Predicting toxic drug effects in humans - now, that's something we could use more of. Plenty of otherwise viable clinical candidates go down because of unexpected tox, sometimes in terribly expensive and time-wasting ways. But predictive toxicology has proven extremely hard to realize, and it's not hard to see why: there must be a million things that can go wrong, and how many of them have we even heard of? And of the ones we have some clue about, how many of them do we have tests for?
According to Science, the folks at DARPA are soliciting proposals for another crack at the idea. The plan is to grow a variety of human cell lines in small, three-dimensional cultures, all on the same chip or platform, and test drug candidates across them. Here are the details. In keeping with many other DARPA initiatives, the goals are rather ambitious:
DARPA is soliciting innovative research proposals to develop an in vitro platform of engineered tissue constructs that reproduces the interactions that drugs or vaccines have with human physiological systems. The tissue constructs must be of human origin and engineered in such a way as to reproduce the functions of specific organs and physiological systems. All of the following physiological systems must be functionally represented on the platform by the end of the program: circulatory, endocrine, gastrointestinal, immune, integumentary, musculoskeletal, nervous, reproductive, respiratory, and urinary.
The request goes on to specify that these cell cultures need to be able to interact with each other in a physiologically relevant manner, that distribution and membrane barrier effects should be taken into account and reproduced as much as possible, and that the goal is to have a system that can run for up to four weeks during a given test. And they're asking for the right kinds of validation:
Proposers should present a detailed plan for validating integrated platform performance. At the end of each period of performance, performers are expected to estimate the efficacy, toxicity, and pharmacokinetics of one or more drugs/vaccines that have already been administered to humans. Proposers should choose test compounds from each of the four categories listed below based on published clinical studies. These choices should also be relevant to the physiological systems resident on the platform at the time of testing and should include at least one test compound that was thought to be safe on the basis of preclinical testing but later found to be toxic in humans.
i. Drugs/vaccines known to be safe and effective
ii. Drugs/vaccines known to be safe and ineffective
iii. Drugs/vaccines known to be unsafe, but effective
iv. Drugs/vaccines known to be unsafe and ineffective
Now, that project is going to keep some people off the streets and out of trouble, for sure. It's a serious engineering challenge, right off the bat, and there are a lot of very tricky questions to get past even once you've got those issue worked out. One of the biggest is which cells to use. You can't just say "Well, some kidney cells, sure, and some liver, yeah, can't do without those, and then some. . ." That's not how it works. Primary cells from tissue can just die off on you when you try to culture them like this, and if they survive, they (almost invariably) lose many of the features that made them special in their native environment. Immortalized cell lines are a lot more robust, but they've been altered a lot more, too, and can't really be taken as representative of real tissue, either. One possibility that's gotten a lot of attention is the use of induced stem cell lines, and I'd bet that a lot of the DARPA proposals will be in this area.
So, let's stipulate that it's possible - that's not a small assumption, but it's not completely out of the question. How large a test set would be appropriate before anyone puts such a system to serious use? Honestly, I'd recommend pretty much the entire pharmacopeia. Why not? Putting in things that are known to be trouble is a key step, but it's just as crucial that we know the tendency of such an assay to kill compounds that should actually get through. Given our failure rates, we don't need to lose any more drug candidates without a good reason.
We're not going to have to worry about that for a while, though. DARPA is asking for people to submit proposals for up to five years of funding, contingent on milestones, and I still cannot imagine that anyone will be able to get the whole thing working in that short a period. And I think that there's still no way that any system like this will catch everything, of course (and no one seems to be promising that, fortunately). A system sufficient to do that would be like building your own in vitro human, which is a bit out of our reach. No, I'd definitely settle for just an improved look into possible tox problems - every little bit will definitely help - but only if it doesn't set off too many false alarms in the process.