Needle in a Haystack
By Tom Nugent
On a blustery morning last winter, Sean Prigge ’91 hurried to his lab on a busy street in the middle of Baltimore. For months the biophysicist had been working until at least midnight, day after day, in an almost obsessive pursuit to destroy malaria, a disease that kills at least a million people each year.
At the age of 36, Prigge, who works at the Johns Hopkins University School of Public Health, is one of the youngest superstars in the field of malaria research. That morning he checked his e-mail as soon as he arrived at the lab. When he read the subject line of a message from a colleague, he caught his breath.
New FabH hit!
Prigge (pronounced PRIG-ee) dropped into his swivel chair. His pulse was racing. The e-mail was from U.S. Army Maj. Norman Waters, Prigge’s collaborator at the Walter Reed Army Institute of Research in Bethesda, Md., about 30 miles south of Baltimore. The e-mail related to the search for a chemical compound capable of wiping out malaria cells. Prigge and his team had spent four years seeking such a compound. But it was like looking for a needle in a haystack. So far they had come up empty.
How a tiny parasite can outwit the body’s defenses.
It begins with a bite from an infected mosquito. Once in the body, the malaria parasite manages to sneak past the defenses of the human immune system and set up shop inside the body’s red blood cells. The parasite, as malaria researcher Sean Prigge ’91 explains, feeds on the nutrients of the blood cells, scavenging free-floating glucose and digesting protein.
It finds a formidable adversary in the human spleen, which monitors the bloodstream night and day and will quickly identify and destroy infected blood cells. To avoid such scrutiny, the insurgent parasite manufactures a special kind of adhesive protein that allows it to cling to the walls of tiny blood vessels scattered throughout the body. “By sequestering itself in this way,” Prigge says, “the pathogen avoids the dangerous ride through the spleen.” The malaria cell thus survives long enough to complete its life cycle and, after two days in the body, to spawn nearly 20 daughter cells.
In addition, the pathogen constantly alters the structure of the proteins it deposits on the membranes of infected blood cells. By the time the immune system locks onto one of the decoy proteins, the malaria parasite has already switched to producing another form. Scrambling to catch up, the body sends new antibodies to the scene of the invasion, but the cycle repeats itself. “You could say the malaria bug wears camouflage fatigues,” Prigge says. “By the time the human antibodies respond to it, the attacker has changed its appearance and faded back into the landscape.”
Another strategy is genetic adaptation, in which the bug responds to effective drug treatments by altering its genetic structure over time, reducing the potency of the medications or rendering them completely useless. Malaria is nothing if not persistent. “What is really remarkable,” Prigge says, “is that once drug resistance develops, the parasites remain drug resistant, even if years or decades go by without any further exposure.” —T. N.
Malaria is caused by a parasite that consumes the body’s red blood cells. Usually transmitted through mosquito bites, the disease was eradicated from the United States in the 1950s, according to the Centers for Disease Control, but it remains common in many developing countries. The World Health Organization reports that every year, 300 to 500 million people contract the illness. The disease is also returning to the United States, which today reports more than 1,000 cases per year—some due to local transmission but most as a result of foreign travel.
Once in the body, the parasite grows and multiplies, thanks in part to a malaria enzyme—FabH—that is essential for making new fatty acids. Symptoms can include high fever and chills. According to the WHO, malaria kills between 1 million and 2 million people annually, mostly in sub-Saharan Africa. The majority of victims are younger than 5. (Close to 3 million people died of AIDS-related illnesses in 2005; around 4 million each year become newly infected with HIV.)
Like a Sumo wrestler can stifle his opponent, the right chemical compound could, in theory, disable the FabH enzyme. Deprived of the fatty acids required for growth, the parasitic cells would starve and die.
Prigge’s team had analyzed thousands of compounds and had sent a promising one—it had worked in the test tube—to Waters, who’d injected it into lab mice with malaria.
Prigge opened the e-mail, hoping for good news.
Malaria is becoming increasingly—and frustratingly—fatal. While the disease is treatable, many patients never get the medications they need: access to pharmacies is limited, and the most effective drug cocktails are also the most expensive. Even more worrisome, the parasite has become resistant to many standard treatments. “Almost as fast as we can come up with new drugs to stop it,” Prigge says, “the parasite adapts and finds new ways to defeat them, along with new ways to continually defeat the human immune system.”
Today a handful of labs around the world are seeking better weapons against the parasite, and Johns Hopkins ranks near the top of the list. It has established the Malaria Research Institute as a think tank devoted exclusively to combating the disease. Important initiatives are also under way at such places as the Harvard School of Public Health, Imperial College in London and a tropical disease institute in Switzerland.
Some approaches concentrate on developing vaccines, while others attempt to modify the biochemistry or genetics of the Anopheles mosquito, which transmits the ailment from one person to the next. Another tactic is to spray chemicals to kill the mosquitoes. Prigge’s malaria project is one of a dozen under way at Johns Hopkins. All are part of the institute, created in 2001 with a $100-million anonymous donation. Last summer, one of the Hopkins teams identified a gene in the mosquito’s DNA that helps it to defend against the malaria parasite, while another Hopkins study named astemizole, a once popular allergy drug, as a potential treatment for malaria.
The National Institutes of Health has given $2 million to support Prigge’s approach. Prigge’s eight-member department, which spends around $500,000 each year, studies the metabolic function of the parasite. “The complexity,” Prigge says, “is just mind-boggling.” The malaria cell has 5,300 genes and more than 24 million base pairs of DNA in the genome, he explains, making it about 10 times the size of a bacterial genome. (The human genome has 3 billion base pairs.)
In the lab, Prigge uses a futuristic-looking tool to eyeball the position of individual atoms within a malaria protein. The $600,000 contraption, known as an X-ray crystallography machine, is outfitted with a needle-like tube that fires an X-ray beam at a crystallized protein sample. A computer then uses the X-ray data to calculate the protein’s atomic structure. The result of the calculation is a three-dimensional screen image showing the position of thousands of atoms. It looks like a complicated Tinker Toy model. Such an image helps researchers to determine how various chemical compounds will interact with the protein’s physical structure. The machine is extremely delicate, and safety precautions are crucial, as even brief exposure to the X-ray beam will cause serious radiation burn.
Ever since his days at Amherst, where he majored in physics, Prigge has been working late nights in the lab. Prigge is the son of William ’62 and grandson of Alan ’30. His mother, Kirsten Olsen Prigge, graduated from Wells College in Aurora, N.Y. His first mentor at Amherst was Joel Gordon, the Stone Professor of Natural Science (Physics), Emeritus. With Gordon, Prigge studied materials called superconductors, which have no electrical resistance when cooled below a certain temperature. Often, he did the work at odd hours in the basement of Merrill Science Center. “It was very exciting,” he says, “sitting down there in the small hours of the morning, surrounded by glowing instrument panels, wires and liquid nitrogen slowly boiling away.” The work was intense and, to Prigge, exhilarating. “It felt at times,” he says, “as if I was on the set of a Hollywood science fiction thriller.”
Prigge’s other mentor was physics professor Kannan Jagannathan, the Bruce B. Benson ’43 and Lucy Wilson Benson Professor of Physics. “Jagu has a real gift as a mentor,” Prigge says. “It was the work I did for Professor Gordon that left me with a passion for independent research, and it was Jagu who steered me toward biophysics.” Jagannathan remembers his student as focused and disciplined. “Once he set his mind to a research project,” the professor says, “there was no stopping him. He seemed unusually tenacious and dedicated.”
Prigge’s discipline extended beyond the lab. A native of Fitzwilliam, N.H., a small town near the borders of Massachusetts and Vermont, Prigge put himself through Amherst on an Army ROTC scholarship. Mornings began early with physical training and classes at the University of Massachusetts, where he took part in the ROTC program. During summer breaks he attended basic training at Fort Bragg, N.C., and jump school at Fort Benning, near Columbus, Ga.
After graduating from Amherst, Prigge studied biophysics, which is the physics of organic systems, at the Johns Hopkins School of Medicine. He received a Ph.D. from Hopkins in 1997. He then joined the internationally renowned malaria team at Walter Reed, quickly rising to the rank of major.
While the Army might seem an unconventional place to research malaria, it has been a major player in the field of study for more than a century. In fact, the Walter Reed Army Institute of Research is named for a surgeon who, in the late 1890s and early 1900s, made key contributions to the understanding of infectious disease transmission. During World War II, Army commanders discovered that malaria could halve the combat effectiveness of military units in endemic areas of the Pacific theater. Later, intense research at the institute led to the discovery of several anti-malarial drugs. As Prigge observes, most anti-malarial drugs used today were created at Walter Reed.
It was at Walter Reed that Prigge met Norman Waters, an infectious disease specialist who has devoted his Army career to the discovery of new anti-malarial drugs. Waters, like the professors at Amherst, quickly noticed Prigge’s tenacity. “Sean thinks nothing of locking himself in his lab for a week at a time,” Waters says. “But he’s also got a sense of humor. He knows how to laugh at himself.”
In 2001, administrators at Johns Hopkins asked Prigge to build a research group that would focus on attacking the basic metabolic pathways on which malaria cells rely for survival. He considered it the chance of a lifetime.
Prigge found promising news when he opened last winter’s e-mail from Waters: the lab mice, whose life expectancy had been only six days, had survived for 25. But much work remains. Prigge continues to study the compound that extended the life of the lab mice, expecting that additional screening will expose any glitches.
For example, the scientists need to figure out whether the compound, when taken orally, is able to enter the bloodstream. If blocked from the bloodstream, it will never be a practical treatment for humans. “There are so many ways that compounds can fail,” Prigge says. “We have not jumped over those hurdles yet.” He and his team continue to test back-up compounds as well.
Someday, Prigge’s research might culminate in a new drug cocktail for malaria patients—one that can be produced and disseminated widely. But even a success like that will not be the end of the story. “The struggle against malaria won’t end with the next new drug,” Prigge insists. “This is a disease that has been ‘cured’ many times, and yet has ultimately found a way to survive. It’s like that scene in Jurassic Park where the biologist warns the other scientists that, sooner or later, the dinosaurs they’re cloning will find a way to reproduce on their own.” The realistic aim is control, not eradication. “Our goal,” Prigge says, “is to learn enough about the parasite to stay one step ahead of it.”
So he continues to labor in the lab, hoping for even modest inroads against a parasite that, in his view, is as clever, cunning and persistent as a skilled predator. For Prigge, the fixation can be a lonely one; he’s had to sacrifice time with his wife, Anastasia, a county prosecutor in Annapolis, Md., and sons Alex, 6, and Ethan, 4. Away from the lab, he enjoys taking the kids to soccer and T-ball games. He also does carpentry work. And when the lab gets too solitary, he reminds himself of a statistic he once came across: every 30 seconds a child dies of malaria.
That thought usually renews his focus.
—Tom Nugent is a freelance writer based in Michigan.
Photos: Samuel Masinter '04