“Let’s go wait in the lab. John’s more comfortable in the lab” said Dr. Kara, whereupon I let out a sigh of relief, entered my designated haven and wrapped myself gingerly in lab-grade cotton swabs and lay myself down on a carefully-arranged nest of discarded lancet covers, breathing easily at last. As dysfunctional as it sounds, I suppose it’s true. I am more comfortable - or at least nominally more useful- in the lab attached to a Malian slum clinic than in the adjacent waiting room, full as it is of women and infants chattering in Bambara and staring wide-eyed at their first toubabu. In the clinic, I take up space and oxygen, in the lab I can actually diagnose.
The lab is pretty sparse, if you’ll believe it. A tile countertop about ten feet long, with enough space for a microscope, a couple boxes of test kits, a bottle of disinfecting alcohol, and a can of Raid for when the flies get so numerous that their buzzing makes it impossible to pretend we’re in a clean environment. Diagnostic work is fairly straightforward. A child with a fever probably has malaria, a feverish adult is checked for typhoid. Pregnant women are tested for HIV as a matter of course, and a persistent cough will get you checked for TB. That’s what we can provide here, and that, along with intestinal worms, covers most of what makes people sick. The doctor orders one or two tests from our limited repertoire and the ladies of the lab are expert in each, while I trail along as the eager novice. With the exception of TB, all require a violation of bodily integrity and extraction of anywhere from a few drops to a tube of that sacred substance, poo. Sorry, blood.
The actual diagnostic procedure sometimes seems redundant. On my first day in the clinic, I saw a child no more than three years old, looking utterly spent. Not tired, the way babies are supposed to look when they haven’t slept, but weathered, rusted through, thoroughly devoid of any energy. For him to lift his hand was like starting a 1970s East German Trabant. Picking up this child’s hand, it lacked the springy response that a digit full of coursing blood should have. Anemic. It was agonizingly clear that this child, like hundreds of thousands of other Malian children, had malaria. The human immune system, so the theory goes, develops a sort of natural tolerance over time that keeps malaria at arm’s length. Rather than immunity, which is more like being bounced from the door of a high-society New York nightclub, this is more like going to a party at your ex-girlfriend’s house. You can technically enter, but any attempt at conversation quickly dries up, and you stand off to the side doing nothing exciting, talking with the people that brought you there about which Kardashian has the best nose-job. Malaria is truly dangerous in people who haven’t built up that managed immunological awkwardness, namely children and visitors from Malaria-free zones. And so, knowing full well what I would find, I picked up the half-inflated leather pouch that was this poor infant’s index finger, and drew blood by pricking his finger as gently as possible with this.
Like how a shark gently plays with a seal
And then, in order to ossify in this child’s mind once and for all that the devil is a skinny white man with patchy 3-day stubble, I took the finger and squeezed it until two drops of scarce lifeblood flopped onto a microscope slide, which I put under the scope to confirm that 1: Mad men isn’t as good as everyone says it is 2: Candy and scantily clad ladies make Halloween the king of holidays, and 3: Junior has malaria.
The big blue spots are blood cells, the little ones are out-of-focus parasites.
At the end of the day, malaria is only as critical as the poverty in which it exists. It is readily treatable (although the jungles of Cambodia are producing drug-resistance as fast as we can develop drugs), which means the reason millions die every year is not because it is a superbug, but because there are billions of people in the world for who cannot get to a clinic, cannot afford the medication, or live near a clinic that does not have a sufficient supply chain to regularly furnish life-saving tablets. In a sense, that makes the tragedy more poignant. It’s not that were facing an insuperable foe, it’s that we can’t get our shit together as a global society to put two dollars worth of pills into the mouths of babes.
The other scourge I’m qualified to test for tells a different story. HIV is far from curable, but it is fairly easily preventable, and there are cases where this is especially obvious. The first person I met here that is HIV-positive is named Koura. She just turned 10. My boss, Annie, has taken her to be sort of a symbol of our project - symbolic of how easy it is to live normally with HIV, and yet poignantly symbolic of how easy it would have been to give Koura an entirely different lot in life. Koura is bright in every sense of the word, with good grades and a sunny disposition, so it irks Annie somewhat that Koura wants to be “une secretaire” rather than a doctor. Koura was infected at birth from her mother, either during the act of birth when the blood of mother and child come into contact, or thereafter as virus particles can be transmitted through breastmilk to the infant’s defenseless and teething mouth. It is staggeringly easy to prevent transmission from mother to child – a single dose of antiretroviral therapy as the woman enters labor drops the probability of transmission by 70%, while a full regimen during the end of the pregnancy to decrease viral load coupled with artificial milk decreases the risk of transmission to effectively zero. As a result, this kind of straightforward, high-yield intervention is the first one that many clinics, including ours, focus their limited resources on. We test every pregnant mother for HIV, and the logistics and financial arrangements by which we do this have attracted women from as far as the South side of the river to our little clinic in a North Bamako slum, and in the process has become the model of village-level care that the Malian Ministry of Health is looking to bring to scale.
My first day was a popular day for pregnant women. Awa, the lab matriarch, wasted no time showing me a few tests in quick succession. Jab the finger, squeeze a drop of blood, this time onto a freshly opened HIV-test strip. I add a droplet of chaser, and the blood slowly moves up the strip, towards the two successive windows. “Watch”, she says sharply, “if the blood moves through and forms a line in the second window – like that – that’s the control. If it stops in the first window, it’s positive”. Piece of cake. She does another just to be sure I get it, then goes back to keeping records in her plastic-bound ledger book, and huffs my name as the third woman, my first test, walks in.
I don’t remember what she looked like, or how she dressed, I was focused on not screwing up the test. I took her finger, this time much firmer and healthier than the one belonging to this morning’s infant, carefully swabbed it with alcohol, removed a lancet from the package, and poked her finger. She hissed her discomfort, confirming that these lancets are vicious. Even her blood looked better than the morning’s tyke. It came out naturally, and in a healthy-looking orb, unlike the baby’s reluctant dribble, which lacked surface tension or any other sign of vitality. I touched it to the test strip, watched as it sucked the blood up, then added a quivering drop of chaser, gave her a test tube to bring back full of urine, and sat down to wait.
There’s no need to be unduly nervous – Mali’s HIV prevalence rate is less than 2%. That’s about three or 4 times the US or Canadian prevalence, significantly lower than an inner city like the South Bronx, an order of magnitude lower than the truly catastrophic countries like Malawi, Lesotho, and South Africa – leaving it on par with a country like Ukraine. Granted, the poor in a slum like Sikoro, which attracts seasonal migrant workers from rural Mali, are probably at somewhat higher risk, and people who have recently had unprotected sex – pregnant women necessarily included – are higher still. Still, the other two were negative, the odds were still on my side that everything would go swimmingly.
It would be appropriately theatrical to say that it felt like the moment of truth, that time slowed down, that everything became a blur as I heard my own voice reading out what I saw over the crescendo of Hitchcock’s string quartets, and as Awa stood up to confirm that I had read it right, that everyone’s focus narrowed to the fateful distance that a bundle of selenium-bound antibodies travelled on a specially-coated sheet. Instead, while the woman was down the hall pissing into a tube, the sounds of footsteps and chatter continued to pepper us from the hallway, the two flies in the lab continued chasing each other in a display of strength that was either territorial or coital, the chairs continued to screech across the tile, the little red line stopped where it stopped, and I read out the result. Awa got up to check it, and the pregnant woman whose name I still didn’t know came back into the lab. We took the vial of urine from her and asked her to roll up her sleeves, we needed more blood. To be sure. I stuck around for another hour and a half after that first test, and tested two more women for HIV, and one more child for malaria. At around lunchtime, the patient flow slows to almost nothing, so we went home.
Malian life, especially in a village, or a slum/village hybrid like Sikoro, is almost absurdly familial. In each house, you’ll find a family cramped into communal quarters in a way reminiscent of the opening chapter of Charlie and the Chocolate Factory. Now take that house, and surround it with a cluster of similar houses, with grandpappies and mommies and aunties and cousins all grouped, three to a bed, into an impenetrable family unit. Those that live in nearby houses become de facto family. They share the responsibilities of raising each other's children, including the practice of discipline and sometimes even breastfeeding. They watch each other’s belongings when one goes to market or to the countryside, they eat together, they pray together. There is no privacy, only community, so one person’s relationship gossip quickly becomes the village’s business. If someone is sick, the community is sick. Sometimes quite literally, as you can imagine what this arrangement can do for transmission of cholera, measles, or tuberculosis; sometimes only figuratively, as when the community rallies around the malade, bringing food and support. The family is everything. This is why divorce destroys women, because the man gets to keep the family. She is shunned, without family she has nothing – after all, nobody will hire a woman so morally base that she cannot keep a family. The only other thing that can get this all-important membership revoked, especially for women, is HIV. It is something about which not a lot is known in the villages, only that it is an incurable hex that causes healthy people to inexplicably waste away. It is through exile, through ostracism, through stigma, that HIV ruins lives, long before clinical manifestations like candidiasis, tuberculosis, and toxoplasmosis exact their toll. Treatment is available, and increasingly (but not universally) affordable. But there is no treatment for complete social dislocation. It is this new leprosy that wreaks so much damage.
As I walked home after clinic with Lauren, who had been helping the midwives all morning, she told me about one woman that learned today that she was HIV positive, and whose anguished wailings got her message across perfectly clearly without the need of a translator. I nodded.
That brings me to the need for an HIV vaccine, and to the other lab, the “real lab” with centrifuges and sterile hoods and incubators. In 1983, the Secretary of Health and Human Services said we were five years away from a vaccine against HIV. Twenty-seven years later, we are an optimistic ten years away. The problem? There are many. Let’s start with viruses in general, and why they’re harder to kill than bacteria. Bacteria have their own machinery, quite literally. They have their own little factories with their own moving parts. When destroying something, like in any good James Bond flick, it’s easier to throw a well-aimed wrench in the gears of some insidious machine to make the bunker blow up from the inside out, rather than going to the effort and expense of calling in a nuclear strike. So if you design a specifically shaped wrench to jam those moving parts, Kablamo! Bacteria die. Viruses don’t offer this particular solution, as they use your and own machinery. They write malicious instructions that co-opt your cellular factories to their own ends, so designing a wrench to jam your own moving parts would be inadvisable, less of an elixir and more along the lines of, say, rabies.
Ok, viruses are jerks. Now, HIV in particular. HIV replicates fast, and is the most mutable pathogen in the world, which means that it evolves faster than anything else ever has, and in a flat-out adaptation footrace can outrun your natural immune system. A single virus on day one will produce something on the order of 5 billion viruses on day two. Moreover, HIV’s machinery is fairly inaccurate. While this seems like a good thing, it’s not. It means that of the 5 billion new viruses, there will be a millions of errors that produce new, random gene sequences. Many will be useless and may shrivel up and die, but some (and one is enough) will acquire some new escape mutation that lets it paint a tunnel on the cliff face and Roadrunner its way from your immune system. If your body homes in on a target, it can kill billions of viruses, but the ones that have mutated multiply to take their dead partners’ places. It’s like fighting a Hyrda made of quicksilver.
"Beep-beep", he snarled, adding, "this is how I feel about mixed metaphors"
It’s worth mentioning that each one of these virus particles that invades a cell writes itself into your genome. It doesn’t just float around and bother your cells, it enters the very code that instructs cells to be cells. The unique code that James Watson, Steven Colbert, Ozzy Osbourne and a steadily-growing number of others have paid a pretty penny to sequence, all in the hope of unraveling a bit of that primordial information that distinguishes each one of us from the other 7 billion people in the world and the billions more that lived before. This sacrosanct code, locked away in the safest centers of the cell, is where HIV makes its bed. It comes as close as biochemically possible to infecting your soul. Happy nestled there, the virus can happily sit down and shut up for years at a time, knowing that as your own cells multiply, its genetic code multiplies along with it, and these sleeper cells can one day wake up, have a coffee, read the paper and run your shit, to the tune of the aforementioned 5 billion viruses per infected cell per day.
Lastly, (and this is important), HIV attacks your immune system. Which means that if your immune system is activated, it gives the virus everything it needs to grow stronger and multiply. Still, an activated immune system is your only hope of fighting off the virus, but only if aimed exactly right. It’s like trying to catch a bullet in your teeth if you have one bulletproof incisor. It’s your best chance, but if you don’t do it just right, you’re in for a world of hurt. So fighting it is, uhh, tough, so the best defense is to prevent it from ever entering your body in the first place. Ergo, vaccine.
Vaccinology is all about mimicry. If you can show the body’s defenses what the enemy looks like, without the unpleasantness of actually being attacked by things that can kill you, you have a decent chance of surviving the real thing. That’s how pretty every vaccine on the market works, starting with the first one, developed by a horny English coot with a thing for milkmaids. In brief, Edward Jenner, or rather, Edward Jenner’s penis, noticed that of all the bedraggled, unwashed bints roaming the British countryside in the 1790s, by far the least-haggard looking were the dairy wenches. Since extremely restrictive and catty milkmaid sororities did not yet exist, he deduced that the reason they looked homely, rather than grotesque, was environmental. Looking further into the problem, as a good scientist’s penis should do, he discovered that milkmaids were the prettiest because their faces hadn’t been subjected to the ravages of smallpox. If you’re ever thinking about moving to 18th-century England, keep in mind that most women’s faces looked like the fields of Ypres and Passchendaele in 1918. Except milkmaids. Milkmaids, as it turns out, had lesions on their hands and arms that were far less unsightly, and came from cowpox, vaccinia.
"I'd hit that" - Louis Pasteur
So in his effort to make British girls look pretty, a noble mountain to climb if there ever was one, he took some cowpox virus and gave it to a kid – presumably a street urchin or grad student - and then tried his good-golly-bestest to give that kid smallpox. Oh, how far medical ethics have come.
When that kid didn’t suffer unspeakable torment, Jenner knew he was onto something We now know that vaccinia looks enough like smallpox, variola, to educate the immune system to fight it off when the real thing happens. Soon, vaccination (from vaccinia, get it?) replaced variolation (taking pus from the lesions of smallpox sufferers and blowing them up other people’s noses. I’m serious.) as the a-plus super-duper way to prevent smallpox. Once we had solved the disease that caused so much unnecessary suffering and ugliness, we could move on to polio, influenza, diphtheria and the like.
Really really really makes her wanna zig-a-zig ahhh
Here’s the good news. We have a vaccine against HIV that has been shown to provide sterile immunity in primate tests. Hurray! Details? Fine. The vaccine is a live-attenuated vaccine, which means it’s alive, making a few billion copies per day, but it’s been weakened so it theoretically can’t destroy cells. It’s a strategy that works for flu vaccine, polio vaccine, and several others. Satisfied? Good, roll up your sleeves, you’re first. You may be hesitating. You may be saying “but wait. Flu and polio viruses others aren’t wildly speculative, sketching up rough drafts of zany newfangled upgrades for themselves like mad scientists after a pitcher of FourLoko, nor do they 5 billion copies per day, flinging a seemingly endless supply of viruses around your cellular space like a monkey hurling feces at a passing groups of kindergarteners on their first tour of the zoo.” You would be right. You would be one of many people to tell the health department to where to stick the needle for even considering putting live HIV into your bloodstream, regardless of how cleverly it’s been declawed. The health department and FDA are staffed by some pretty savvy people, and they were able to nip this one in the bud by bravely not proposing that we vaccinate with live HIV.
So where does that leave us? Good question, Virginia. The research pipeline has a few dozen potential candidates, although only a handful look to have serious prospects for success. To get a vaccine from the idea stage to the clinic generally takes about 15 years and costs around 5 billion dollars. In the case of the elusive HIV vaccine, it’s been 25 years and 25 billion dollars and we’re not done. The first landmark vaccine trial, known as the STEP trial, was funded by pharma colossus Merck and enrolled around fifteen thousand people. The results that came back in 2007 were gutting. Not only had the vaccine failed to prevent infection, it had made recipients more likely to acquire HIV. By activating the wrong part of the immune system at the wrong time, the vaccine had been counter-productive.
Failure is part of working in science. It is a labour that calls for full-time dedication, and the process of discovery by definition means that we don’t know what’s going to happen. Science, curiously, requires a considerable amount of faith. Faith in your own abilities, as well as faith that a capricious biological system about which we know only what we can obliquely measure will reward your asceticism. Nature does not owe you her secrets, she is not obliged to give you positive results, or even intelligible ones. Nature is not bound to function in a way we hold to be logical and intuitive. Everyone who has done any work in science knows this. Sometimes, the project in which you invest hour after diligent hour for a weeks, months, or years, simply collapses, offering no explanation, no alibi, nothing but an unyielding granite disposition. Sometimes there are early milestones of success, block after block is placed exactly right, until, inexplicably, Jenga. I cannot imagine what it must have been like for the hundreds of scientists, the brightest of us, the first out of the gate with early breakthroughs, who painstakingly evaluated every component, delivery vehicle, and auxillary signal in the vaccine, optimized the dosing, sifted through hundreds of spreadsheets, and the payout is the knowledge that the vaccine makes people more likely to die early. Or the funders, who held to a noble vision, whose commitment was unshakeable in the face of skeptics, and who were met with the brusque news that a piddling ball of nucleic acid once again outsmarted us.
It is deeply heartening to contemplate how far we have come in the three short years since Step. I had the pleasure of attending the 2010 AIDS Vaccine Conference in Atlanta, and what moved me most was the stalwart optimism of all those researchers who spent day after day at their benches, working for a breakthrough. And breakthroughs have come. This year, RV144, a vaccine colloquially known as the “Thai Trial” bore its results to the world, and was shown to decrease infection risk by 31%. It’s less than a third, not nearly enough to be clinically relevant, but it is a huge gain. It proves, for one, that a protective vaccine is possible, providing the first firm footing to justify 25 years of unrequited optimism. Much more analysis is required before we figure out what exactly the vaccine did to ward off the virus, and as we crunch the numbers, we can trim our sails. At the same time, science has illuminated new vaccine targets, and new methods to attack them. We finally know something about how, specifically, the body fights off HIV at the port of entry, something we didn’t know – and didn’t need to know – about smallpox, polio and measles. We have learned more about our own immune system by studying HIV than perhaps any other threat to the human body, and this corpus of knowledge that will continue to pay dividends. Just as the concerted investment in the Apollo missions brought back moon rocks, but also Doppler radar, satellite TV and Velcro; our attempts to prevent and cure HIV are already shedding light on how we can protect ourselves from pandemic flu, bioterror attacks, and even diabetes.
And so it is back to the lab where Lauren and I are validating, piece by tedious piece, components that may one day be included in an HIV vaccine. Each person’s immunological reactions are unique, and each person’s HIV mutates to the point that it practically its own species. As the theory goes, in order to be a vaccine candidate, the component we use must be reliably present in a large proportion of viruses from around the world, and they must also be recognized by a large proportion of human immune systems. Among this impossible diversity, we have selected pieces that pop up with suspicious frequency, and we are confirming that they actually cause a stir, immunologically speaking. If they are uncommonly common and highly reactive, we can use them in a vaccine. The details are uninteresting, we take HIV-positive blood, isolate the interesting cells, expose them to our preselected components, and see if they recognize them as a previously-seen threat. Everything must be purified, exact, and rigorous, because this is a project that requires us to understand Nature and then improve on it, not something that humans tend to do particularly well in the long run.
In the clinic, I deliver news that instructs people to count themselves among the number of infected. At lab, we use their blood, with its encrypted invaders and microscopic battlegrounds, and ask questions that may yield answers that spare millions of people from the anguish of the woman I tested that morning. Surely a more palatable project. Surely, then, the lab is a more comfortable place for me to be. We will not finish by the time we leave, but we will have made progress. We are training the researchers in Bamako to do this, not only so that we can spare the cost of travel and the time devoted to blogging and devote it to research and advocacy, but so that the people that speak the language of the laboratory also speak the vernacular of the clinic waiting room. So that the people whose business it is to take blood and make it speak can provide something to support and shelter the shattered woman who provided it, knowing full well that her neighbours will hear of it and understand what it means.
