There Will Be Blood

I’m only here because it didn’t work. I’m happy to be here, but it’s uncomfortable to follow this joy back to its logical source. It’s all kinds of inappropriate to derive pleasure from the stumbling blocks of anybody’s project, even more so when that project is an HIV vaccine.

Spelunking With a Laser Pointer

Any vaccine we desighas to account for the incredible amount of variety in viral genetics as well as the multiplicity of human genetics. The latter has been long overlooked, but its implications are grave. Just as humans have genetically determined blood types that determine what kind of blood you can receive if you need a transfusion, humans have different serotypes or HLA types (Human Leukocyte Antigen, if you care), that are roughly the same phenomenon applied to your immune system. Whether a donated organ is accepted or rejected is dependent on a match in this serotype. In the context of infection or immunization, different serotypes respond to different antigens, so one person may respond to a particular part of a bacteria or virus, while someone else may respond to a completely different part. When designing what parts to include in a vaccine, we need to take into account not only that the vaccine needs to enable people to shoot at a moving target, but also that many people are shooting from different distances and vantage points. Therefore, we need to test our individual vaccine components many times, each time against people with different serotypes. We tested the B7 serotype in Providence, and we’re testing A2 in Bamako.

The person that has been running the experiment here in Bamako is Kotou Sangare, a Master's student at the University of Bamako. Kotou is, in every respect, a character. He looks like Marlo Stanfield and acts his opposite. Kotou is a man whose smile starts somewhere behind his eyes and radiates out across his face and out into the world. He walks around like he has “Sir Duke” playing in his head on a loop. He will often abstain from eating or drinking for twelve hours at a time to be closer to Allah, but he never mentions his faith unless pressed and has vehemently nixed the idea of ever sending his children to a Madrassa. He knows his way around the lab, he’s quick, thorough, patient and precise.

The impression that we were under as we prepared for this trip was that Kotou, for all his personable qualities, was the problem. He doesn’t know how to ELISpot tests, claimed the project manager. That would indeed be a problem, given that those tests comprise about 95% of our project. He can't manage his lab, it seemed. They had sent chemical reagents to Bamako, which had disappeared. He claimed to have followed protocol, but the cells died and the data were lost. It took him four months to even get started. That’s why the project stalled.

Lauren and I were sent to Bamako to confirm those suspicions and to pick up the slack. We have been sent here by the various business and academic tendrils controlled by Anne De Groot, a brilliant immunologist and intensely driven doctor, the brains behind this potential vaccine. Lauren works for Epivax, the biotech company Annie runs, and I work for the department she chairs at URI. The project is under the purview of GAIA vaccine foundation, and NGO of which she is the founder and scientific director. GAIA works at a clinic in Bamako providing HIV care and treatment, TB treatment and maternity ward support while building out the required infrastructure that will be necessary to do clinical trials of that the completed vaccine.

However, GAIA is short-staffed, and much of the project management has been shoved over to people at EpiVax, who do all sorts of other work and may or may not necessarily care about the vaccine project, which is unfunded and time-consuming. They are busy people who have had extra work thrust on them by their boss, so they are unlikely to go digging for any unlikely answers where Occam’s razor will do. Moreover, they don’t speak French, and Kotou’s English is mediocre, so communicating about obstacles would be a problem if they were even inclined to do so. Technical minds gravitate towards technical solution, and the conclusion reached in Providence was that what held these experiments back was in the lab, a single, smiling weak link.

The Best Laid Plans of Lab Mice Usually Involve Survival

Vaccine research requires expensive equipment, a steady supply of disposable tools and chemicals, refined technique, and an infrastructure that guarantees things like a steady supply of electricity and clean water. Mali is the fourth least developed country in the world. The conflicts here are obvious. Luckily, the lab we work in is the beneficiary of a multimillion dollar grant from the US government, which facilitated its pimpification, whereby the lab was taken away from the hard-working, noble researchers, worked on by a former rapper and his team of sassy and zany technicians, who installed multiple incubators, sterile hoods, centrifuges, and put plasma screen TVs in the gene sequencer.

It is a far cry better than the lab at the Bamako Med School - a typical lab in Bamako left to fend for itself - which has no reliable source of water, little gas and no chemicals from this century. Even with our advantages, it is difficult to run two-day experiments when you never know that there will be electricity available for the duration of the period. Not to mention the vulgarity of the amount of waste that goes on in a lab, compared to the pinching resourcefulness of poverty. Tubes that cost the equivalent of a family’s weekly income are used once and tossed. According to the doctrine of sterile technique, which dictates cleanliness in much the same way that Leviticus does - everything that could have possibly touched anything that was ever in the vicinity of any chemical at all is unclean and has to be thrown away. It’s not unreasonable, we are working with HIV-positive blood after all, but the island of sterility in our lab seems about as far from Bamako as you could possibly be.

We came here full of piss and vinegar and with two suitcases brimming with over a hundred pounds of equipment and reagents, to fix the problems in the lab. We spent a week ironing out supplies and fending off the demands of clinic politics, and still no results. We learned that Kotou knows exactly how to do ELISpots, but he was given inactivated chemicals and instructed to follow a dead-end protocol. It turns out that our hypothesized quick fixes failed to account for one thing. The limiting reactant here is HIV-positive blood from Sikoro, and we're not getting it. None of the HIV-positive patients come into the clinic to donate blood. The problem is not at the lab, but at the clinic.

“Are we calling them?”

“Yes, we’re calling them. They schedule an appointment but don’t come.”

“Are we telling them why this study is important?”

“Of course. ”

“Are we telling them they will be compensated”

“Yes. 2000 CFA ($4.50)”

“Maybe the doctor is keeping the money?” A week of investigation reveals that he is not.

“Why don’t they come?

“They just can’t.”

“How do we fix it?”

“Education campaigns in schools and the village for a few months or years.”

HIV, Syphilis and Nuremburg

Our study critically depends on HIV-1 positive blood from otherwise healthy, non-pregnant patients who have been infected for more than a month but are not under treatment. We are expected to get this blood from the 100-200 HIV-positive patients in our catchment area, most of whom we diagnosed as HIV-positive when we tested them because during pregnancy. Our work serves to find patients that are almost universally ineligible for the study. When we find someone that by chance, or when we wait out a pregnancy and early childcare and ask the patient to come in to give blood, we have to compete with all of the other stresses and strains of a new HIV-positive mother. Taking care of the household, manning the stall in the market, cooking meals, and the other tribulations of life in Sikoro.

This brings us to the problem of medical ethics. This is an all-important part of research, borne of the need to prevent the atrocities of human subject research in Nazi concentration camps and the famous Tuskegee trials where men with syphilis were denied treatment and forced to die heinously as bacteria made their way into the brain and subjected it to a game of Worms Armageddon. Reports recently came to light of an even worse trial perpetrated by American researchers in Guatemala in the 1940s, whereby subjects were actively infected with syphilis. From a sociopathic data-seeking point of view, the researcher benefits from sick subjects. Obviously, to act on this is disgusting and inhuman and not only violates public trust in science, but violates the purpose that science serves. Ethical review boards are charged with litigating against the temptation to cut corners and exploit the grey areas that pop up in the complexity of real life. 

Modern research ethics abides by three main principles. First, the fate of each and every individual subject is unequivocally more important than all of the research. If the study concerns acquisition of disease, everything attempt must be made to prevent subjects from getting sick. In the case of an HIV incidence study, this means providing counseling on risk reduction, free condoms, and free testing to all subjects, which requires a larger number of subjects, increases the cost, necessarily reduces the broad applicability of the data, because it cannot represent those who were not study subjects and did not receive counseling, condoms, testing, etc. Second, there can be no undue coercion of any kind. You may not force subjects to participate or restrict their rights to end their participation at any time. Undue coercion includes things that might be seen as beneficial, such as providing preferential treatment or excessive payment that may cause the patients to participate for the sake of the money or status. Study remuneration is fair compensation for time and expenses, not payment for a service. Third, complete confidentiality must be maintained.

In our case, the first is not limiting, as there is no conflict between our research and the health of the patients. The third only complicates matters insofar as only Doctor Koné can contact the patients. We can’t, for instance, have our Peer Educators go visit a patient before the appointment to remind them of their appointment or escort them to the clinic. It is the complexities of the second criterion, the absence of any coercion, that hinders the study, insofar as it makes it economically near-impossible for poor Malians to participate. We can subsidize transport, but we can do nothing to cushion the opportunity cost of a day’s work as well as the extra expense of food, neither of which are trivial. In our ethical vigilance, we make sure that the donor gets a raw deal in order to make sure they are not giving blood for any but the most honourable reasons.

Blood is sacred in Malian society. I have already mentioned this, but it bears repeating. Blood is your very essence, and giving it up is a profound act. Blood drives are difficult, people give blood if and only if a neighbor or relative needs it, in which case the mother mobilizes the entire family to give blood at once. Giving blood because you have HIV and it would be useful to some Toubabus up on a hill is a different story, and entails opening yourself up to the full brunt of stigma.

So we have both willingly and unwillingly stacked the deck against our own success. The people that manage our project didn’t know this when they sent us out here, assuming that what could be done in Providence could just as easily be done in Bamako.

Stuck In A Rut

This is in some ways a typical story of NGO work in the developing world, especially technical work. Technocrats design the operation, and when it doesn’t go to plan, assume it is because of a paucity of technical knowledge on the other side. They don’t have the insight, experience, interest or time to ask the right questions, so they provide their own answers. The wholesale difference of life and business between Providence and Bamako. Science in general, and vaccine development especially, is implicitly built a modernistic conceit that assumes away any inconvenient human strata. If we develop the right vaccine, it was thought, we will defeat the disease. Period. Reality tells a different tale – Measles kills 300 000 children annually and is the leading cause of blindness, but we’ve had a vaccine for that for years. Whooping cough kills kids all the time. Polio still cripples people in India, Afghanistan, Pakistan and Nigeria (Aside to India: You can have a space program or you can have polio. Not both). Measles in Niger does vastly more damage than HIV in America. These plagues are diseases for which we have had vaccines for half a century, but science as a whole considers the human application and implementation of its fruit to be an afterthought. Not coincidentally, science has a hard time believing that the human element may entail some cultural, social, and other non-technical problems that are not immediately surmountable. What we do in the lab is inseparable from what we do in the clinic, and what we do in the clinic is firmly embedded in how life works and doesn’t work in Sikoro.

We arrived in Bamako worried about what we would do when we ran out of reagents – what would we do about the 13th patient, for whom our calculations left only half a test-kit? In just over half the allotted time, we have received donations from three patients, and I was at the clinic to witness the most recent one. She looked, as most HIV patients do for most of their lives, strong and healthy, there was nothing about her that betrayed her status. Normally we need 5 test tubes (50 mL) of blood.  After two tubes, filled drip by tedious drip, and she started to swoon, then moan, and began to fade. The sight of her own blood leaving her body was too much. As soon as it was clear she was fainting, it was a mad rush to remove the needle, clear the bed, get her off the chair and onto the bed, and to free her from the tubing that bound her arm. The latter was my job, and is I reached up her arm, avoiding like the plague the inside of her elbow where the needle had been, wrestled with the surgical tubing that restrained her circulation, pulled it free and let her lie down as she let delirious groans escape her throat. And as I stood up, I saw Awa, just to my left, holding the last tube of blood at her hip, with the ruddy glint of the syringe tip still pointing up and vaguely in my direction. It must have been a foot away from me, and I know that even if I get stuck, proper treatment gives me a 99% chance of safety. But still I could have sworn that the needle was, or seemed like, millimeters away from my skin. It might as well have grazed the hairs on my forearm, I thought. And it was very nearly my turn to swoon and faint, as I contemplated the glinting possibility of a new biological condition, one that I would share with this woman and the others upon whose broad backs our study is built. It is a very odd feeling indeed to look at someone like that and think "your life is my worst-case scenario, and I have never come closer to it than just there", and then to realize that we need her to make sacrifices for us.

We whisked the blood off to the lab and performed a successful ELISpot test, with Kotou’s capable help. We are closer to completing our study, and therefore closer to an HIV vaccine, than we were that morning. Despite the problems and our inability to grasp them, we are pushing forward, largely on the strength and spirit of the weakest and sickest here.

As we left the clinic, we walked past the woman one more time. The last time I will ever see her, though she will continue to exist in my life as a data point. I looked at her and she returned a look, gaunt and deflated, incongruous with the proud black and gold Malian batik that wrapped her from head to calf. My muscles congealed and my throat thickened, as my relief at having a test subject was suddenly saturated with a feeling something like shame and a lot like inadequacy, knowing that while my Bambara is abysmal, that has nothing to do with why I can’t begin to know how to thank her.

You Have Been Poked By John Rozehnal. Poke Back / Ignore

“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 18^th-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.