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These little blood-suckers trying to poke through the mesh are all infected with malaria. Luckily, these ones have a strain that only infects mice.
One bite from an infected mosquito gives you a pretty good chance of catching malaria.
But raise the number of infected mosquitoes and - without some sort of prophylactic or experimental vaccine - infection is basically certain.
"Five bites will infect 100% of you," says Dr. Sean Murphy, an assistant professor of laboratory medicine at the University of Washington and an investigator at the Malaria Clinical Trials Center (MCTC) at Seattle Biomedical Research Institute. Five infected mosquitoes are enough to deliver a malaria load that will infect basically anyone.
Murphy knows this because part of his job is to intentionally infect people with malaria. It's a way of testing different potential vaccines and drugs to see if any can successfully and consistently prevent infection.
"One of the reasons malaria [research] has advanced so much in the last 10 years is that we have these models," where they get to watch the infection progress in people, Murphy tells Business Insider.
These types of trials, known as challenge trials, are perfect for studying malaria - a dangerous but curable illness that still kills more than 400,000 people a year. The number of people affected by the disease make it one that merits study; the fact that it's curable means that regulators are willing to allow medical institutions to infect volunteers, so long as they catch and treat it right away.
Volunteers here get tested every day. This allows researchers to see how the parasite progresses through the body - long before anyone gets "truly sick" with full-blown malaria, according to Dr. Jim Kublin, the principle staff scientist working with vaccines and infectious diseases at Fred Hutchinson Cancer Research Center and the medical director at Seattle MCTC.
Still, the fact that the volunteers are treated before they get "truly sick" doesn't mean they aren't sick enough to start feeling awful.
To further test some treatments, others have been bitten by hundreds or even more than 1,000 infected blood-suckers.
There were "terrible, terrible headaches," for about a week, bad enough to make it impossible to focus, according to Inaki Martinez-Creel, one volunteer who conducts research at the University of Washington. Other volunteers compared it to the worst parts of a really bad flu. Martinez-Creel was fundraising for Doctors Without Borders (MSF) when he was infected, and so he thought he'd benefit from better understanding the sort of illness that MSF dealt with on a regular basis.
And he was lucky enough to receive treatment at a point that started before most people even realize they have malaria. As soon as researchers saw his blood test results, Kublin says he drove out and met Inaki on the side of the road to get meds to him.
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A mosquito dissection station.
Getting infected
For the challenge trials, mosquitoes are raised at Center for Infectious Disease Research (CIDR) labs. The larvae develop in water-filled pans in a hot and humid room, and the young mosquitoes are transferred from the pans to small buckets (many that used to hold ice cream) before they are infected with malaria. Some are infected with parasites that infect people, others that infect animals like mice or rats.
Mosquitoes don't live long lives, and for the Plasmodium parasites responsible for malaria to survive, they have to pass through a host (human or other animal, depending on the species of parasite) before infecting another mosquito. The parasite has to live for about a week in a mosquito before it can be transferred back to a human. In people, the parasite needs up to a week in the liver before moving to the blood and causing actual malaria. That's a pretty specific life-cycle for a "bug," one that has what researchers would call weak or choke points, which happen both in mosquitoes or in a host's liver. Many researchers are trying to create medications that stop the parasite either in the mosquito or before it finishes its cycle in the liver.
Volunteers are usually given some sort of experimental vaccine or prophylactic before being bitten. Scientists at CIDR will then select infected mosquitoes, place them in a jar with an opening, and put that opening against a volunteers arm.
Then, they wait.
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The infected.
Most people are bitten by five infected mosquitoes, enough to guarantee that if the vaccine doesn't work, they'll get ill. To further test some treatments, others have been bitten by hundreds or even more than 1,000 infected blood-suckers.
There's often an awkward wait for the mosquitoes to decide to feed. It's a little hard for most volunteers to sit there and watch, the scientists involved in the work say.
Aside from Seattle, there are a few other places where these sorts of challenge trials are done - the US military conducts them at Walter Reed - but one of the biggest hubs for malaria research is Seattle. Some of the people who volunteer to get infected work with research institutions and there are also plenty of college students who could use a little extra cash who volunteer.
While the rainy Pacific Northwest might seem an odd place to study a disease that many people - somewhat incorrectly, in fact - think of as "tropical," there are a ton of resources in the region dedicated to the illness. The Bill and Melinda Gates Foundation plays a big role in that, but so do a number of other medical institutions, like Fred Hutch, the University of Washington, CIDR, and others, many of which Business Insider recently visited. Many of the groups who focus on trying to eradicate malaria are headquartered in the region.
Ending Malaria - and other diseases too
The goal of this work is to find a sort of vaccine that will cause the immune system to recognize malaria parasites and kill them off before they finish developing.
Unfortunately, developing a vaccine for malaria is much harder than developing a vaccine for many bacterial or viral illnesses. Pasteur was incredibly lucky that he worked with smallpox, several researchers mentioned, as that vaccine was relatively simple. A form of a related cowpox virus was enough to tell our immune systems to kill anything that resembled it, like the smallpox virus.
A researcher demonstrates a rapid test that can be used to diagnose malaria.
Malaria is "a problem of complexity," says Murphy. Unlike a bacteria or virus, the parasite is a eukaryotic cell, complex, much like our own human cells. We can't tell drugs or our immune system to automatically kill cells that are so similar without damaging ourselves. Most viruses have 10 or 12 different genes. Bacteria might have a couple hundred. Malaria has more than 5,000. That makes it hard to find the right part of the organism to target with drugs.
There have been some successes, though, largely because of these challenge trials. There are larger clinical trials going on for one vaccine candidate right now, and there are currently more drugs in the malaria pipeline than at any other point in recent history, according to experts at the Gates Foundation. But none of these treatments are complete or ready yet, and in the end, they may fail. Even though malaria is "curable," the main treatment we use for one of the two worst forms of malaria can't be used on a large number of patients. They have a genetic mutation that makes the disease less severe when they are infected, but it also makes the drugs used to treat the infection incredibly dangerous. It's a complex fight.
In the meantime, these challenge trials and intentional infections will continue. Researchers have considered using the same facilities to test drugs for dengue and Zika. It might work for dengue, though intentionally infecting people with Zika might be a bad idea, since it seems it may be sexually transmissible long after the infection has been cleared from the blood.
The fact that malaria is curable for now is a good reason to continue these tests, painful as they may be.
Kublin didn't have to drive out to find another volunteer, Molly Perry, who also sought treatment the moment she started to feel the first signs of the disease.
"It was pretty bad, I was banging down their door for meds," she says. But she knew how bad even a "mild" or preliminary case of malaria might be. "They prepared us for it."