When I first began working in a lab, I was incredibly naive about what it took to cure a disease. Now, as a jaded and pessimistic veteran, I am firmly steeped in an 'I'll-believe-it-when-I-see-it' attitude. Since many of you have not experienced the constant crash-and-burns of translational research, I'd like to share a short story on one of my many, many failures to illustrate why drug development is so goddamn hard.
Maybe five years I noticed a particular protein that was aberrantly expressed in several of the mouse models of schizophrenia/bipolar disease we studied. Looking into it, I discovered that this particular protein had never been studied for a link to either disease. Seeing an opportunity to pinpoint the cause of the disease, I turned down the alleyway to see where things went.
Over the next six months I performed a series of experiments to investigate the function of the mystery factor. I am not going to go into too much of the minutiae, but my probing revealed that this factor seemed to be missing in the brains of animals used as models.
Scientists use common sense as well (sometimes, when it doesn't cost too much). Since the piece was missing, I wanted to see what happened when we replaced it. By conducting a bit of mouse brain surgery, we were able to infuse this reagent directly into the brains of the rodents. I was hoping this would correct several significant deficits that we believed were the ultimate cause of the behavioral- and cognitive symptoms of schizophrenic patients.
Unlike most projects I touch, this worked really, really well. A number of the aberrancies we associated with the disease disappeared after a few weeks of treatment. Interestingly, these gains tended to persist some time after treatment was stopped, suggesting the possibility that we were doing more then just palliative care - we might actually be creating a disease-modifying state, which is a circumspect way of saying 'permanent cure'*. Suffice to say, everyone in the group had a huge science boner.
There was, however, one small problem**. My colleague, who'd done the infusions, reported that the animals were behaving strangely following the injections. Immediately, my thoughts turned to seizures, which are an occasional side effect of some classes of CNS drugs. My science boner ebbed.
As you may know, there's a formidable physiological barrier that prevents drugs from entering the brain. To neuroscientists, this is a significant impediment to testing new drugs (especially our early efforts, which aren't optimized for getting into the recluses of the brain). To administer this particular compound, we'd had to perform brain surgery on more than a dozen mice, implanting a cannulae (basically a hollow tube used to deliver medicine) smaller than a human hair into the fluid-filled ventricle of the animal's brain. This is painstaking work, obviously, but necessary to what we were trying to test.
As I watched on, my colleague dispensed a tiny bolus of drug through the tube. As he moved on to the next animal, I remained focused on the first recipient, surveying the rodent for any sign of distress or behavior change.
For about ninety seconds, the little guy was fine, scurrying around his cage as he would normally. Then he paused for a moment to run a paw over his scalp. Nothing abnormal there, mice groom themselves frequently. But then he stopped again and scratched twice. Within a minute, he'd stopped moving and was sitting there, rubbing his face like the world's worst Texas hold'em player trying to bluff an off-pair deuce/seven.
My initial inclination was that we were infusing too much fluid into his brain, causing compression of the cerebral tissue accompanied by some pressure and pain. There was a problem with this idea, though - the control mice (those receiving the same volume of fluid, just without any drug in it) showed no signs of this altered behavior. After verifying the calibration of our machinery, I moved on to more esoteric possibilities.
The only other thing that could explain what I'd witnessed (the most likely, really) was that the animal was responding to the treatment in a way we hadn't anticipated. Up until now, I'd focused mainly on the interaction between the treatment molecule and the pathways involved in schizophrenia. However, it's rare that a molecule or protein does only one thing in a system as complex as mammals. Thus, what I was seeing could be a side effect.
Following this new hypothesis, I began searching PubMed for any known functions associated with molecule we were using. Buried in the literature, I found an article that clearly explained why this project was cataclysmically fucked. You see, among its many functions, the agent we were infusing was involved in afferent transmission of pruritic stimuli. Plainly, the shit was making the animals itch like a motherfucker.
When I returned to the lab, it was painfully obvious that this was the correct answer. All the mice that had received the drug were sitting miserably in the corner of their cages, constantly scratching themselves like they were suffering from a superhuman strain of pubic lice. Those receiving the highest levels of drug would scratch those eternal, phantom itches up to several hours. I'm sure they weren't happy with us.
In the end, the project ended up going nowhere, and the company decided to disclose the findings. I was left in a pool of tears, scratching ineffectually at the invisible wounds suffered by my massive ego.
OK, not really. Shit like this happens all the time in labs. A promising project is derailed by an unexpected hiccup. At this early juncture, the only person who really cared was me, the guy who'd poured about 1% of my lifespan into a dead end.
But my failure can serve to illustrate a couple of key points about drug discovery. First and foremost, this story underscores a very real difficulty in developing drugs - whether or not they work well is only one factor we have to consider before determining whether they're suitable for implementation or even moving them to a clinical trial. In my case, we never actually tried to make a real drug, but sometimes we have a compound that is quite advanced before a critical flaw is uncovered. Witness another situation I heard about where a new drug was about to go into clinical trials. As a final safety precaution, researchers injected the compound into monkeys (this is done because monkey physiology is so close to humans'). After receiving the drug, all the monkeys began projectile vomiting - turned out the compound triggered uncontrollable nausea that was undetected in previous testing (want to know why? read to the end). The entire project ended in a pool of vomit after millions of dollars and thousands of man hours invested. No one made a mistake, it's just the kind of shit that happens sometimes when you try to monkey (pun intended) with complex biological systems.
Shit happening is also a reason that drugs are so expensive. In my case, I spent six months running this hypothesis down and, despite careful and judicious experimentation, and had nothing to show for my efforts in the end. I was "correct" in the sense that my treatment strategy showed real promise, but we were derailed by a simple side effect that just happened to be a deal-breaker. Show me a psychiatric patient who would trade their imagined delusions for a very real neverending itch and I'll try and take the idea back to our marketing department. Nevertheless, the cost of failure is real - the cost of my salary and reagents used is priced into the retail price of our successful compounds. I think that's fair, or at least I think it's capitalism.
*This is not to say that we had a cure. We weren't conducting micro brain surgeries for fun; we were doing them so that the protein could penetrate the blood-brain barrier. Swallowing this protein in pill form would likely be useless after the stomach's acids had broken down the compound. Using the protein was simply a way to establish proof of concept; knowing we were on to something meant that we could then develop a small molecule drug that would (hopefully) be the starting point for a real medicine.
**Technically there were two small problems. The second was that a certain type of cancer tended to overexpress one target of the factor I'd identified; if a patient were to develop this type of cancer while taking the drug, the treatment could very easily make things worse by stimulating the tumor. While not a deal-breaker per se, the fear of what could happen did factor in the decision not to pursue this factor for further clinical development.
Answer to the Question:
Why did no one determine that the compound caused uncontrollable nausea? Turns out that all the initial studies were done in rodent models of the disease in question. This was an unfortunate choice in this case, as mice and rats are physically incapable of vomiting.
Noah's Inner Monologue
Scribblings of a man who can barely operate an idiotproof website.