Carbon 12, nitrogen 14 – for that matter, hydrogen 1. Everyone who’s had to study even a bit of chemistry has had to learn the molecular weights of the elements, figure molecular weights from formulas, and so on. But these numbers aren’t quite as round and even as they look, and the consequences of that are sometimes surprising. And at the moment, at least three companies are trying to turn the whole idea into a huge amount of money.

My scientific audience will have guessed immediately that I’m talking about isotopes (although some of them may well be wondering where the pile of money comes into it). For those who don’t make a living at this sort of thing and have put such topics out of their minds, it’s the number of protons in an atom’s nucleus (the atomic number) that determines what sort of element it is. Carbon, for example, always has six protons. But there are neutrons in there, too, and those can vary a bit. Six protons and six neutrons gives you a nucleus of carbon-12, which is the most common. But one out of every hundred or so carbon atoms has seven neutrons instead of six: C-13. That’s a perfectly stable isotope of carbon, and is much beloved by chemists for its behavior in NMR experiments. If you push that neutron count too far, though, you get unstable radioactive nuclei. That’s where the famous carbon-14 comes into the picture (six protons, eight neutrons). You can have carbon-11, too, although it’s pretty hot stuff. Hydrogen, for its part, has the usual one-proton nucleus in its most common form, a one-proton-one-neutron stable form called deuterium, and a radioactive form with two neutrons called tritium, found in isotope labs and the innards of hydrogen bombs).

Radioactive isotopes have a long history in medicine and biochemistry, both as therapeutic agents (for cancer) and as tracers. But what about stable isotopes? Until recent years, not as much. But modern mass spectrometry machines are so good at what they do that they’ve eaten into a lot of the applications that used to be reserved for radioactive isotopes – more on that in another blog post; there are some ingenious tricks there. And those three companies I mentioned are trying to take advantage of yet another property, known as the kinetic isotope effect.

Imagine a bond between a hydrogen and a carbon as being between two metal balls, one of them twelve times as heavy as the other, connected by a spring. This is about as simplistic a picture of a carbon-hydrogen bond as you could possibly come up with, but for this purpose that model works disconcertingly well. Imagine then replacing the smaller ball with one that weighs twice as much as the original one; that’s a replacement of hydrogen with deuterium. Now, how will the behavior of that springy system change?

Well, that’s sophomore physics, weights and springs, and that’ll tell you that it’s now harder to twang the second system around. We see that exact effect in chemistry. A carbon-deuterium bond breaks about six or seven times slower than a carbon-hydrogen bond under room-temperature conditions. So where exactly is the big money in this effect?

Consider what happens to a drug when it’s ingested. Through the gut wall it goes, into the hepatic portal vein, and directly into that vast shredder we know as the liver. Various enzymes go to work tearing your unrecognized drug structure apart, the better to sluice it out through the kidneys as quickly as possible. And there’s the opportunity: a great many of those enzymatic reactions involve breaking carbon-hydrogen bonds. What if they were deuteriums instead?

That’s what Auspex, Protia, and Concert Pharmaceuticals are all working on. They’re taking existing drugs, whose metabolic fates are known, and battening their structures down with deuterium atoms in hopes of improving their half-lives and general behavior. And thus far, the idea seems to be working out. Auspex announced last fall that they'd seen good results (PDF) in the clinic with a deuterated version of venlafaxine (brand name Effexor, a well-known antidepressant. Concert, for their part, has announced that they've improved the antibiotic linezolid, sold as Zyvox. Protia - well, as far as I can see, Protia has been very quietly filing patents on deuterated versions of every big-selling drug that they can think of. What they're doing in the lab seems to still be under wraps.

Is this going to work? Good question. To a first approximation, you'd think it probably would, particularly for drugs whose main liabilities are poor pharmacokinetics (or side effects driven by a particular metabolite). But there are complications. For one thing, deuterium is not completely innocuous in vivo. I strongly doubt that the dosages of deuterated pharmaceuticals could present any kind of problem, but if you load up a higher organism with exchangable deuterium, trouble ensues. For humans, it would seem that you could, in theory, go a week or so on a few liters a day of straight deuterated water before you'd have to worry, which is nonetheless an experiment that I would strongly discourage. So the amount of deuterium picked up through metabolism of a prescription drug should have no effect - but there's always the possibility that the FDA, in its risk-averse mode, might make you jump through some extra hoops to prove that.

Another (much more real) risk is that the whole strategy will burn itself out. Clearly, the existing startups are working off the fact that no one has traditionally bothered to claim deuterated versions of their patented compounds. That is surely already changing, and if something hits the market it'll change big-time, reminiscent of Sepracor's old business model of grabbing unclaimed metabolites and enantiomers. And, of course, the three companies in this space are surely already throwing elbows into each other's IP space already.

But there's still a window of opportunity, and these folks are going for it. Isotope effects could end up being rather more immediately valuable than anyone ever knew. . .