#SBS10 Day 3 – Smart mice and blowing House, M.D.’s mind: Drug discovery in epigenetics
At the afternoon session of the Society for Biomolecular Science in Phoenix, it’s all about epigenetics, the study of heritable changes that don’t involve changes in genetic sequence. Epigenetics explains why identical twins turn out a little different and even clones won’t be exactly identical.
Manfred Jung from Freiberg kicked off the session giving an overview of recent developments in epigenetics and presented what would become the central theme of the afternoon: Here are some diseases which haven’t received the amount of attention they deserve, here are some enzymes and proteins that cause the diseases when there’s something wrong with them, here’s how to target those enzymes. Go get ‘em, boys!
Yes, it is, in fact, Lupus.
So it turns out that when DNA is modified by removal of the suppressive methylation pattern on the CD40L gene, it makes T cells hyperactive. This hyperactivity makes them start to react as if the body’s own native proteins are in fact foreign, leading to the myriad bizarre symptoms of systemic lupus erythematosus, or lupus. Various things can cause this, everything from too much UV exposure to diet to simple aging. The good news is that if you’re a guy, you’re 10 times less likely to have a problem, because one of your copies of CD40L will have been X-inactivated. Actually, there’s good news for everyone. Richardson showed that there’s a direct correlation between the level of demethylation of the gene and the severity of symptoms, leading to fairly obvious targets for drug discovery. Other immunoinflammatory diseases – scleroderma and rheumatoid arthritis – also have an epigenetics angle via Fli1.
Stephen Haggarty, the guy who gave a good stem cell talk earlier, also had something to show on epigenetics. While it’s clear that some aspects of intelligence can be inherited, the genes involved are not well understood. Using behavioral testing, Dr. Haggarty was able to show that the memory and mood of mice was affected by agents that altered the methylation status(i.e., the epigenetics) of genes involved in learning and memory. Interestingly, inhibiting one protein, HDAC2, enhanced memory while inhibiting another enzyme, HDAC1, affected mood. The problem is that this mechanism of altering gene expression by these epigenetic changes is a general mechanism that works in all cells, so if you administer a drug, you may well affect the level of repression or expression of the gene of interest, but you’re almost certainly going to be affecting a whole host of other processes as well. Couple that with the poor brain penetration of these relatively large, poorly soluble, hydrophobic molecules and you can see where the challenges lie for drug discovery. Still, Dr. Haggarty did a great job outlining these challenges and since 18 of the 300 genes known to be involved in learning and memory are susceptible to an epigenetic etiology, I would expect pharma interest in this area to remain strong.
One final note: When I was working on GSK3beta inhibitors for modulation of stem cells in bone repair, people always asked me if I had any data on the bones from bipolar patients treated with lithium. It turns out that lithium is also a GSK3beta inhibitor. I wonder what other effects the inhibitors he worked with have? Also, Dr. Jung has a new book out on epigenetics. Check it out.