The next revolution in science?

From the DEC/JAN 2006 issue of Seed:


These tiny, eccentric proteins are challenging a central paradigm in molecular biology: that genes are the sole unit of inheritance.

Science has been progressing at a fantastic speed this decade. For old timers such as myself, the replacement of paradigms in biology has been intellectually bearable, but only just so. I was born and educated in the era before 1950, when life was the domain of proteins, and I had to adapt myself to a new way of looking at life after the discovery of the double helix and the nature of the genetic code. James Watson and Francis Crick’s seminal paper, in 1953, finally provided the structural and chemical explanation of how cells store, use, and pass on information to daughter cells. This gave rise to the central paradigm in molecular biology: that structural information in the cell flows irreversibly from gene to protein, intrinsic to which is the concept that the sequence of amino acids in a protein entirely governs its final structure. Similarly, what is true for protein synthesis is also true for the mechanisms of heredity: that the genome (the full complement of genes in a cell) controls phenotype (all the characteristics of a living organism).

More than a half-century later, a large majority of biologists believe that the mechanism postulated by molecular biology is not only true, but the only conceivable system in life. Yet, a small number of researchers have recently discovered provocative anomalies that are threatening this scientific idea. The question then is this: Is the central paradigm of molecular biology—that all genetic information is stored and transferred digitally through DNA—the only possible explanation of how life evolved, or are there other mechanisms of heredity in living organisms? Evidence is mounting that hereditary information can be transferred in an analogous way through the prion.

The word “prion” was coined by Stanley Prusiner at the University of California San Francisco in 1982, as an acronym for “proteinaceous infectious particles.” The term was chosen to emphasize that the infectious agent he was studying was a protein, not something “contaminated” by viral nucleic molecules, as had been suggested. For at least 25 years, scientists had suspected that strange agents, called “slow viruses,” were behind degenerative brain diseases including scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and kuru and Creutzfeld-Jakob disease (CJD) in humans, but they hadn’t been identified. Prusiner was the first to hypothesize that the causal agent common to all these diseases was a prion. The idea was received with great scepticism by the biomedical community, which demanded an explanation for how a molecule without DNA or RNA could trigger disease. But Prusiner went on to experimentally prove his theory and to discover that prions are actually just misfolded, endogenous proteins that can cause other proteins to change shape, thereby transmitting structural information from one molecule to the next.

This work was a minor revolution against the established dogma that only viruses and bacteria—organisms that carry nucleic acids—could be infectious, and demonstrated that structural information from an infective molecule could be transferred solely by a change in shape, rather than in the amino acid sequence of a protein. Curiously enough, the prion anomaly did not arouse great interest among biochemists, perhaps because it came out of the distant world of infectious disease.

More recently, prions were found to have a role in another sacred domain of biology: the transfer of hereditary information in a non-Mendellian fashion from parents to offspring. It was in yeast that researchers first found evidence that prions could alter the expression of enzymes from one cell to another. Far from being pathologic, this form of protein-based information flow was an adaptive mechanism, conferring evolutionary advantages onto recipients. And recently, Susan Lindquist at the Whitehead Institute in Cambridge, MA (who has been working on prions with her group since 1993) has found a notable example: a molecular chaperone, the prion Hsp90, that strengthens the hereditary evolution of drug resistance in diverse fungi. But it is the evidence that prions play an important role in the formation and maintenance of long-term memory—discovered by Eric Kandel at Columbia University in New York—that seems to me of greatest importance.

Scientific revolutions concern the replacement of an old paradigm by a new, incommensurable one. However, the conflict of paradigms often does not end with the death of the old one. Rather, the new theory is incorporated into the older framework so as to make it more universal. Physicists have become quite used to this and have been quick to adapt their common views to new theories. But I wonder if we are not, today, in a new epistemological situation in which two apparently incompatible paradigms can exist simultaneously:  in this case, the classical (molecular biology) paradigm and the prion paradigm. After all, is it not the case in physics that Albert Einstein attempted for 40 years to reconcile the relativity and quantum paradigms, with no success?

Molecular biology is at a turning point and we have to accept that both nature and nurture—in the traditions of Darwin and Jean-Baptiste Lamarck, respectively—coexist in the laws governing life. The weight of the new evidence from prion research is simply too powerful to ignore. Biologists need to get used to the idea that there’s no end in sight when it comes to new insights and scientific breakthroughs—an idea that has long been accepted by physicists who are subject to regular scientific revolutions. I wonder if knowledge is, like the universe, basically endless and in constant expansion, just as the complexity of life itself is also expanding infinitely.

Bussard is an honorary professor at the Pasteur Institute in Paris, France.

Originally published February 13, 2006


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