Scientific Method / Science & Exploration

Super muscled mice reveal both biology and the challenges of patenting it

New experiments produce mice with a mega-musculature, telling us more about …

The open access journal PLOS One will be releasing a study that expands our understanding of the control of muscle growth. It's a good study, in that it provides a clear example of some of the logic behind scientific discovery, while at the same time providing a hook that should help it attract public attention: Schwarzenegger-style mice with four times the muscle mass of normal ones. At the same time, it also provides a great example of the messy interface between scientific research and patents in the biotech industry.

The lone author of the paper, Se-Jin Lee, was following up on his previous work on Myostatin, a gene that appears to be involved in suppressing the development of the musculature. Mice in which the Myostatin gene has been knocked out have an overgrowth of muscles that leave them twice as bulky as their normal peers.

Myostatin happens to belong to a large group of soluble signaling molecues, the TGF-Β superfamily, that share a structure and common signaling mechanism. The superfamily has been subject to extensive study (including by yours truly), and some of those studies have revealed the existence of many molecules that can bind to the TGF-Βs and prevent them from signaling. Lee's lab has shown that some of those inhibitors, including follistatin and the follistatin related gene (FRG), can both bind to and inhibit Myostatin.

Here's where the good example of scientific logic kicks in. If Myostatin is the only TGF-Β that influences muscle mass, then the only role played by FRG in this process would be to limit the amount of active Myostatin. Logically, if this were the case, the mice with Myostatin mutated would be indifferent to changes in the dose of FRG. Lee tested this by breeding mice lacking Myostatin with those expressing extra copies of FRG. Instead of seeing no effect of FRG dose, the combination of low Myostatin and high FRG produced megamice with four times the normal muscle mass. To any experienced mouse handler, the legs on these beasts look freakish, with the normal muscles replaced by huge bulges.

The logic of the experimental setup leads to an obvious conclusion, namely that Myostatin is not the only regulator of muscle mass, and the remaining factors are also likely to be TGF-Β members that can be inhibited by FRG. It's a nice, clean result.

In contrast to the clean science, the intellectual property issues are relatively complex here. There are a number of diseases that are caused by a reduction in muscle mass or growth, and manipulation of Myostatin signaling would be an obvious way to try to treat them. This led Lee and his parent institution, Johns Hopkins, to obtain patents related to the use of this gene. As such, the paper has an extensive "Competing Interests" section, which I'll quote in full here:

Myostatin was licensed by the Johns Hopkins University to MetaMorphix (MMI) and sublicensed to Wyeth. The author is entitled to a share of sales royalty received by the University from sales of this factor. The Johns Hopkins University and the author also own MMI stock, which is subject to certain restrictions under University policy. The author is a paid consultant to MMI and to Merck. The terms of these arrangements are being managed by the University in accordance with its conflict of interest policies.

Now, it might be easy to view this as cloud hovering over the work, but that sort of gut reaction would actually be misleading. The new work shows that Myostatin is only one part in a more complex system that regulates muscle growth—the results actually reduce the significance of the gene. Worse yet, they show that some of the other factors involved are parts of the TGF-Β signaling system, which has the subject of to extensive publication and patenting for years. In short, these results can potentially harm the company that their author owns stock in.

Knee-jerk reactions aside, it's entirely possible that, in his role as advisor to these companies, Dr. Lee has already told them of these results, and that the relevant parties have already figured out a way to work around or take advantage of them. But, in that case, it's not at all clear how any conflicts of interest, should they even exist, might play out.

PLOS One, 2007. DOI: 10.1371/journal.pone.0000789

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