This article was taken from the March 2013 issue of Wired magazine. Be the first to read Wired's articles in print before they're posted online, and get your hands on loads of additional content by <span class="s1">subscribing online.
Arranged neatly on a granite worktop in a windowless underground laboratory at the Scripps Institute in San Diego, California, are 16 small syringes filled with pure cocaine. Stacked up against the back wall are four rows of steel cages, each housing an albino mouse. The mice are being given a shot that contains 15mg/kg of the drug -- enough to get a human high.
But although they're all injected with the liquid, only some of the mice demonstrate signs of restlessness. Over the next half-hour, eight of the red-eyed rodents scurry back and forth wildly, nibbling at their tails and pawing at the metal mesh of the cage. The computer screen next to them reflects their frenzy; each time they cross the cage, a laser beam tracks their movement and the computer logs it, the numbers increasing relentlessly. The other half of the group is eerily calm; they groom themselves at the backs of their cages and sometimes venture timidly towards the front. "These guys have been vaccinated," says the lab technician, watching them closely. As the scientists hoped, these mice display no signs of a drug-induced high because they have been injected with an anti-cocaine vaccine: a shot that can numb cocaine addiction.
Across the road from the lab, in an oak-panelled office that resembles a library, sits the man behind this effort, Dr Kim Janda.
He is a medicinal chemist at the Scripps Research Institute, a private biomedical research organisation based in the wealthy San Diego suburb of La Jolla. Over the last 25 years, Janda has worked on anti-addiction vaccines with a single-minded obsession. "I've tried to invent every kind of drug vaccine --cocaine, nicotine, crystal meth, heroin, even marijuana, morphine and alcohol," Janda says. "Not all of them worked." But today's experiment could make all those years of toil worthwhile.
Similar vaccines are currently being tested on patients in psychiatric clinics around the US and the Netherlands. The experimental therapy works exactly like a flu jab: once an addict has been injected, his or her immune system should recognise cocaine as an intruder and send out antibodies to bind to the drug molecules in the blood. Since the cocaine never reaches his brain, the patient can't get high -- and, over time, scientists hope the brain will stop craving it.
There is no definitive proof of the drug's efficacy yet, but if it is approved, this vaccine will be the first licensed medical treatment for cocaine addiction -- and analogous versions could help treat other types of drug addiction.
Published research on addiction vaccines has been around since at least 1978, but advances have been gradual rather than dramatic.
Practical problems have emerged. There is resistance from those who believe vaccines would dampen the "moral" struggle against drugs; funding is hard to come by; and creating a universal therapy that works for genetically varied patients is a significant scientific challenge. But, according to Janda, the vaccine is on the brink of a breakthrough: it has already moved from lab tests into the real world, where it is being given in controlled settings to addicts who have run out of treatment options. Results from trials in 2013 could determine whether it will ever be applied widely as a one-stop cure for addiction.
In the Janda lab, a buzzing sense of anticipation hangs in the air. Janda is tall and has the lean build and loose-limbed energy of an athlete, often wearing football shorts and flip-flops to work. On an average day, you will see him striding round the lab with a steel pointer, looking over the shoulders of graduate students and postdoctoral students who are concocting heroin, meth or cocaine vaccines in bubbling glass flasks. "Sometimes I'm tempted to do things others would consider illogical, because I'm not an expert," he says. "That's how discoveries get made -- by accident."
By scientific standards, Janda is the expert. He has written at least 50 papers on the subject since his first successful cocaine vaccine, published in Nature in 1995.
For this experiment, he pumped 18 rats full of cocaine to test the effects of the jab. That paper alone has been cited 130 times. "His work has changed the whole field," says Ivan Montoya, deputy division director of the US National Institute of Drug Abuse (NIDA), which funds and evaluates research into addiction therapies. Janda's long-time Scripps colleague and friend, medicinal chemist Dale Boger, agrees. "He has taken jumps, while the rest of us are content with iterative steps," he says.
But when he started work at Scripps in 1985, Janda had no knowledge of addiction neuroscience or vaccinology -- he was a pure organic chemist with a fascination for drug molecules and a crazy idea. This idea came to Janda as a postdoctoral researcher, where his job was to design special molecules called anti-cocaine catalytic antibodies: proteins that are engineered to chew up molecules of cocaine when they hit the bloodstream. "That was a spectacular failure, but in the process this idea of a vaccine struck me," Janda says. "I thought, 'Why can't I engineer small molecule drugs so they are visible to the immune system and attacked from within?'" Although physician Anthony Killian had attempted a vaccine against heroin in the 70s, Janda wouldn't find out about it until five years into his research. Instead, he spent months learning the basics of how vaccines worked and realised "it was a no-brainer": if he could create an analogue of an addictive drug like cocaine and modify it to trigger the immune system, he could leave the human body to do the hard work.
Today, addiction treatments have not moved far beyond the 12-step programme, a set of moral guidelines prescribed by Alcoholics Anonymous in the 30s. Currently, cocaine and methamphetamine addictions have no licensed cures worldwide. Heroin is primarily treated using methadone, which itself can lead to dependence and is not a cure-all. In a study conducted by the London-based UK National Addiction Centre in 2001, 40 per cent of patients were still using heroin at least once weekly after five years of methadone treatment. Nicotine, despite several approved therapies, is still used by a billion people worldwide and kills about six million of those a year, according to the World Health Organisation. Illicit drug use may be society's most expensive epidemic: in 2005, it was estimated to be costing the UK government over £15 billion and the US federal government $467.7 billion (£291 billion) annually. The UK think tank, the Centre for Policy Studies, estimates that the annual cost of maintaining methadone treatment and paying benefits to Britain's 320,000 heroin addicts is £3.6 billion. In comparison, producing and rolling out a twice-yearly vaccination would be cheap -- other vaccines have proved very cost-effective. The NIDA's Ivan Montoya estimates a nicotine vaccine alone would have a $2 billion market worldwide.
Janda's idea has definitely caught on; the NIDA spent $12.3 million on funding 17 projects last year alone. But it was not as well received when Janda first suggested it. "We had our fair share of ridicule and disbelief," Janda says. "People thought it was a gimmick, a quirky way to attract funding with no real medical merit." That made Janda more determined than ever to get it working. "I don't like being told I can't," he says.
The shot will not be given as a preventive treatment, but as a therapy for addicts who are attempting to quit. What's novel about the vaccine is that it treats addiction as a physical disease, rather than a psychological problem to be solved by willpower. "People need to get over the idea of addiction being a moral failure," Janda says. "It's nothing but a disease of the brain."
When drug molecules enter the brain, they mimic or interfere with naturally occurring chemicals we produce. Cocaine, for instance, stimulates a network of pathways in the brain to release large amounts of the chemical dopamine, which in turn triggers the brain's reward system; to be cured of an addiction, you need to stay completely drug-free so your brain can rewire itself and start normalising the release of natural chemicals that were disrupted by the drugs. "The vaccine is a very clever way to approach drug dependence, because it doesn't touch the brain, unlike all other treatments," Montoya explains. It works by vacuuming the drug up from an addict's blood before it can get to the brain, thus preventing the "high". That way, the brain has a chance to wean itself off the drug and extinguish the addiction pathway.
The first vaccine Janda attempted, in the early 90s, was a cocaine vaccine he called GNC: "That's for Gold Nugget Cocaine, because we thought we were going to make a lot of money off it,"
Janda says. Usually, drug molecules are too small to be noticed by the immune system when they enter alone. So GNC is a synthetically made cocaine molecule linked to a large, conspicuous protein such as the cholera bacteria or tetanus toxin. The protein acts as a banner and flags cocaine up as a danger to our body's defences. This is then bound to an adjuvant such as the chemical alum, which is added to augment the initial immune response.
A cocaine-specific antibody, Janda explains, is like a tiny Pac-Man floating in your blood that can swoop in and swallow any cocaine molecules you inhale. The key to the vaccine method is designing a molecule that can rouse the body to deploy sufficient antibodies to mop up the drug; if antibody levels are too low, drugs taken later will find their way into the brain. "The danger is that drug users will overdose themselves accidentally, trying to amplify the weak high," he says.
Janda says he is up for the challenge. "That's how I play sports, and that's how I do science -- I give it my maximum." He got to university on a football scholarship and still plays three times a week. In fact, it was a bad ankle break while playing football in his second year of college that drove 19-year-old Janda to academia. "I was so bored, I started studying in my spare time," he says. "I found I quite liked medicinal chemistry."
After college, Janda was offered a place at the University of Arizona to pursue a PhD in organic chemistry, under Professor Bob Bates. "Kim discovered three new general reactions during his PhD -- something many organic chemists don't do during their whole careers," says Bates, now 78. "It was when he was here that a cot
[camp bed] appeared in the lab." Apparently, Janda would spend every Thursday working straight through the night and into Friday. "On Friday, at about 5.30pm, I'd stop and go out, go crazy," Janda says. His student habits haven't died: he spends seven days a week in his lab at Scripps, often brainstorming new ideas on his giant blackboard late into the night. On Fridays, like old times, he heads down to the Scripps bar at 5pm, sometimes with a postdoctoral student from his lab, where he relaxes with a bourbon on the rocks. To test out his late-night ideas, Janda collaborates with George Koob, a neuroscientist also at Scripps. "Koob is the Pope, you need an audience to see him," Janda says.
Koob is considered one of the world's foremost authorities on addiction and tests scientific theories on rats and mice. "We initially moved into the vaccine area because of Kim's skills as an immunochemist," Koob says. "My lab is the physiological end of Kim's enterprise -- we essentially tell him whether his vaccines work or not." Although the first generation of GNC prevented rats from getting high, Janda was unable to find a sponsor to test it in humans. "Cocaine addicts aren't a good investment for big pharma," he shrugs. "They are a big risk, so drug companies feel they won't make enough money back." But because he was convinced of the social impact such a vaccine could have, he decided to keep going until he had a product that investors couldn't refuse.
The Koob lab is spread across three floors all devoted to studying chronic substance abuse in animal models. Here, in the soundproof underground labs, tests are underway for Janda's fourth version of the original GNC vaccine (now called GNE) as well as a brand new prototype: a heroin vaccine that he intends to test in the US, Russia and China, countries where heroin addiction is a serious problem. In Koob's absence, a bearded French neuroscientist called Olivier George oversees the animal facilities. "The results are really piling up here. We have heroin running -- it works.
Cocaine -- it works," he says. In November, Janda published a paper showing his methamphetamine vaccine worked too. "The effect in our animals is dramatic. Their drug intake, it's like on/off," George says.
Meg Haney has seen how cocaine vaccines work first-hand -- and in humans, not mice. Haney is the associate director of the Substance Abuse Research Center at Columbia University in New York City, where she runs laboratory trials to determine if specific experimental therapies are worth pursuing. In 2010, she tested a cocaine vaccine called TA-CD, developed by a small UK-based biopharmaceutical called Celtic Pharma, on ten cocaine-dependent men. The goal was to see whether the vaccine could trigger antibodies and whether the antibodies had any effect on the men's "high". The vaccinated men, who were not seeking treatment, were given 50mg of cocaine two nights a week for 13 weeks, and observed. "I've been testing treatments for a long time and nothing has done what this vaccine did," Haney says. The first thing she found was that the vaccine didn't work for everybody -- it only triggered antibodies in half the group. But the interesting part was that these five men stopped feeling the acute effects of cocaine within four minutes of smoking the drug. They showed reduced euphoria, energy and hyperactivity (about 80 per cent less than usual) and also reported using less cocaine when outside the lab. "They were actually annoyed, because it felt like they were throwing their money away," she says. She also found that the high-antibody group started off spending on average $89 per week on cocaine, but by week 13 of the study spent roughly $40. The low-antibody group showed no significant change in their spending. The study, published in the Biological Psychiatryjournal in 2010, concluded that the outcome was "more robust than any other medication tested with cocaine using similar laboratory procedures".
TA-CD is now an experimental human treatment being tested at the Baylor College of Medicine in Houston by psychiatrist Dr Thomas Kosten, who is Janda's main rival in the field. Originally developed in the 90s, around the same time as the GNC, the vaccine only went into advanced human trials last year, and is being tested at six sites around the US. A group of 300 volunteers, aged between 18 and 64 years, was part of the study, which concluded in September 2012. At the Houston site, therapist Katrina Campodonico counselled vaccinated patients throughout the trial. Although the medical data has not been analysed yet, she saw marked behavioural changes in her patients. "Many found employment, reported a decrease in depression and far better family relationships," she says. Although previous trials of TA-CD have shown positive results, the vaccine is an early generation that has not been improved upon since its inception in the 90s. "The results are out in March. If it works, and we get pharmaceutical interest, we could have this approved and licensed in two-and-a-half to three years,"
Kosten says. Janda, however, is dubious: "I'm not convinced this is the best one to move forward into the clinic," he says. "We know our newer vaccine generations work better in the animal models, so we need to pick and choose our battles."
Large pharmaceutical companies such as Pfizer and GSK have put their money into nicotine vaccines, and are working to develop their own prototypes. In fact, a nicotine vaccine called NicVAX is the only one that made it through human trials in 2011. Produced by Nabi Biopharmaceuticals in Maryland, NicVAX was the research community's big hope: if it worked, it would be an enormous cash cow and big pharma would be scrambling to license others. The vaccine, however, proved to work no better than a placebo in a final-stage trial in the US. Despite the failure, NicVAX is still in trials at Maastricht University in the Netherlands, where it is given in combination with Champix, an existing smoking-cessation medication. The plan is to see if the vaccine can boost effects of an existing, imperfect treatment, rather than cure addiction single-handedly.
In April 2011, Angela Hendricks was persuaded to sign up to the trial by her brother, who had also enrolled. The 46-year-old Dutch government worker had smoked her first cigarette at 15, and had never tried to stop before. The odds were stacked against her: the World Health Organisation says up to 80 per cent of smokers relapse when trying to stop and it takes the average European smoker roughly seven attempts to quit. But a few months into the new treatment, Hendricks quit cold. Today, 14 months on, she has yet to touch a cigarette.
The results from the study are still being analysed, so Hendricks doesn't know whether it was the vaccine or Champix that made her stop, but she says the effect of the shot was "extreme".
It made her tired at first, and feverish, but the cravings slowly stopped. "A year later, the desire for cigarettes is no more than a flash in my mind," she says.
Janda's lab has stayed focused on cocaine and heroin, where treatment options are fewer. Last year, his fourth-generation cocaine vaccine was shipped to the New York lab of gene-therapy veteran Ronald Crystal, at Cornell University Medical School.
Crystal became interested in addiction vaccines after reading a
Newsweek story on the topic and called Janda, asking if they could collaborate. For Janda, it made financial sense to partner with a scientist who had resources to move his vaccine into a clinical trial, so he agreed. Crystal is trying out a new protein carrier: the adenovirus, or common cold. "We attached Kim's cocaine analogue to the outside coat of the cold virus and it turns out that's a very effective way to raise antibodies against cocaine," says Crystal, 71. Late last year, Crystal received $2.8 million from NIDA to test this version on cocaine addicts in the spring. "The prospects look terrific," he says, "but we have to wait for results from the human trials."
What Janda is most excited about, though, is his heroin vaccine. "Heroin is nothing but a pro-drug -- it breaks down into another molecule, similar to morphine, within a minute," he says. "So you've got to block that before it gets to the blood-brain barrier." The heroin vaccine he designed in 2011 matches heroin's own behaviour exactly: the vaccine breaks down to attack each individual component of the heroin molecule, making it far more targeted. Researchers tested the vaccine on several rat models and looked for long-term decrease in drug use or relapse (the results are about to be published). "And it worked. It worked like gangbusters."
In fact, venture capitalist Stephen McCormack has pledged to see this vaccine through to human trials. McCormack is a biomedical engineer who has founded a number of biopharmaceutical businesses over the last 30 years, including one with Nobel Prize winner Thomas Kundig. His latest, Exela, is interested in tackling addiction. "This vaccine could be a game-changer for patients who are chronic relapsers or who are non-responsive to methadone," he says. McCormack knows clinical trials are expensive and this one, being the first of its kind for heroin, could cost up to $50 million before a treatment hits shelves, "but I would be willing to go through with this until the end", he adds. McCormack hopes Janda and Koob can start testing their product within two years.
[Quote##"I want to see the drug I made cure people while I'm still around. It's got to be the same feeling as winning a game.
And I play to win"##Dr Kim Janda##FullWidth]
Despite the sense of excitement about a vaccine disrupting addiction medicine, few believe it would eradicate substance abuse entirely, as if it were some kind of virus. It is more likely to protect relapsing addicts by cushioning them if they fall off the wagon. "It's not a magic bullet," admits George Koob, "but I envision a day when someone might take meds for withdrawal symptoms, have psych counselling but also take an immunisation, so if they slip their brain is buffered, and the slip won't cause them to feel anything." The main scientific obstacle to overcome is genetic variability: it is impossible to predict which individuals will generate high or low levels of antibodies, as Meg Haney's cocaine trial discovered. "We've done studies showing that about 20 per cent of people we vaccinated have a gene that doesn't allow them to respond to the vaccine," Baylor's Thomas Kosten says. This suggests a licensed vaccine in the future might be tailored to addicts who are genetically likely to respond better.
The final hurdle is money. But the NIDA's Montoya is hopeful the vaccine will attract investment, not least because it has fewer side effects than any therapy currently on the market. "Today, even health insurance is paying for a lot more addiction treatments than it was ten years ago," he says. According to Montoya, treatments such as methadone need not compete with vaccines, because addiction therapies are like antibiotics: "Some things work for one subset of people and some for others, so you can never have enough options," he says.
In Janda's office at Scripps, it's Friday afternoon; he leans back in his chair and taps his ornate gold watch, indicating his time for the day is running out. He's got a lot to do before he heads out for his evening bourbon -- other than the vaccines, his lab is conducting a classified government research project on the bio-warfare agent botulinum toxin and is investigating a tropical disease called river blindness. But every day, he comes in with just one goal: to have one vaccine surmount all the obstacles and be available to patients. "I want to see the drug I made cure people while I'm still around," he says. "It's got to be the same feeling as winning a game. And I play to win."
Madhumita Venkataramanan is assistant editor of Wired*. She wrote about Hugh Herr's prosthetics in 11.12*
This article was originally published by WIRED UK
