Sep 30 2010
ead of a fantastic new initiative on The Edge website that proposes to study cancer by involving physical scientists (in this case informatics titan Danny Hillis) in collaboration with biomedical investigators. The leaders of the National Cancer Institute are very keenly aware of how little progress has actually been made in the treatment of cancer. They’re thinking very laterally in giving funding to people like Hillis (whose historical basis has been in the engineering and computational sciences) to work on cancer. From the sounds of the announcement Hillis has clearly embarked on a systems approach.
From the Edge article:
We misunderstand cancer by making it a noun. Instead of saying, ‘My house has water’, we say, ‘My plumbing is leaking.’ Instead of saying, ‘I have cancer, we should say, “I am cancering.’ The truth of the matter is we’re probably cancering all the time, and our body is checking it in various ways, so we’re not cancering out of control. Probably every house has a few leaky faucets, but it doesn’t matter much because there are processes that are mitigating that by draining the leaks. Cancer is probably something like that.
NCI is creating a program where physical scientists can be the principle investigators, partnered with the co-investigators who are clinicians and biological scientists. Giving money to physical scientists is a pretty radical idea and apparently it is very controversial within the biological community. Of course, no research biologist or pharmacologist wants to turn over the rudder to an information guy. But there are some good reasons to be at least open to the possibilities of the idea.
In his autobiography, Surely You’re Joking Mr. Feynman!, Richard Feynman makes a rather telling observation about the difference between physicists and biologists. He was quite struck by the sheer amount of information that biologists felt compelled to keep in their heads at all times, unlike physicists, who often carried much less information, and felt quite comfortable about it, knowing that there were ample opportunities to use reference materials as needed.
That, in my opinion, constitutes the divide between the traditional, reductionist ways of researching the life sciences, versus the newer ways of system biology and informatics via complexity and information theory: One assumes that you have to be smart to get smarter, whilst the other assumes that you can get smarter by being more stupid.
In order to understand what’s actually going on, we have to look at the level of the things that are actually happening, and that level is proteomics. Now that we can actually measure that conversation between the parts, we’re going to start building up a model that’s a cause-and-effect model: This signal causes this to happen, that causes that to happen. Maybe we will not understand to the level of the molecular mechanism but we can have a kind of cause-and-effect picture of the process.
Here we diverge a bit, although perhaps only in choice of syntax. Granted, we cannot possibly conceive of an approach to cancer that doesn’t involve protein coding. But an exclusively ‘first-intentional’ frame of reference (DNA to RNA to proteins) risks overlooking already established secondary and tertiary feedback and control mechanisms (post-translational modifications such as protein folding and epigenetic alterations) that inevitably factor into the transcription of cancer genes, the inhibition of apoptosis (cell death) and the development of metastatic potential.
Crick’s Central Dogma and reductionist parsimony got us this far (and for that there is much to be thankful for) but from here on in, I suspect that they will be critical parts of the error-trapping subroutines, but will not drive new discovery.
Glycans (complex chains of sugars, often bonded to proteins or lipids) are also important cellular determinants and carriers of information. For example, the simple sugar galactose serves as a recognition marker that determines the survival time of many serum glycoproteins in the circulatory system of man, the rabbit and the mouse. In bird and reptile species the recognition marker appears to be primarily n-acetylglucosamine. Clearance systems in which fucose and mannose are the markers have also been found. Notch receptors are highly conserved intercellular signaling pathways that direct embryonic cell-fate decisions. These receptors are regulated by ‘Fringe’ proteins. Recent evidence shows that Fringe is a fucose-specific GlcNAc-transferase. (1,2)
Changes in N-linked glycosylation are known to occur during the development of various diseases. Increased branching of oligosaccharides, in particular fucosylation, has been associated with cancer metastasis and has been correlated to tumor progression in human cancers of the breast, colon and melanomas. Numerous clinical studies have shown a clear correlation between changes in the makeup of cell surface sugars (aberrant glycosylation) status of primary tumors and invasive/ metastatic potential of human cancers, as reflected by 5- or 10-year survival rates of patients. (3)
Sugar changes even appear to influence the energetic changes in cell polarity. Many epithelial cells normally become polarized, with at least two distinct plasma membrane surfaces. In the case of the intestinal epithelium, proteins are oriented either basolaterally (toward the blood) or apically (toward the lumen). Hepatocytes (liver cells) are unusual in that they polarize in three dimensions rather than as a two dimensional sheet. The basolateral surface is in contact with the blood, while the apical surfaces of the cells form the bile canaliculi. Glycoproteins directed to these surfaces may be selective or even specific for the apical or basolateral surface, and thus maintenance of this polarity depends upon the continuous sorting of newly made proteins and membranes. (4)
Recently, it has been suggested that fucosylation of N-linked glycan within polarized hepatocytes directs glycoproteins to the apical surface and into the bile, and as a consequence, fucosylated glycoforms are normally rare in the blood, and are enriched in the bile. Thus, if cancer cells become “depolarized”, it is reasoned that fucosylated glycoforms would rise in abundance in the blood. (5)
These are single, tiny examples, describing a challenge of mind-numbing complexity. Many other classes of glycoconjugates impact metastasis, such as the proteglycans, mucins and glycosphingolipids.
I will eagerly await the developments from such a imaginative mind and the creative tensions that will inevitably result from its academic juxtapositions.
Yet when I hear ‘cancering’ I still think about glycans.
- Brückner K, Perez L, Clausen H, Cohen S. Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature. 2000 Jul 27;406(6794):411-5.
- Moloney DJ, Panin VM, Johnston SH, Chen J, Shao L, Wilson R, Wang Y, Stanley P, Irvine KD, Haltiwanger RS, Vogt TF. Fringe is a glycosyltransferase that modifies Notch. Nature. 2000 Jul 27;406(6794):369-75.
- Hakomori S. Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)-lipid metabolism. Cancer Res 1996;56:5309-5318
- Mehta A, Block TM. Fucosylated glycoproteins as markers of liver disease. Dis Markers. 2008;25(4-5):259-65.
- T. Nakagawa, N. Uozumi, M. Nakano, Y. Mizuno-Horikawa, N. Okuyama, T. Taguchi, J. Gu, A. Kondo, N. Taniguchi and E. Miyoshi, Fucosylation of N-glycans regulates the secretion of hepatic glycoproteins into bile ducts, J Biol Chem 281(40) (2006), 29797–29806.