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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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« Muddying the Water For Fun and Profit | Main | Consequences of Aneuploidy »

August 27, 2002

Aneuploidy, or What're A Few Chromosomes, More or Less?

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Posted by Derek

My recent posts about the Ames test (see July 29 and July 30) went into some detail about its use for estimating the mutagenicity of a compound. And mutagenicity is of course a bad thing, because increased DNA damage is generally held to be a factor in carcinogenesis.

But just how that works is the subject of some major disagreement. To wit: How many mutations does it take? How quickly do cells mutate under normal conditions, anyway, and do different types mutate at different rates? How much are those rate differences influenced by the environment? Are all cancers caused this way?

These question all bear on a current hot topic: do cells become cancerous due to some specific small mutations, or because of wide-ranging genomic instability (aneuploidy)? The latter hypothesis is having its inning recently, as witness some major articles in the July 26 issue of Science. This genomic instability is, by all accounts, a real junkpile of broken and reglued chromosomes. It really makes you respect what you can to the basic machinery of a cell and have it still function. Aneuploidy is found in a wide range of cancer cells - but is it a cause of cancer, or is it an effect?

The specific-mutation hypothesis has had a deservedly long run. Many candidate genes have been discovered, and they've been the subject of massive research efforts. At this point, there's little doubt that they're important, although their importance varies greatly between tumor types. Typically, these genes code for proteins that are important for cell growth - either positive factors or negative ones. Mutations that switch positive growth factors permanently on can lead to a cancer, as can those that wipe out the braking functions of a negative growth factor.

An example of the former is the ras oncogene, important in bladder tumors, among others: a single DNA base switch leads to an amino acid substitution (valine for glycine) in the expressed protein. That sends this protein into a permanent "on" state in its cellular signaling cascade, with out-of-control growth the result. And a good example of a negative-control mutations is p53, a protein whose normal function is in one of the cell-cycle checkpoints. It's part of the error-checking machinery. If p53 is functioning correctly, cells with many types of DNA damage are prevented from going on through cell division. Several mutations have been shown to impair p53 function, though, and these are found in a wide variety of aggressive tumor lines.

And it's not just single point mutations like these, either. Fusion proteins (front part from one gene, back part from another, for example) can lead to the same problems, as can mutations that don't change a protein's structure, but change the amount of it that's expressed in the cell. It usually takes more than one of any of these mutations to really set off a tumor.

Where things start to get messy, is when you try to figure out where those changes are coming from, and if they're always associated with cancer. The aneuploidy advocates believe that some cell types are prone to genomic instability, giving them a much greater chance of racking up enough mutations to become cancerous. Even that's subject to dispute. Does that mean instability toward point mutations, or toward large-scale chromosome breakage and shuffling? There's evidence pointing both ways.

While many chemical carcinogens are known to produce mutations, others don't seem to cause any. (Those are presumably the ones that an Ames test would miss, a prospect that keeps toxicologists up at night.) Peter Duesberg's group at Berkeley claims that such compounds do cause aneuploidy, though, and that this state is one of the early events in tumor development. And yes, that's the same Duesberg whose HIV theories keep the adjective "controversial" glued to his name. There's a group at Johns Hopkins whose work supports this sequence of events, too - and work from Harvard that argues against it. It's going to be a while before anyone gets this all sorted out.

I think it's likely that answer is going to turn out to be a mix. Gross chromosomal disturbance would certainly seem likely to cause either cell death or conversion to a cancerous state. Making this a one-size-fits-all precondition, though, seems like overreaching. But that goes for the small-mutation crowd, too. They have some good examples on their side, but there are plenty of cancers that don't fit into the established categories very well. It seems quite plausible that some cell types are more susceptible to chromosomal abnormalities than others. At the very least, some would be expected to be more susceptible to smaller mutational changes. At some point between these two, the explanations start to converge.

As a medicinal chemist, what I'm interested in are new drug targets. That's where aneuploidy is still a bit young, as a well-investigated hypothesis, to offer me anything to work on. Are there particular enzymes that could be targeted to reduce genomic instability, active-site switches to throw on or block? No one knows yet. I'll watch the debates with interest, but the parties involved should call folks like me when those questions are closer to being answered.

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