adeyi, a Nigerian physician who coordinates public health programs for the World Bank. And then it must find the money, which could run as high as $400 million to $500 million per year. "We're still looking for the subsidy itself," he says.

TOOLS ARE NOT ENOUGH

White has no patience with such dallying in the face of what he believes is the world's biggest public health crisis. When I first walked into his university laboratory a few blocks from Victory Monument in central Bangkok, he was staring at his computer while on the telephone with Nosten. The topic wasn't their latest trial. He was reading to his protégé the oft-circulated scientific joke about the newly discovered element, administratium, which impedes every reaction with which it comes in contact.

It's a good time for the malaria-control community, he admits. President Bush and Prime Minister Tony Blair are talking about it. Money is pouring in, not just for research, but also for healthcare delivery systems in poor countries where malaria is endemic (and armed conflicts are not underway). But, he says, "the failure of the global eradication campaign in the 1960s left a deep, deep scar."

In the wake of that failure, a generation of research has produced better strategies for deploying bed nets and insecticides. It has produced a powerful new drug that, if massively and properly deployed, can sharply reduce the levels of circulating parasite, including those most resistant to existing drugs. "We've got the tools, he says. "We need to recapture the idea that you can get rid of it."

Speaking to me in a border clinic nearly 200 miles to the north a few days after I saw White, Nosten agrees that it can be done, but he can see the hurdles that remain. His well-stocked clinics provide first-rate care to the thousands in Karen who find their way to his doorstep. For instance, the SMRU staff eventually found a blood donor for the 24-year-old pregnant woman, and they administered artesunate alone for seven consecutive days. Under their careful supervision, the treatment was long enough to ensure that all the parasites were cleared from her body. A week after becoming ill with malaria, she returned to her home in Myanmar in excellent health.

But on the day I visited the clinic, the day Nosten wrestled with how to treat her, he stared across the river into her homeland, once known as Burma. A military junta rules the country and does very little to combat the malaria plague on its mountainous borders. "Our clinics cannot replace a failing public health system," Nosten says. "We're here to do research."

References
1. See, for instance, R. McGready et al., "A randomized comparison of artesunate-atovaquone-proguanil versus quinine in treatment for uncomplicated falciparum malaria during pregnancy," J Infect Dis, 192:846-53, 2005.[Pubmed]
2. For the earliest published result of a randomized clinical trial using artemisinin-based combination therapy, see F. Nosten et al., "Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination," J Infect Dis, 170:971-7, 1994.[Pubmed]
3. A.V. Pandey et al., "Artemisinin, an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme detoxification systems in malarial parasite," J Biol Chem, 274:19383-8, 1999.[Pubmed]
4. V.I. Carrara et al., "Deployment of early diagnosis and mefloquine-artesunate treatment of falciparum malaria in Thailand: the Tak malaria initiative," PLoS Med, 3:e183, June 6, 2006.[Pubmed]
5. R. Hutagalung et al., "A randomized trial of artemether-lumefantrine versus mefloquine-artesunate for the treatment of uncomplicated multi-drug resistant Plasmodium falciparum on the western border of Thailand," Malaria J, Sept. 22, 2005 (www.malariajournal.com/content/4/1/46, accessed Nov. 4, 2006).[Pubmed]
6. H. Noedl, "Artemisinin resistance: how can we find it?" Trends Parasitol, 21:http://www.gooznews.com/mt/mt.cgi?__mode=view&_type=entry&blog_id=7&id=578&saved_changes=1#404, 2005.[Pubmed]
7. N.J. White, "Assessment of the pharmacodynamic properties of antimalarial drugs in vivo," Antimicrob Agent Chemother, 41:1413-22, 1997.[Pubmed]

In September 2003, the US 26th Marine Expeditionary Unit entered Liberia for a brief peacekeeping operation. While ashore, more than 100 marines contracted Plasmodium falciparum malaria. Five of the cases were so severe, they had to be rushed back to the United States for emergency treatment with intravenous quinidine, a derivative of quinine. In the most severe malaria cases, intense fever and nausea demands immediate intravenous treatment for its fast action and because patients can't keep anything in their stomachs.

"At first we didn't identify them as malaria cases, so it advanced to severe malaria," says Lieutenant Colonel Bryan L. Smith, director of the Armed Forces Research Institute of Medical Sciences (AFRIMS) clinical trials center in Bangkok. "That kicked us in the rear about better diagnostics. Then we realized we didn't have the best drug in the world - artesunate."

In the 1980s, the military had taken steps to add a derivative of artemisinin to the list after learning about it from the Chinese military. The move followed decades of malaria breakthroughs from the Walter Reed Army Institute of Research (WRAIR): chloroquine in 1949, sulfadoxine-pyrimethamine in 1983, mefloquine in 1989, doxycycline in 1992, and atovaquone-proguanil in 2000, to name several.

But then, Thomas Brewer, then at AFRIMS, discovered that the preferred derivative, arteether, caused brainstem lesions in animals. He suspected it would affect all the drugs in the class. As a result, artemisinin research took a backseat while the unit focused on other drugs. "Early on, we didn't appreciate its real importance," recalls a rueful Brewer, who's now with the Bill and Melinda Gates Foundation.

A year after the 2003 Liberia fiasco rejuvenated the program, WRAIR filed a 1,400-page investigative new drug application with the Food and Drug Administration and quickly completed a first round of safety trials for an intravenous version of artesunate. Col. Peter Weina, who directs the artemisinin project from WRAIR's Silver Spring, Md., headquarters, still hopes to have a final efficacy trial underway this winter, even though they were recently dealt a setback when their industrial partner, Sanofi-Aventis, pulled out of the collaboration. "They feared they would be asked to provide it at a loss to the developing world," Weina said.

While a US FDA-approved intravenous antimalarial drug will be warmly welcomed by malariologists, they're upset by the military's glacial pace. White at Mahidol University in Thailand led a team that published a seminal study in the Lancet last year, showing that intravenous artesunate was 33% better and less toxic than quinine for treatment of severe malaria.(1) However, their study used a Chinese version of the drug, which doesn't meet western manufacturing standards, and thus can't be used by the US military or purchased by aid agencies for the developing world.

1. South East Asian Quinine Artesunate Malarial Trial (SEAQUAMAT) group, "Artesunate versus quinine for treatment of severe falciparum malaria: a randomized trial," Lancet, 366:717-25, 2005.[Pubmed]

Nicholas White and Francois Nosten were not the first clinicians to use artemisinin in a human trial. That honor belongs to Li Guoqian, now a senior professor at the Guangzhou University of Traditional Chinese Medicine (GUTCM).

Military necessity has always been a major driver of antimalarial therapeutic advances, and when Vietnam president Ho Chi Minh asked Chinese Community Party leader Mao Zedong for help in combating a disease that was disabling more of his soldiers than were American bombs during the Vietnam War, traditional Chinese medicine, especially qinghaosu, seemed like a good place to start. (At the time, both Vietnam and China were cut off from global supplies of chloroquine, then the drug of choice for treating malaria.)

Mao, in the midst of unleashing a Cultural Revolution that would temporarily destroy schools that taught western medicine, asked Zhou En Lai to establish a military research project on malaria that utilized China's schools of traditional medicine. Committees were soon established at every school, according to Li. A first organizational meeting was held at a Beijing restaurant on May 23, 1967, and they became known as the 523 committees.

The Beijing 523 committee discovered a method of isolating the active ingredient in qinghaosu. It took about four years to stumble on a low-temperature method of extraction, thus confirming the wisdom of a 1,600-year-old recipe: In 340 A.D., medical author Ge Hong wrote in Zhou Hou Bei Ji Fang (Handbook of Prescriptions for Emergency Treatments) that soaking a handful of qinghaosu in about a liter of cold water and then straining and drinking the fluid would provide relief from fever.

The first batches of the drug were sent to Li Guoqian, who ran the largest 523 committee in southern China in guangzhou. The son and grandson of traditional practitioners, Li graduated from GUTCM in 1955 and eventually gravitated toward malaria research. While the other 523 committees raced to discover drug candidates, he established clinics in the malaria-infested jungles of the southern province of Yunnan, which runs along Burma's northern border. He remained there from 1971 to 1974.

Li, now 70, recently recalled for me the first patient he treated with artemisinin. "He was 13 years old, a primary-school student. He had very severe malaria symptoms. I gave him an oral tablet -- 100 milligrams." The results, he says, amazed him. "Chloroquine was the fastest drug, but even it took 12 hours before you saw a change in parasite load. So, I didn't check the patient until the following day. I couldn't find the parasite! This I had never seen." He tried it on a second patient with the same results. Within 48 hours, the parasites and the fever were gone.

He eventually tested it in 18 patients, 14 of whom had Plasmodium falciparum. He compared them to six patients he treated with his limited supplies of chloroquine. "The parasite decreased more than 95 percent after 16 hours with artemisinin," he said. "To get the same results with chloroquine, it took 40 hours." He never published the research. "It was a military secret," he laughs.

It wasn't until 1979 - the same year Deng Xiaoping traveled to the United States and kicked off China's rush to modernization - that People's Daily, the main organ of the Chinese Communist Party, announced the results of the 523 research program. It was too late for Vietnam's soldiers (who by that point were fighting China on their northern border), but the world had a new weapon in the war against malaria.

Some of the nation's leading cardiologists were upset by the recommendation. Writing in the Journal of the American Medical Association a few weeks later, they called on the FDA to reject muraglitazar because Bristol-Myers Squibb and Merck, its manufacturers, had failed to provide an accurate measure of the medication's risk.

"I'm increasingly concerned that these panels have become unbalanced," says Steven Nissen, M.D., of Ohio's Cleveland Clinic, a co-author of the JAMA article and former chair of the FDA's cardiovascular drugs advisory panel. "We have to make certain we have a balance of experts, [including] people who deal with the complications and side effects."

"There's too much bias toward bringing new treatments to market," adds Art Levin, director of the Center for Medical Consumers in New York and the consumer representative on the FDA Drug Safety and Risk Management Advisory Committee.

The FDA regulates companies that account for 25 percent of the U.S. economy. Its job is to protect the public from unsafe drugs, faulty medical devices and contaminated food. But 100 years after the birth of this federal agency, many doctors, consumer groups and lawmakers worry that the FDA is becoming less effective in carrying out its mission.

The hazy relationship between the FDA's advisory committees, such as the one for the diabetes drug, and the companies the agency regulates is just one issue raising concerns about the effectiveness of the FDA, which is still considered the gold standard among food and drug regulators around the world. Two other issues are a reported backlog of more than 800 generics awaiting approval and what the FDA acknowledges is the lax monitoring of drugs after they are approved and on the market.

"A lot of people are nervous about what's in their medicine cabinet, and for good reason," says Sen. Chuck Grassley, R-Iowa, a leading agency critic on Capitol Hill. "[The FDA] has become too cozy with the industry it regulates ... That's not a recipe for full trust and faith among consumers."

Acting FDA Commissioner Andrew von Eschenbach, M.D., the director of the National Cancer Institute who has been nominated to head the FDA permanently, insists the agency is working to protect the public. "We are making a tremendous commitment to the whole area of drug safety," he told Congress in March.

Serious questions about conflicts of interest at the FDA arose in 2004 when the painkiller Vioxx was taken off the market because it increased the risk of heart attack and stroke. Concerned that similar drugs might pose the same risk, the FDA convened a special advisory committee to evaluate the evidence. The agency almost always follows the advice of advisory panels, whose members are usually drawn from prominent medical institutions outside the FDA. Critics say most of the outside advisory panels include scientists with ties to the firms whose products are under agency review.

The panel that analyzed Vioxx, Celebrex and Bextra voted in February 2005 to keep them on the market, even though Vioxx had already been pulled. Only later did the media report that nearly a third of panel members had ties to makers of the drugs. Had their votes been excluded, the drugs would not have gotten a positive vote.

An FDA spokesman says advisory panelists are screened to "carefully weigh any potential financial interest with the need for essential scientific expertise" to protect public health.

"One of the conundrums," says Carl Peck, former director of the FDA's Center for Drug Evaluation who now heads the Center for Drug Development Science in Washington, is that the scientists "who are capable of making an informed decision are the very ones who typically are called on by drug companies and FDA to advise." He argues that limiting advisers to those who've never had research or consulting agreements with drugmakers could reduce the pool of qualified experts.

But Eric Topol, M.D., of Ohio's Case Western Reserve University disagrees. He says it's "essential for the 'jurors' to have no conflicts. There are many people who would qualify who have absolutely no ties to industry."

After the Vioxx decision, the FDA pledged to tighten its review process by creating an internal Drug Safety Oversight Board. The group has come under fire for meeting in secret, but the FDA says information from the companies involved is confidential. Peter Gross, M.D., outgoing head of the FDA's drug safety advisory committee, has urged more transparency, with "public representatives" named to the board.

The FDA gets more than 20 percent of its $2 billion annual budget from industry user fees, which are paid by companies seeking the FDA's OK to market new products. The fees, which account for nearly half of the new-drug office's budget, were mandated by law in 1992 to speed up the approval process by enabling the FDA to hire more reviewers.

"That's the problem," says Nissen of the Cleveland Clinic. "It would be smarter if we funded the FDA through public dollars. In terms of our national budget, it's trivial."

"I understand the importance of bringing new medications to market," he says. "But I just want to make sure we've appropriately balanced risk with benefit."

Meanwhile, just under 3 percent of agency funds is devoted to monitoring drug side effects. The FDA recently reported that drugmakers failed to begin two-thirds of post-approval studies it had requested. The agency has hired a consulting firm to assess the problem.

"The greatest flaw in our post-marketing system," Peck says, "is that it's voluntary by physicians and patients. This needs to be fixed."

He adds, "Everything needs improving, all the time."

By Merrill Goozner

In November 2004, California voters approved a ten-year, US$3 billion stem cell research program to pursue cures for diabetes, Parkinson disease, spinal cord injuries, and other chronic conditions. Campaign organizers also claimed the state would receive royalties from new therapies, economic development in the form of jobs and taxes, and access to cheaper medicines [1]. Once the initiative passed, its proponents sought to scale back unrealistic voter expectations about rapid advances in the field—recent revelations of scientific fraud involving a prominent stem cell scientist will undoubtedly have that effect.

Yet the goal that stem cell therapies resulting from the initiative will be made affordable for state residents remains in place. Toward that end, some California legislators are focusing on how the newly created California Institute for Regenerative Medicine (CIRM) should handle intellectual property (IP) generated by its grants. In August 2005, at CIRM's request, the state-funded California Council on Science and Technology (CCST) recommended that CIRM adopt with minor variations the federal Bayh–Dole system [2].

The 1980 Bayh–Dole Act gives research institutions the primary responsibility for maximizing the health- and economic-development benefits from government research funding. It encourages researchers or their institutions to patent inventions generated under government grants and transfer the technology to private firms. While the act gives the federal government the power to influence the affordability of the resulting technologies, it has never used this authority. The CCST report, embracing that stance, discouraged efforts to recoup revenue through high licensing fees and postponed a discussion of preferential pricing for state residents [3]. The report suggested such approaches would inevitably hinder the development of the public–private collaborations needed to bring new therapies to market.

While regional governments frequently fund biomedical research in Europe, California is the first state in the United States to embark on a large-scale program. The size of its commitment suggests that the state will be a major patron of stem cell research for years to come. This gives California a unique opportunity to create a climate that will not only be hospitable to innovation but also simultaneously deliver affordable medicine. The state government can do this by redefining how government, medical researchers, and the private sector interact. In doing so, it could serve as a model for reforming the US and global biomedical innovation systems.

Change is necessary for two reasons. First, under the current system, new technologies, no matter how marginally effective, come to market at the highest prices. These advancing medical technologies are a major cause of rapidly rising health-care spending throughout the industrial world. Second, biomedical innovation in the US, long considered the global leader, has slowed markedly in the past half decade. Despite escalating research spending in the public and private sectors, the number of new drugs and biologics recently approved by the US Food and Drug Administration (FDA) has fallen below previous eras. And those new therapies that have been approved tend to have less significance than medical advances of the past. While the popular press excitedly reports that breakthroughs in nanomedicine, targeted therapeutics, and genomic medicine are just around the corner, applications to launch clinical trials have fallen well below the levels of the early 1990s. Something beyond the usual culprit—higher failure rates—is at work [4].

Patent Thickets
The IP system may be contributing to the slowdown. The current innovation system encourages researchers to patent and commercialize discoveries that in an earlier era were considered basic science insights. This has led to an active market in the building blocks of further research, which can be anything from a genetic sequence or a cell receptor to the reagents needed to culture cells. This proliferation of basic science patents has raised the bar—what economists call transaction costs—for other researchers who want access to those research tools. While many researchers, especially in academia, find ways around patent restrictions, and many companies have no trouble executing license agreements, there are cases where “patent thickets” have discouraged other researchers from pursuing similar or subsequent lines of inquiry [5].

The stem cell field, which is still years away from its first approved therapy, has already experienced patent thicket problems. In May 2005, Nature drew attention to the case of Jeanne Loring, an embryologist at the Burnham Institute in La Jolla, California [6]. She claimed her startup firm collapsed when it couldn't get access to embryonic stem cells at a reasonable price from the Wisconsin Alumni Research Foundation, which owns James Thomson's seminal patents in embryonic stem cell research. The Wisconsin Alumni Research Foundation has granted several exclusive licenses to Geron, Inc., which funded his work [7].

A recent survey by the United Kingdom Stem Cell Initiative identified nearly 18,000 stem cell patents issued around the world since 1994, with two-thirds issued in the US [8]. The Washington-based law firm of Sterne Kessler Goldstein and Fox has warned clients that “any company or research institution that plans to develop stem cells for therapeutic purposes may face a number of blocking patents and applications that will require licenses, if available” [9]. The potential for patent licensing restrictions to slow the pace of research is impossible to quantify, but surely exists. How does one count the decisions of researchers who eschew a line of research because they don't want to bother securing the necessary licenses or material-transfer agreements? How does one count the decisions of researchers to avoid fields entirely because someone else has already locked up key inventions? How can one predict if cascading licensing fees will make downstream research prohibitively expensive?

Jumping into the Pool
CIRM and other stem cell funders can become catalysts for cutting through this patent thicket. They can require that all grant recipients agree to donate the exclusive license to any insights, materials, and technologies that they patent to a common patent pool supervised by a new, nonprofit organization set up for that purpose. A patent pool serves as a one-stop shop where investigators can obtain no-cost or low-cost licenses for subsequent research. Patent pools have been successfully used in other high-technology industries such as consumer electronics and software to facilitate the development of new technologies that either require common standards or rest on a common base of basic research. Several patent law firms and close observers of medical research have suggested that patent pools can work in biomedicine [9,10].

There is already some official interest in the patent pool approach, at least for early stage research. The CCST report to CIRM suggested mechanisms such as broad-use licenses could be used to facilitate the sharing of software, databases, and other research tools (see page 14 in [2]). The UK Stem Cell Initiative, a public–private partnership, included a call for a new UK Stem Cell Cooperative “to maximize the cross-fertilization between those involved in the subdisciplines of UK stem cell research” (see page 8 in [8]).

But the stem cell patent pool needs to reach beyond the early stages of research if it is going to maximize the chances of this targeted research campaign eventually producing therapeutic results. As researchers move further down the development trail, the pool can serve as a clearinghouse for all researchers in the public or private sector to gain permissions for pursuing the next stage of their research at minimal transaction costs, including time. Moreover, the pool authority can act as an agent for resolving challenges that will inevitably arise as the research progresses, including enforcing ethical standards. For instance, the pool authority in cooperation with the FDA can set common standards for cell line preparations as research moves toward the critical clinical trial phase. And the pool should have the scale to leverage the cooperation of existing patent holders whose IP predates formation of the pool or whose future research will be funded by other governments, nonprofits, or private firms.

The pool can also influence accessibility to the fruits of downstream research. As a condition for obtaining a pool license, any researcher would have to contribute any IP that results from using the pool license back into the pool. In the software world, this is known as open-source licensing, which was used successfully to develop the still-evolving Linux computer operating system and which is being pursued in agricultural biotechnology (R. Jefferson, personal communication; [11]).

There is one major stumbling block for the use of an open-source patent pool to facilitate stem cell research. Unlike software or even agriculture biotechnology—where the end products are relatively low cost, and the costs of development are relatively evenly distributed throughout the development process—biomedical research costs escalate once a therapeutically useful product reaches clinical trials. Applied research can take five to ten years from the start of human safety experiments. While the costs of pharmaceutical research are less than the drug industry claims, the investment required can run into the tens or even hundreds of millions of dollars. As a result, this developmental research has almost always been funded by the private sector [12]. (There are, of course, many exceptions to this rule: the early HIV/AIDS medications, many cancer drugs, some vaccines, and the development of several rare-disease therapies have been entirely funded by government agencies.) The private sector's price for taking these late-stage risks is exclusive rights to the technology. Its reward, if successful, is the right to charge whatever the health-care marketplace will bear.

Eyes on the Prize
However, there is an alternative to the exclusive rights/high prices model used by conventional markets. A government body such as CIRM could establish a major prize for companies and institutions that collaborate to produce a successful stem cell therapy. The prize would have to be large enough to justify the substantial investment required to carry out the final stages of research. It would also have to be large enough to share with the upstream patent holders whose basic and applied research became part of the pool that led to the new therapy. One could imagine prizes in the billions of dollars based on considerations such as the prevalence and public health impact of the disease, the difficulty in developing its cure, and the capital investment required to achieve results. A prize system has been proposed at the federal level [13].

A prize system, coupled with an open-source patent pool, is entirely consistent with the existing IP system. Inventors and their institutions would retain the IP rights to their inventions. Any revenues generated from the prize could be shared with the inventor and reinvested in research and education. Though the rights to the invention would be turned over to the pool, the technology-transfer officials at an institution would still have an incentive (their share of the prize) to aggressively pursue its use by downstream scientists in the public or private sectors if they feel their invention is not being properly utilized.

Division of the prize could be based on mandatory arbitration among patent holders [14]. Or it could be based on the value of the research contracts that led to the underlying IP and were invested in clinical trials. Basing the prize on investment would weight its distribution toward the parties that conducted the final phases of research—usually private-sector firms—since the trials are generally the most expensive part of therapeutic development.

Governments can finance the prizes using tax-exempt bonds since a prize will only be awarded for success. At that point, the bonds can be repaid by a surcharge on each use of the new therapy as it rapidly diffuses through the health-care system. Once the prize has been awarded for a successfully developed stem cell therapy, the pool authority can grant licenses to one or more generic manufacturing firms, which can then compete to sell the therapy to health-care providers and the public on a cost-plus basis [15].

Wouldn't the surcharge to finance the prize, when added to the cost-plus production by generic manufacturers, add up to the same high prices for medicines generated by the current system? Not at all. This “shared prize model,” calibrated to the true cost of research and development, eliminates the 30%–40% of pharmaceutical industry revenue generated by wasteful marketing costs. The prize provides no rewards for industry research and development that goes to develop medicines that duplicate the action of medicines already on the market. Financing the prize with tax-exempt bonds ensures that the surcharge will be based on the lowest-cost capital available.

Conclusion
By combining a patent pool, an open-source model of IP development, and a shared prize system for developing stem cell therapies, the California state stem cell program can point the way to a new medical innovation system for the 21st century. This model could be used by all advanced industrial economies grappling with how to pay for the rising cost of the new medical technologies sought by their ill and aging populations.

References
1. Baker L, Deal B (2004) Economic impact analysis: Proposition 71 California Stem Cell Research and Cures Initiative. New York: Analysis Group. Available: http://www.ag-inc.com/AnalysisGroup/uploadedFiles/News_and_Events/News/Proposition_71_report.pdf. Accessed 1 February 2006.
2. California Council on Science and Technology [CCST] Intellectual Property Study Group (2005) Policy framework for intellectual property derived from stem cell research in California. Interim report to the California legislature, governor of the state of California and the California Institute for Regenerative Medicine Riverside (California): CCST. Available: http://www.ccst.us/ccst/pubs/IP/IP%20Interim%20Exec.pdf. Accessed 1 February 2006.
3. US Food and Drug Administration [FDA] (2005) Original INDs received calendar years 1986–2004. Rockville (Maryland): FDA. Available: http://www.fda.gov/cder/rdmt/Cyindrec.htm. Accessed 1 February 2006.
4. Heller MA, Eisenberg RS (1998) Can patents deter innovation? The anticommons in biomedical research. Science 698–701.
5. Eisenberg R, (2001) Bargaining over the transfer of proprietary research tools: Is this market failing or emerging? In: Dreyfuss RC, editor. Expanding the boundaries of intellectual property: Innovation policy for the knowledge society Oxford University Press. pp 223–250.
6. Wadman M (2005) Licensing fees slow advance of stem cells. Nature. E-pub 18 May 2005. Available: http://www.nature.com/news/2005/050516/pf/435272a_pf.html. Accessed 1 February 2006.
7. Geron (5 November 1998) PNAS reports derivation of human pluripotent stem cells from cultured primordial germ cells. Menlo Park (California): Geron. Available: http://www.geron.com/pressview.asp?id=562. Accessed 1 February 2006.
8. UK Stem Cell Initiative (2005) Report and recommendations. London: UK Department of Health. Available: http://www.advisorybodies.doh.gov.uk/uksci/uksci-reportnov05.pdf. Accessed 1 February 2006.
9. Ebersole TJ, Edmond RW, Schwartzman RA (2005) Stem cells—Patent pools to the rescue? Washington (D. C.): Sterne Kessler Goldstein and Fox. Available: http://www.skgf.com/media/news/news.176.PDF. Accessed 1 February 2006.
10. Kesselheim AS, Avorn J (2005) University-based science and biotechnology products: Defining the boundaries of intellectual property. JAMA 850–854.
11. Pollack A (10 February 2005) Open-source practices for biotechnology. New York Times B: 1.
12. Goozner M (2004) The $800 million pill: The truth behind the cost of new drugs. Berkeley: University of California Press. 296 p.
13. US Congress (2005) Summary of the medical innovation prize fund, HR 417.109th Congress. 1st session (26 January 2005). Available: http://bernie.house.gov/documents/prescriptions/rd_read_the_bill.htm. Accessed 3 February 2006.
14. Kesselheim A, Avorn J (2005) University-based science and biotechnology products: defining the boundaries of intellectual property. JAMA 293: 850–854.
15. Barton JH, Emanuel EJ (2005) The patents-based pharmaceutical development process: Rationale, problems and potential reforms. JAMA 294: 2075–2082.

The opportunity is there, but market forces alone won’t realize it.

By Merrill Goozner

If the “mission accomplished” photo-op was the defining moment of the Bush administration’s foreign policy, the president’s recent visit to the National Renewal Energy Laboratory in Golden, Colorado, defined its energy policy. One week after he embraced alternative energy in his State of the Union address, Bush’s budget axed 32 employees at the nation’s premier alternative energy lab, a facility that developed key technologies for hybrid cars and photovoltaic cells. His political operatives didn’t even know what they had done until a few hours before his visit, triggering a mad scramble to restore the jobs to avoid embarrassing the president.

Too late. Reporters had a field day. But they should have paid more attention to the rest of the administration’s proposed federal budget, the ultimate arbiter of national energy policy. Bush’s TV rhetoric was disconnected from reality.

Programs that could reduce greenhouse gas emissions and lower U.S. dependence on foreign oil got short shrift. Instead, the president proposed lavishing new resources on long-range research programs that had more to do with rewarding key corporate backers -- “clean coal” and nuclear power, as well as corn-based ethanol -- than with building a comprehensive, sustainable energy system.

Under the president’s plan, home weatherization assistance programs will be cut by nearly a third; investment in geothermal, hydropower, and solar heating and lighting programs will be eliminated; and aid for upgrading local building codes (a key element in improving energy efficiency) will be ended. “The states will now have to become the true laboratories of innovation because the federal budget is not helpful,” said New Mexico Governor Bill Richardson, who headed the Department of Energy in the Clinton administration.

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In the decades since president Jimmy Carter donned a cardigan to declare energy efficiency the moral equivalent of war, the United States has essentially relied on market mechanisms to wean itself from oil. This was a departure from the 1975 Energy Policy Conservation Act, which required automakers to achieve specific fleet averages in miles per gallon. Unfortunately, corporate average fuel economy (CAFE) standards, which were remarkably successful in achieving their initial goals, were abandoned as a strategy. The CAFE goal was last raised in 1990.

As inflation-adjusted oil and gas prices fell from their 1980s highs, markets responded the way markets do: mindlessly. The U.S. transportation sector became even more dependent on cheap foreign oil; the unanticipated SUV loophole made a mockery of the fuel standards (SUVs are counted under the weaker light-truck standard, not the tougher passenger vehicle one, even though that’s how most are used); the electricity sector adopted natural gas as the primary supplement for coal; and the overall economy lagged far behind its European and Japanese rivals in both energy efficiency and adding renewable sources like solar, wind, and geothermal into the energy mix. Concerns about global warming, air pollution, and defense outlays required to maintain access to Middle Eastern oil were ignored.

During the current Bush administration, these trends accelerated. In earlier days, political proponents of alternatives were driven from the national dialogue by an administration with deep personal, political, and financial ties to fossil fuel industries. Vice President Dick Cheney, launching an energy strategy hatched in secret with his energy industry cronies, famously claimed that energy efficiency and alternatives may be signs of “personal virtue” but have no place in the national strategy. Even after 9-11, which presented the nation with a golden opportunity to move down a different energy path, nothing changed.

However, energy markets have belatedly begun to reflect some of the hidden costs of U.S. reliance on fossil fuels. Hurricane Katrina and global warming, instability in many of the oil-producing regions of the world, growing competition for supplies from China and India, and accumulating evidence that the globe has finally reached its peak oil-producing capacity have kept oil more than $60 a barrel and gasoline prices well above $2 a gallon. Home-heating oil and natural gas prices have increased 16 percent and 24 percent, respectively, in the past year.

Mr. Market is responding to the changed circumstances, sort of. The use of alternatives to oil and gas is exploding. Demand for hybrids, solar installations, and wind power is rising at a 30 percent annual clip. But this consumer-driven response begins from such a small base that it would take decades to push fossil fuels from their preeminent position. Bush’s contradictory strategy both promotes more oil exploration and hopes to hasten energy diversification by giving a push to the supply side. At some point, the cost of alternatives, presumably, will fall below the cost of importing oil.

Unfortunately, it’s the same strategy that minimalist proponents of energy alternatives and reduced dependence on foreign oil have used for three decades without success. The sunk costs of oil, gas, and coal dependency -- the transportation infrastructure, the sprawl, the power plants, the industrial and commercial buildings and processes (not to mention their political influence) -- create inertial forces that adjust to every increase in fossil fuel prices the way a frog adjusts to rising water temperatures. It doesn’t know that it is cooked until it’s too late.

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Three potentially powerful political streams could push the government toward more active intervention in energy markets. Labor and its allies have launched an Apollo project to promote the good -- jobs and technological potential of alternative energy strategies. Environmentalists continue to sound the alarm about the consequences of global climate change. And in the wake of 9 -- 11, a vocal element within the national security establishment recognizes that breaking the foreign oil habit requires breaking the oil habit entirely. Operating under the umbrella Set America Free Coalition, they responded to the president’s speech with a call for “a focus on deployment, not only R&D.”

A comprehensive government strategy would proceed on multiple fronts: not just biomass fuels, but higher fuel efficiency standards; not just more research into wind, solar, and geothermal power, but increased state requirements that they be deployed; not just industrial energy efficiency, but higher efficiency standards for lighting, home-heating systems, appliances, weatherization, and building codes. “There is no slam dunk,” says Scott Sklar of the Sustainable Energy Coalition.

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Energy consumption in the united States can be divided into three distinct sectors: transportation, electricity generation, and the industrial/commercial/residential sectors. Each consumes roughly one-third daily demand for energy. Each requires its own strategy.

In transportation, the United States should raise the CAFE standard while giving the U.S. auto industry a three-year breathing space for retooling. In addition to lifting the SUV/light truck exemption (except for legitimate working vehicles), the fleet average should be raised to 40 miles per gallon (mpg) in 2010, 50 mpg in 2013, and 60 mpg in 2016. Every vehicle coming off the assembly line should, starting in the next model year, be a flexible-fuel vehicle that can run on any type of alcohol or gas-alcohol blend -- roughly a $150 per car add-on that will have less impact on the new car market than requiring seat belts and air bags.

Transforming the electricity sector will require a mix of federal and state policies, because most utilities are state-regulated. Twenty states and the District of Columbia already ask utilities to obtain a certain percentage of their electricity from renewable sources like wind, geothermal, solar, or hydroelectric power. At least 15 states have taxed electricity consumers to fund investment in renewables and energy efficiency, which provides a far greater return on investment than building new power plants. All states need to adopt such standards. The federal government should play a stronger role in easing the permitting process for new renewable energy facilities. It should also make permanent the current temporary tax breaks for renewables. “Business won’t invest based on a tax credit that needs to be renewed every two years,” says Michael Eckhart, president of the American Council on Renewable Energy. “Globally, the market demand is quite good. The question now is whether we’ll have a domestic industry producing it.”

The building and industrial sectors also need a boost from government to leapfrog ahead on efficiency. Revamped building codes and appliance standards and the strategic use of tax incentives would create thousands of jobs retrofitting America’s industrial and commercial sectors. This could reduce energy usage, increase profitability, and restore the competitiveness of lagging U.S. industries.

Greening the U.S. economy has obvious security and environmental benefits. But it is also a high-growth strategy that can provide millions of well-paid jobs for working-class Americans, who are currently the biggest losers from oil dependency. It will never be achieved without the strong hand of government leading the way. In 1961, President John F. Kennedy vowed to put a man on the moon in less than a decade, and the U.S. government got the job done. Is there any reason to think that this nation couldn’t rise to the energy challenge?

Merrill Goozner is a Prospect senior correspondent.

With some drug researchers hiding crucial data in clinical trials, there is a way to get better science on drug safety

By Merrill Goozner

The specter of researchers hiding damaging data when drug companies financed their clinical trials is once again haunting the medical publishing establishment. Last week, the editors of the New England Journal of Medicine accused Merck-funded researchers of not reporting three deaths in the trial that led to the approval of Vioxx, the pain reliever subsequently pulled from the market because it caused heart attacks in some patients.