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More on the new genomic bandwagon

by Robert Teitelman | Published March 20, 2012 at 11:53 AM

In the Financial Times today, Clive Cookson offers up what almost appears to be a companion piece from The New York Times a few weeks ago on genomics and the promise of data-rich personalized medicine. Two almost makes a trend. Cookson's take on this is heavier on the scientific explanation than the Times and more focused on cancer. As a piece of explanatory journalism it's excellent. But like the Times article, which focused on Silicon Valley and its role in driving sequencing costs down to the consumer level -- the proverbial "1,000 genome" -- the FT offers up the most optimistic take possible on these developments. In a positioning that suggests some nervousness, Cookson saves his biggest catch for the last two paragraphs: James Watson, the co-discover of the double-helix structure of DNA, a longtime power in molecular biology and, later in life (he's now 83), a major promoter of genomics (in fact, he ran the U.S. sequencing project in its early days). Watson, says Cookson, is "bursting with enthusiasm." He quotes Watson: "We have made immense progress recently but no one in the cancer community wants to be seen jumping up and down with excitement, because researchers have been over-optimistic in the past." Of course, Watson isn't one of those cautious bureaucratic souls. "New science of the past year makes me optimistic that the back of most incurable human cancers may be broken in the next five to 10 years."

Really? A decade at most? Who am I to question the great Watson? Well, why the hell not? Over an incredibly distinguished career, Watson, in books and interviews, has shown an absolute genius for blather, sometimes to provoke, sometimes to point fun at, occasionally just to be cruel, but mostly in the name of promotion and fundraising. He is irrepressible, controversial and shrewd. It makes all but the most scientifically anchored opinions that come out of his mouth suspect, which may be why the FT tucks him at the very end, where most readers will never go. All this is not to say that the approach Cookson describes does not show promise, like so many other approaches. But to say that we will have "broken the back of incurable cancers" in that short a time period -- consider that it can take as long as a decade to get a drug through the Food and Drug Administration; that we are talking here about combination therapeutics, modified to attack a wide number of cancer phases; and that there don't appear to be viable combinations or the diagnostic ability to drive the approach fully in place yet -- and the suspicion grows that Watson is offering the same salvation song he offered in the run-up to the initial genomic-sequencing project.

What is the approach? Well, the cancer establishment, like any number of other academic disciplines, has discovered how alluring the evolution metaphor can be, particularly when it's linked to the genome. Cookson describes an approach that acknowledges the underlying genetic chaos of cancer (a reality the cancer establishment, he admits, has long recognized). Cells that become self-propagating often display an enormous range of genetic diversity, which makes it difficult to target and fully eradicate them. Cookson compares it to the rapidly mutating HIV virus, which could only be contained using a combination of drugs. This helps explain previous conundrums, notably drug resistance to cancer drugs. What's new and interesting here is that some biologists seem to be arguing that once this accelerated evolution begins, that it proceeds through a regular branch-like progression that resembles Darwin's evolutionary tree. That is, there's an elusive homogeneity beneath the heterogeneity, or at least uniformities that can be attacked.

"On the face of it, the heterogeneity of cancer within a single patient is bad news for diagnosis and treatment," writes Cookson. "It shows that a single biopsy may not reveal what is going on with someone and explains why many cancers are so hard to eradicate -- especially once that have spread beyond their original organs to remote 'metastatic' sites around the body, where different conditions drive their evolution. But on the basis that knowledge is power, researchers can see a way forward. 'This underscores the importance of targeting common mutations found in the 'trunk' of the evolutionary tree, as opposed to the 'branches,' which may only be present in a relatively small number of cells,' says [Charles] Swanton [professor of personalized medicine at the University College London Cancer Institute]."

Any time the cliché "knowledge is power" appears in medical research, you should go on the alert. Particularly note how early in the game this is, and how theoretical so much of this appears to be. Cancers are not only heterogeneous genetically, in terms of the genotype, but in their physical appearance and location, the phenotype. Do all these cancers share a common evolutionary path? Have we fully mapped all the combinations of mutations in trunks and branches and subbranches? Do we know any combinations? How will we get these drugs to the cancerous cells in question? As even Cookson says, "Scientists will need to pin down the 'driver mutations' present in the 'trunk' of each cancer's Darwinian tree -- and marry them up to new targeted drugs emerging from clinical trials worldwide." In other words, Watson notwithstanding, we've barely begun.

Watson is sly. He never really explains what "breaking the back" really means. His notion that cancer researchers don't want to overpromise is belied by the giddy quotes punctuating Cookson's story. "We will have the tools to back cancer into the evolutionary dead-end," says one researcher. Adds Swanton, bizarrely: Using genomics is like moving from black and white to color television in terms of pixels. Many of these quotes proceed metaphorically, an eternal temptation in cancer research from silver bullets to cancer genes to the genomic language of DNA, and they shift imperceptibly from theory to known fact. This approach combines a sort of trifecta of metaphors: cheap genomics, evolution and cancer as a virus. " 'Drug combinations must be the way forward now that we know cancers are evolving in the body, just like viruses,' says Mike Stratton, director of the Wellcome Trust Sanger Institute, a genome research centre near Cambridge, and a leader of the cancer genome project. 'We should be able to control even metastatic cancer if we can find the right combinations of drugs, just as we can control HIV.' " Does cancer really behave like a virus? Well, HIV turned out to be a great success. Why not?

Underlying all this is the same powerful faith that drove The New York Times' optimism: that cheap genomic data will reveal this taxonomy of cancer mutation and evolution and produce biological markers from embattled, often cash-poor biotechs and drugs from wavering, productivity-challenged pharmas. Why not? Again, anything is possible, but after four wearying decades of the cancer wars, one remains skeptical of transformational progress. Evolution, after all, may be very slow. - Robert Teitelman

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