Local research targets global killer
Seattle Times staff reporter
This mosquito insectary, which looks like a walk-in freezer but feels like a sauna, is at the heart of Seattle Biomedical Research Institute's new South Lake Union building. It's also at the heart of researcher Stefan Kappe's quest for a vaccine against one of the world's leading killers: malaria.
Halfway around the globe from the places where the mosquito-borne plague kills more than a million people a year, closer to 3 million by some estimates, Kappe hopes to make Seattle the birthplace to the mother of all vaccines — the one to wipe out malaria. And he's got help.
Upstairs from his lab is Dr. Patrick Duffy, one of the world's top malaria experts. He runs the malaria program at SBRI, a nonprofit research outfit, and splits his time between here and Tanzania, where he's working on a vaccine aimed at protecting pregnant women and their babies from the disease.
A few miles away is the Program for Appropriate Technology in Health, or PATH. Its Malaria Vaccine Initiative, which funnels money to research programs around the world, has 10 vaccine-development projects going on, including two in trials in Africa.
The biggest helper of all is around the corner, in a gray and glass office building on Eastlake. Since making global health its priority five years ago, the Bill & Melinda Gates Foundation has given $528 million — out of a total of $3.8 billion in global health grants — for projects based in Seattle. Nearly $165 million of that has gone for malaria research.
But it may take all of that and more. The single-celled malaria parasite has foiled science's attempts at a silver-bullet vaccine for a half-century. In the meantime, it has only gotten trickier, having developed resistance to the drugs that once kept it in check.
"In South Asia and particularly in Africa, the parts of the world where 90 percent of the deaths occur, not only is malaria unabated, but it's actually worsening in the last couple of decades," says Dr. Tom Brewer, senior program officer in the Gates foundation's infectious-disease program.
The program has poured nearly $300 million into malaria efforts, from mosquito control to preventive drugs for kids to new drug research. But the biggest chunk of the money has gone where program officials think the ultimate solution lies: a vaccine.
The Gates foundation launched SBRI's malaria-vaccine program with $5 million in seed money five years ago, then gave it $10 million last year for Duffy's pregnancy malaria experiments. The money allowed the institute to quadruple the number of malaria researchers to 44 and to build the insectary it needed to bring Kappe on board.
Originally from Germany, the 39-year-old scientist was lured to Seattle last fall from a post at New York University by SBRI's rising reputation and its friendly relations with the Gates foundation, one of the most coveted funding sources in malaria circles. Kappe settled into life as a Belltown bachelor and has spent the past months staking his claim, in the form of patent applications, on a little-understood aspect of malaria.
A new strategy of attack
Unlike most malaria researchers, who focus on what happens when the parasite takes up residence in blood, Kappe, who has a doctorate in molecular biology, thinks the key to creating a viable vaccine hides in what's known as the liver stage.
When the malaria parasite lands in the human bloodstream by way of a mosquito bite, it beelines to the liver, where it finds harbor from the immune system and multiplies thousands of times over. After about a week, the parasites — now in a new form — burst out of the liver cells and back into the bloodstream, where they invade and rupture red blood cells over and over. This is when the fever and chills start, and death may result.
"The liver stage has really been a black box in the field," Kappe says. That's because it can't be studied in the lab easily. "I like unexplored territory ... this was an opportunity to be at the source rather than the tail end of something, to be in the exciting place where you're doing it just because you want to know."
He calls himself a "pioneer" in this regard, and there's something about his deadpan Teutonic accent that makes such pronouncements come off as authoritative rather than cocksure.
But to prove his theories he needs millions and millions of sporozoites, the stage of parasite that lives in mosquito salivary glands and lodges in the human liver. So The Swamp is a factory of sorts. It churns out thousands and thousands of mosquitoes each week so that their salivary glands can be dissected and sporozoites collected.
That's where Jack Whisler comes in. He's the mosquito keeper and foreman of the sporozoite factory. While he explains the life cycle of the small, buzzless mosquito scientifically known as Anopheles stephensi, one of the species that spreads malaria, an escapee alights on his forearm. He's got about a million other charges to attend to, so he smooshes the tiny fugitive with little ado. He receives about five bites in a typical week.
"That's nothing compared to what I get on a weekend hiking trip," he shrugs, nonplussed because the mosquitoes in this room haven't yet been infected with malaria. Plus, the malaria used in this lab is a version that doesn't affect humans, only rodents.
Learning the ways
Whisler, whose English degree didn't exactly prepare him for this new career at age 50, fell into the position by accident because he had helped raise mosquitoes for his father's botany lab at the University of Washington.
Since he was hired last summer to start up the temporary insectary at SBRI's old building and help transition to the institute's new, state-of-the-art digs in the spring, he's come to know the ways and rhythms of Anopheles. For instance, he discovered the larvae, darting around in a pan of water, thrive on a pulverized mix of Special K cereal. But as every child with a fish tank learns, portion size is a delicate balance.
"I was paranoid for months that I'd come in and the whole colony would be dead," he says. "But now I've gotten a feel for it, how they're swimming, if they're walking on the ground instead of flying. Now I'm starting to relax."
Once he's got a batch of adults, he relocates them to a separate incubator and feeds them their first blood meals, courtesy of an anesthetized mouse. The mouse is infected with a rodent version of malaria and passes the parasite on to the blood-sucking female mosquitoes. About three weeks after they've received their blood meals, their salivary glands brim with sporozoites.
"That's the reward. When we get a lot of sporozoites, I know I've done my job," Whisler says, beaming with pride.
Lab technician Nelly Camargo is a salivary-gland dissector extraordinaire. Her petite, nimble fingers can process about 150 mosquitoes an hour — with an output of about a couple of million sporozoites. Looking through the microscope, she decapitates the mosquito with a long needle and scoops out the salivary glands.
"Here's what we're looking for," she says, brandishing a minuscule, transparent globule with her needle.
Already, the sporozoite factory has yielded major victories. With help from a colleague at the University of Heidelberg in Germany, Kappe has identified key genes that are active in the sporozoite only when it burrows into the liver. He knocked out one of these genes and created a new strain of parasite. He's now using his genetically modified parasite to inoculate mice.
It turns out once his modified parasite lodges in the mouse liver, it gets stuck there and never floods into the bloodstream. Meanwhile, it's thought that the immune system has time to figure out that there's an invader in there and develop defenses. So when Kappe infects the mice with the regular malaria parasite, it gets eliminated in the liver and never causes illness.
He's convinced the liver stage is malaria's "Achilles heel."
"If you control it right there, the parasite will never be able to take a foothold," he says.
Some promising results
So far, about six months into the experiment, Kappe has induced full protective immunity in about 50 mice.
"This is groundbreaking work — it has the potential to be the holy grail of malaria vaccines, to not only prevent disease but to prevent infection," says Ken Stuart, director of SBRI.
Most malaria-vaccine candidates are focused on protecting a segment of the population or curbing the really serious cases, but Kappe's hints at the potential for breaking the chain of the parasite's life cycle and completely wiping it out.
"I like to think big," he says, grinning.
Brewer, of the Gates foundation, is "cautiously impressed."
"There have been many vaccine constructs that have protected mice, but mice are not humans," he says. "Still, it's a major milestone to be able to protect those mice like that."
The next steps are to find out exactly how this immunity was brought on and apply the technique to Plasmodium falciparum, the malaria parasite that causes most of the deaths in humans. Kappe has applied for a Gates grant to do exactly that.
A second mosquito chamber is sitting empty now, waiting for the mosquitoes that will incubate human malaria in their salivary glands. "There will be more sophisticated safety precautions when we get falciparum in here," Whisler says, passing through the air lock and past a small bug zapper propped up against the wall as if on second thought.
Even under the best-case scenario, it would be years before such a vaccine would make it to human trials. And even then, most experts think that any vaccine that's fielded will contain different components aimed at various stages of the parasite. So this could end up as the source of one antigen in a combination vaccine.
"It's foolhardy to predict at this point whether this particular vaccine will turn out to be the answer," Brewer says. "But I think it's appropriate to predict that there will be success in the malaria-vaccine realm, and with all that's going on at SBRI, I'd keep my eye on them."
Julia Sommerfeld: 206-464-2708 or firstname.lastname@example.org
Copyright © 2004 The Seattle Times Company