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Taking the Fight to Parasites

Big drug companies have little interest in developing medicines for parasitic diseases. Michael Wall peers through the microscope as university researchers take the initiative. Illustrated by Liz Bradford and Zel Stolzfus.

Illustration: Liz Bradford

Ramadhan Shehe sweated his way through malaria infections while growing up in Ngozi, a clay-street town of 22,000 in northern Burundi. In 1996, ethnic clashes chased him to Tanzanian refugee camps, where he picked up the disease again and again. Shehe's wife, Jazira, also had malaria. So did the couple's only son, four-year-old Adam, who was born in the camps.

The Shehes don't have to worry about malaria anymore: The United States granted them asylum in 2006, and they settled in Tucson, Arizona, that August. But when they lived in Africa, malaria was a fact of life, another hardship piled atop poverty, governmental corruption, and endless war. It was something to live with, and live through.

“In Africa, everyone gets malaria,” Shehe says, shrugging.

Shehe's passive acceptance mirrors that of the big pharmaceutical companies. For the most part, they stand by while malaria and other parasitic diseases ravage the Third World. More than 500 million people have malaria, and two million die from it every year. Schistosomiasis, caused by a liver-dwelling worm, afflicts 250 million more. Such infections help keep the developing world poor, sapping worker productivity and discouraging foreign investment. Malaria alone stunts the economic growth of hard-hit countries like Burundi by up to 1.5 percent every year, according to research by Harvard economists Jeffrey Sachs and Pia Malaney.

Drug companies are businesses, and tackling diseases of the poor is not a good way to make money. Fighting parasitic ailments may demand a new, non-profit approach, and now university researchers in the San Francisco Bay Area are pioneering one. Funded by government grants and private donations, they have joined the battle against parasites. And they're making headway.

“Our mission is developing drugs for these neglected tropical diseases,” says James McKerrow, director of the Sandler Center for Basic Research in Parasitic Diseases at the University of California, San Francisco. “We're filling a gap that's been left by the pharmaceutical industry."

Also at UCSF, biochemist Joe DeRisi is turning his attention to malaria. His lab recently unlocked a secret of the malaria parasite's life cycle, an advance that has propelled drug and vaccine research. And DeRisi has just embarked on a self-described “crazy project” to attack malaria in an unprecedented way.

Both teams give other scientists free access to their discoveries. In the proprietary world of Big Pharma, that openness simply doesn't exist.

Tough customers

Parasites are formidable foes. They're so complex that it's tough to knock them out at a stroke. For example, the single-celled parasite that causes Chagas disease—a heart-swelling infection that kills tens of thousands every year in Latin America—has 12,000 genes, about half as many genes as humans have. Viruses, in contrast, typically have between four and 100 genes.

The bug responsible for African sleeping sickness has 1,500 genes devoted solely to its constantly shifting protein coat, which hides the parasite from the immune system. It cruises unchecked through the body, killing when it finds the brain.

And parasites know us very well. Unlike opportunistic infections such as Severe Acute Respiratory Syndrome (SARS), which leapt from fowl to people in 2002, parasites are geared to slip through the cracks in our defenses.

“They have existed with us since the dawn of our species, so they have extremely highly adapted means of evading our immune response,” McKerrow says. “That's why they've been successful."

But by and large, Big Pharma has not taken them on. A recent article in the journal Health Affairs estimated that drug companies spend $500 million to $2 billion bringing each new medicine to market. They recoup this investment by selling drugs that treat chronic conditions—such as cancer, diabetes, and hypertension—to the wealthy West.

Parasitic diseases flip this business model on its head. The customers are poor, and they don't keep coming back to the till. In many cases, a couple of pills will zap the protozoans coursing through their bloodstream. The money doesn't roll in.

In 2001, for example, the Swiss company Novartis entered into an agreement with the World Health Organization to sell its anti-malarial drug Coartem at reduced rates. A 2003 WHO audit found that Novartis lost 80 cents on every dose sold. “The companies say, 'We're a business, not a philanthropy,'” McKerrow says.

Big Pharma has increased its anti-malaria efforts in recent years. The World Bank, Western governments, and philanthropies like the Bill and Melinda Gates Foundation have helped to fund new research. However, other parasitic diseases receive almost no attention, and effective malaria drugs are still hard to come by in the Third World. When he lived in Burundi, Ramadhan Shehe simply fought through his malaria infections. “You get a fever, you lie down,” he says. “There was no medicine.”

Video (10.9 mb): Mike Wall interviews the Shehe family of Tucson, Arizona, about their experiences with malaria in Burundi and Tanzania. Slides present statistics about malaria's impacts in the Third World.
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The drugs people do get their hands on are often old and ineffective, defeated by parasites' ability to evolve resistance. For instance, the German government developed the anti-malarial drug chloroquine in the 1930s for its soldiers. The drug is still used widely throughout sub-Saharan Africa, even though it no longer kills Plasmodium falciparum, the deadliest of the four malaria-causing parasite species.

Melarsoprol, the best current treatment for African sleeping sickness, was developed in 1949. The drug is becoming less and less effective, but that's not the only reason to look for something better. Melarsoprol is made from arsenic, and it kills patients 3% to 10% of the time.

Another way

McKerrow decided years ago that Big Pharma's profit-driven model couldn't be counted on to develop anti-parasite drugs. He and others at UCSF began targeting schistosomiasis, malaria, and Chagas in the early 1990s. In 2002, the non-profit Sandler Foundation noticed the team's progress and poured in money to broaden the fight.

McKerrow, a small man with a close-trimmed white beard, sits in his fifth-floor office at UCSF's Byers Hall. To the east stretches the deep blue finger of San Francisco Bay. To the north the layered spires of the San Francisco skyline gleam in the cold light of a January morning. His back is to these brilliant views, yet his large, pale-blue eyes shine.

“[The Sandler Foundation's] charge to us was, 'Let's see what you can do now looking at the five big neglected diseases,'” says McKerrow, who became director of the new Sandler Center. The big five are Chagas, African sleeping sickness, leishmaniasis, schistosomiasis, and malaria.

So McKerrow started his parasite collection. Down the hall from his office, gray incubators line one wall of a room the size of a large walk-in closet. Bright orange “Biohazard” stickers spangle their doors, warning of the nasties multiplying within. A few feet down, thirty plastic shoeboxes fill shelves from ceiling to floor. They're full of aquatic snails, which are packed with schistosome larvae.

McKerrow also brought in hordes of chemists, parasitologists, and computational biologists—his team numbered more than 100 at last count. He organized the Sandler Center like a pharmaceutical company, with ten different groups specializing in various stages of drug discovery and design. But the Center wasn't in the game to get rich. McKerrow's colleagues resolved to post their best leads on a free website they've named Low Hanging Fruit. And they got to work.

Looking for hits

At the Center, the search for new drugs starts on the computer. Scientists troll through huge databases of compounds, then run computer simulations to see how a target chemical might take out a vital parasite part. This technique was pioneered at UCSF.

If a compound clears this hurdle, it's tested against the actual bug. The researchers can run thousands of chemical-vs-parasite bouts every day. They use a high-speed system that automates everything: Robots drip drabs of chemical into hundreds of tiny dishes, and computers count the dead parasites at trial's end.

The next step is a test in a parasite-infected rodent. The most promising chemicals are further analyzed and tweaked before finally advancing to human trials. One compound, a treatment for Chagas, is now ready for human testing. While its therapeutic use may be years off, this is big news for both McKerrow's team and Chagas sufferers. Current treatments don't always get rid of the disease, and the parasite has evolved resistance even to these substandard drugs. A few other chemicals—treatments for schistosomiasis and African sleeping sickness—are also moving along the pipeline.

The onerous process of generating new medicines was off limits to academic researchers until recently. "The expertise and infrastructure existed only in industry until maybe five or six years ago," McKerrow says. But the Sandler Center is doing it now. Groups at the University of North Carolina, the University of Dundee in Scotland, and other institutions are following suit. Industry is beginning to collaborate with these efforts, according to McKerrow; Novartis is now testing drugs against parasites using screens the Sandler Center developed.

These early signs are promising, but, McKerrow says, there is still a long way to go. Some other groups are loath to share their findings, because they want to cash in if they create a profitable medicine. They argue that a for-profit company could make a proprietary claim on their open-source data, potentially blocking a drug's development.

“But that's bogus,” McKerrow says. “If there was a great new drug for kids in Africa with malaria, and some company came along and blocked it to develop a pimple drug instead, this company would be on the front page of The New York Times. They'd be blasted to hell."

University groups like McKerrow's will have to carry more of the load in the future, says Stephen Frye, director of the Center for Integrative Chemical Biology and Drug Discovery at the University of North Carolina, Chapel Hill. "Industry is moving away from drug discovery," he says. "All they care about is what's close to the market"—medicines nearly ready to be advertised and sold.

Pharmaceutical mega-mergers, such as a $68 billion deal between Pfizer and Wyeth in January 2009, have accelerated this trend, according to Frye. Fewer drug companies means fewer risk-takers, fewer corporations willing to try new and different things. And mergers are disruptive. "Pfizer-Wyeth is going to be a disaster for drug discovery," Frye says. "It takes 10 to 15 years for things to get back to normal after a big shakeup like that." This shift away from early-stage research helped drive him out of industry. Before agreeing to lead UNC's new center in late 2007, Frye had been head of GlaxoSmithKline's discovery medicinal chemistry branch. He had worked for GSK for 20 years.

Fighting malaria

One floor down from McKerrow's office, UCSF biochemist Joe DeRisi is taking apart pieces of his DNA-chip arrayer. The machine deposits tiny samples of germ DNA onto 261 glass slides, which researchers examine to screen for unknown viruses, bacteria, and parasites. If a mystery disease pops up somewhere on the planet, a sample of the bug's DNA can be sprinkled across these slides. If it matches one of the reference samples, it will react, glow, and be identified. In 2003, DeRisi's group helped characterize the SARS virus using this method, which he developed. Though he could have made a lot of money, he didn't patent the technology. Instead, he posted a free instruction manual on his website.

Today, however, things aren't going smoothly. The machine, a gleaming silver platform about half the size of a ping-pong table, is acting up. A robotic arm zips around the platform, “painting” each slide with DNA. But the paint is thin in one spot, so DeRisi is tinkering. He should know what to do. He designed and built this thing himself, from the sturdy metal skeleton to the software coding the green “Start” button on the computer screen interface.

“Do you know how much time I spent on that start button?” he asks, laughing. “I put the rivets in the corners and everything.”

DeRisi is 39 but looks younger. He has a thick mop of curly strawberry-blond hair and a thin, angular face. With his wiry build, khaki cargo shorts, and running shoes, he looks more like a high-school cross-country star than the recipient of a MacArthur Foundation “Genius Grant," which he got in 2004.

DeRisi fixes the problem, and the arrayer is off and running. Today it's making chips to test for bee diseases. The lab is investigating the cause of colony collapse disorder, a mysterious malady killing honeybees around the world. But more often, the machine is pressed into service against malaria. DeRisi says he spends half his time dreaming up ways to knock malaria out.

A few years ago, DeRisi programmed the arrayer to create DNA chips covered with 4,500 of Plasmodium falciparum's 5,400-odd genes (another research group sequenced the parasite's genome in 2002). In one part of its life cycle, P. falciparum invades and camps out in red blood cells. This stage, during which the fevers, chills, and nausea of malaria develop, lasts 48 hours. Every hour, the scientists exposed ground-up parasite innards to the DNA chips, looking for hits. The process mapped out which genes P. falciparum turns on as it invades red blood cells, feeds on hemoglobin, and multiplies.

This had never been done before. Learning what genes do, and how they're regulated, opened a window into the parasite's vulnerabilities. Researchers have historically tried to attack the parasite during this red-blood-cell stage, and they now have many more targets for drugs and vaccines.

The experiment also held a surprise. P. falciparum turns on at least 60% of its genes during the red-blood-cell stage. Most of those genes are active only once, and at a specific time. Everything is rigidly structured, like an assembly line. DeRisi thinks this inflexibility is a major chink in P. falciparum's armor: It probably cannot switch genes on and off to deal with environmental changes. "It's like a big virus," he says.

DeRisi's group also collaborates with McKerrow and other researchers. He and Phil Rosenthal, another UCSF malaria researcher, are examining the genomes of drug-resistant P. falciparum from Africa, trying to determine how the parasites fend off medicinal arsenals.

Now, DeRisi also wants to engineer bacteria to attack and kill malaria-infected red blood cells. “It's kind of a nutty idea,” he says. “But it does have potential.” The Gates Foundation thinks so. In November 2008, they gave DeRisi $100,000 to test it out.

Some bacteria attack human red blood cells without causing major symptoms. One example DeRisi gives is Bartonella, the bug responsible for cat-scratch fever. He's working with a UCSF Bartonella expert, hoping to learn enough to genetically engineer a bacterium that will attack only red blood cells swarming with P. falciparum.

Still beyond reach

While McKerrow, DeRisi, and other academics wage war against parasites, the Shehes are making Tucson their home. Ramadhan does the laundry at a nursing home, and Jazira works as a thrift-store stocker. Adam loves Elmo and sings along to all of Barney the dinosaur's songs.

But there is still a lot of Africa in their life. Jazira buys cassava at the Nigerian market, and she cooks tilapia in palm oil. Their apartment complex has the sense of community that prevails in much of the Third World. Friends from dozens of refugee families—Burundians, tall, lean Somalis, and single mothers from Sierra Leone—wander in at all hours. They fill plates with rice and beans and flop on the couch to watch TV.

Jazira calls her folks in Burundi when she can. Ramadhan's parents are dead, but he talks to his sister in Ngozi. When he called a few months back, she was weak and nauseated, freezing cold one moment and burning up the next. She got sick, she lay down. No medicine. But, like Ramadhan, Jazira, and Adam, she pulled through.

Sidebar: Could an Old Foe Come Back?

Illustration: Zel Stolzfus

Pack loads of insect repellent. Wear long pants and long-sleeved shirts. Sleep under a mosquito net. Avoid being bitten.

Such advice is standard for travelers to Cameroon and Cambodia. But it would have been just as relevant for someone visiting New Orleans or Atlanta in the 1930s.

Malaria was a problem in the United States for most of its history. Colonization and commerce brought this Old World disease to the New, and it took hold, hard. By the 1800s, malaria stretched from Montana to Texas, from Massachusetts to Florida. It killed thousands of soldiers during the Civil War. Abraham Lincoln suffered from it growing up.

In the late 1890s, scientists discovered that mosquitoes spread the disease. After that, intensive mosquito control efforts—draining swamps, soaking homes with insecticide—knocked malaria back. Rising prosperity and rural-to-urban migration also helped. But the southern U.S., hot and wet and poor, remained a stronghold for decades.

When the U.S. Centers for Disease Control and Prevention (CDC) was founded in 1946, its charge was to put a boot on malaria's throat. That's why the CDC is in Atlanta and not Washington, D.C. The CDC ran a blitzkrieg campaign against malarial mosquitoes, drenching entire counties with the powerful new insecticide DDT. By the early 1950s, the U.S. was effectively malaria-free.

But is this just a temporary respite? According to the CDC, malaria-transmitting Anopheles mosquitoes are found in every state except Alaska and Hawaii. And at least some of the insects are sucking up infected blood: Travelers and immigrants from the developing world bring 1,000 to 1,500 new malaria cases into the country every year.

Occasionally, mini-outbreaks pop up. In 2002-03, three Virginia teenagers from the same neighborhood got malaria. None had traveled to the Third World, received a blood transfusion, or done anything else high-risk. Palm Beach County, Florida, recorded eight cases of locally acquired malaria in 2003. Many other states report similar clusters.

No cluster has exploded into an epidemic. Health authorities quashed the outbreaks early, or they petered out. “There's certainly a risk malaria could come back,” says Paul Arguin, chief of the domestic response unit at the CDC's Malaria Branch. “But it's unlikely to happen on a massive scale. It probably couldn't fester without being noticed.” Most Americans have screened windows and access to health care, however spotty. This is a wealthy nation, and malaria these days is a disease of the poor.

Story ©2009 by Michael Wall. For reproduction requests, contact the Science Communication Program office.



Michael Wall
B.S. (ecology and evolutionary biology) University of Arizona
B.A. (history) University of Arizona
Ph.D. (evolutionary biology) University of Sydney
Internship: Idaho National Laboratory news office

“If they don't have legs, how come they're not snakes?” I get that question a lot when telling people about my Ph.D. research on Australian legless lizards. When I explain that it's all about ancestry—that snakes are merely the most successful of many lizard lineages to have evolved limbless, elongated bodies—people's eyes usually widen. Evolution is a strange and wonderful thing.

An ignorance of reptilian phylogeny is no badge of shame. But the scientific illiteracy afflicting this country is serious, and I want to help combat it. After working for years as a biologist, struggling to reconcile my scientific and artistic natures, I now realize that my heart is in communicating science. In my reporting about the natural world, I intend to widen many more eyes in surprise and appreciation.

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Liz Bradford
B.A. (art and design) and B.S. (textile technology) North Carolina State University, Raleigh
Internship: Dinosaur National Monument, Dinosaur, CO

It began when my sixth grade science teacher nominated me to the “Girls in Science” program at the Natural History Museum. I was thrilled to learn special lessons behind the scenes at one of the most magical and mysterious places on earth. Here I learned to quickly sketch the animals we observed out in the field, or the aquatic life we found under the microscope. Art became a tool to discover the world around me. I am thrilled to still be doing what I love, combining my passion for art and science through my illustrations.

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Zel Stolzfus
B.S. (biology) Millersville University, Millersville, PA
Internship: Carnegie Museum of Natural History, Pittsburgh, PA

Over the years I've grown accustomed to the feel of a pencil in my hand. Drawing is my natural outlet and has been since I was a very little boy growing up at the edge of the Serengeti National Park in Tanzania, East Africa. Upon returning from Africa to Pennsylvania, I began following a biology track through high school and college. Although biology was tons of fun and a completely natural fit, every time I strayed too far from my university's art department the drawing urge pulled me back in. After college I went to northwestern England to study Science and Natural History Illustration at Blackpool and the Fylde College of Art and Design. The year after that I landed in the Science Illustration Program at UCSC. I've still got that pencil in my hand, gripped tighter than ever now. I'm not letting go.



  Could an Old Foe Come Back?