Alain E. Bussard, "A scientific revolution?: The prion anomaly may challenge the central dogma of molecular biology" (2005)

"EMBO Reports" 2005, vol.6, s. 691-694; http://emboreports.npgjournals.com/cgi/content/full/6/8/691

A scientific revolution?
> The prion anomaly may challenge the central dogma of molecular biology 
> Alain E. Bussard Alain E. Bussard is Honorary Professor at the Pasteur Institute,
> Paris, France. e-mail: [email protected] <mailto:bussardpages%40wanadoo.fr>
> Science, Thomas Kuhn argued in /The Structure of Scientific
> Revolutions (1962) <#B13>, proceeds at two different paces. One is
> what he called "normal science", which professionals, the general public, the press and politicians generally understand as "research
> firmly based upon one or more past achievements that some particular scientific community acknowledges for a time as supplying the
> foundation for its further practice." This stepwise progression towards a better understanding of Nature, by building on established
> knowledge, has been described in a myriad of textbooks, dictionaries and scientific papers.
> However, Kuhn distinguishes this form of knowledge creation from
> so-called "puzzle-solving science". The latter results from anomalies--experimental observations or other evidence--which do not
> fit into the widely accepted theoretical framework of how Nature functions. Puzzle-solving science, according to Kuhn, can therefore
> trigger a scientific revolution as scientists struggle to explain these anomalies and develop a novel basic theory to incorporate them
> into the existing body of knowledge. After an extended period of upheaval, in which followers of the new theory storm the bastions of
> accepted dogma, the old paradigm is gradually replaced. Perhaps the best example of such a paradigm shift in science is the Copernican
> revolution in cosmology: the move from a geocentric to the heliocentric view of our solar system. Curiously, although
> Aristarches had already laid the seeds of heliocentrism in the third century BC, it took another 18 centuries before Nicolaus Copernicus
> proposed that the Earth moves around the sun and not vice versa. Many anomalies, such as the orbit of Mars, were already known at that
> time, but the power of the Aristotelian dogmas, including the geocentric view of the universe, was too strong to be overcome
> easily. Truly speaking, however, the notion of a paradigm, as defined by Kuhn, does not have exactly the same meaning in cosmology,
> physics, chemistry, geology and biology. 
> Is the central paradigm of molecular biology...the only possible explanation of how life evolved, or are there other mechanisms of
> heredity in living organisms? 
> What I propose here is that biology is heading towards a similar scientific revolution that may shatter one of its most central
> paradigms. The discovery of a few small proteins with anomalous behaviour is about to overcome a central tenet of molecular biology:
> that information flows unidirectionally from the gene to the protein to the phenotype. It started with the discovery that prions, a class
> of small proteins that can exist in different forms, cause a range of highly debilitating diseases. This sparked further research,
> particularly by Stanley Prusiner at the University of California, San Francisco (USA), who eventually established that prions induce
> conformational changes in other proteins and thus transmit their conformational information. More recent research by Susan Lindquist
> at the Whitehead Institute (Cambridge, MA, USA) and Eric Kandel at Columbia University (New York, NY, USA) indicates that this may well
> be a form of protein-based information flow, which seems to be important in various biological processes ranging from the
> establishment of long-term memory to the adaptation of organisms to new environments.
> Now we may have to abandon another concept...namely that the primary
> structure of a protein determines its tertiary structure 
> Scientific revolutions are still rare in biology, given that the field, unlike astronomy or physics, is relatively young. Until the
> middle of the eighteenth century, biology was essentially a descriptive activity rooted in medicine and observations of living
> Nature. Early biologists did not practise large generalizations as was the norm in physics or chemistry. During the eighteenth century,
> biologists started to ask themselves how they could explain the enormous variability of living organisms and their ability to adapt
> to their environment. Early thinkers, such as Jean-Baptiste Lamarck, Erasmus Darwin or Georges Louis Leclerc de Buffon suspected that
> environmental factors, over time, trigger physiological changes in the organism, which help it to cope with its surroundings. Lamarck's
> central example was the long neck of the giraffe, which he thought was the result of the animal stretching its neck to reach leaves high
> up on trees. 
> But it was Charles Darwin and his famous theory of evolution that finally provided biology with a sound theory on which to build
> (Darwin, 1859 <#B7>). The idea that all living beings stem from a primordial cell dating back two billion years is, in my opinion, a
> true paradigm. It does not have a heuristic value, unlike paradigms in physics such as gravitation or Einstein's famous equation, but it
> has a fundamental aspect. The striking success of Darwin's theory of evolution and Alfred Russel Wallace's similar theory resides in the
> proposed mechanism: through mutations and reproduction, organisms create new variations that are selected for or against by their
> environment. Although it was widely resisted initially--many people could not accept the idea that humans descended from apes and even
> lower organisms--the work of pro-darwinist scientists, in particular Gregor Mendel and Francis Galton, solidly established the paradigm of
> the evolution of species with the discovery of mutations at the end of the nineteenth century. We must therefore speak of Darwinism as
> the foundation of molecular biology. In fact, Darwin himself was not anti-lamarckian, although the work of his successors eventually
> proved Lamarck wrong. 
> Curiously enough, it was not so much experimental evidence or anomalies that helped to establish Darwin's theory but an
> intellectual movement among biologists: the idea of a goal-directed process was fading away to be replaced by a stochastic mechanism.
> Whether the evolution of species is a true paradigm is subjective--Karl Popper (1976) <#B20> claimed that the "survival of
> the fittest" is simply a pure tautology, although he later distanced himself from this statement.
> Nearly everything that followed Darwin was 'normal science'. The
> search for Mendel's units of hereditary information, termed 'genes' by the Danish botanist Wilhelm Johannsen in 1909, revealed that they
> comprise nucleic acids, and was first published by Oswald Avery and colleagues in 1944 (Avery /et al/, 1944 <#B1>). The seminal paper on
> the double-helical structure of DNA by James Watson and Francis Crick (1953) <#B27> 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, which rests on four pillars of accepted knowledge: (i) all genetic (hereditary) information is stored in nucleic acids; (ii) the
> double-helical structure of DNA explains how this information is stored and copied; (iii) the information is stored in a digital code;
> and (iv) information flows irreversibly from nucleic acids to proteins.
> The discovery that hereditary information is stored in DNA as a
> digital code was a huge advance for biology. This insight by Watson and Crick is as important, epistemologically, as was Darwin's theory
> of evolution. The whole process from Darwin to Mendel, to Avery, to Watson and Crick was a scientific revolution that gave birth to
> molecular biology as a new discipline. Molecular biology now rests on an enormous corpus of experimental evidence and I doubt that this
> will ever just disappear. Its fantastic successes during the past 50 years are due mainly to two things: a fundamental theory to explain
> how information is stored; and an epistemological turn, that is, an extreme reductionism in heuristic processes that allowed
> practitioners to generalize their observations. As Jacques Monod said, what is true for /Escherichia coli/ is true for the elephant.
> However, a small group of biologists have discovered disquieting
> anomalies that could threaten this central theory. 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? Indeed, it seems that we see growing evidence that information can be transferred
> genetically in an analogous way through the prion. 
> At the 1967 Cold Spring Harbor Symposium on Quantitative Biology devoted to antibodies, I discussed with Francis Crick the problem of
> irreversibility of information transfer from nucleic acids to proteins. Although he was ready to accept some kind of reversibility
> between DNA and RNA through retroviruses, he was adamant about the absolute irreversibility of the RNA-protein road: "Nature could not
> proceed in another way." Similarly, Niels Jerne, in his concluding summary at this Symposium, asked "Does the specificity of an antibody
> molecule reside in its primary structure or can different combining sites arise by different folding of identical polypeptide
> chains?...The answer in the former is yes" (Jerne, 1967 <#B11>). This statement further cemented the view that proteins are simply the
> active incarnation of information stored in the DNA, and rang the death bell for the template theory of antibody formation (Haurowitz,
> 1950 <#B10>). 
> But the idea that a protein could transmit information did not disappear. Carleton Gajdusek had already proposed that proteins could
> be infectious, based on his discovery that kuru/ disease was
> possibly caused by a protein from the brain (Gajdusek, 1977 <#B9>). It took a long time before this idea was accepted. Only after an
> extended uphill battle did the biomedical community finally accept Prusiner's theory that proteins are the only pathogen to cause
> scrapie in sheep, bovine spongiform encephalopathy in cattle and Creutzfeldt-Jakob disease in humans (Prusiner, 1982 <#B21>).
> Prusiner's work, which earned him the Nobel Prize, was a minor revolution against an established dogma as the biomedical research
> community believed that only viruses and bacteria--organisms that carry nucleic acids--could be infectious. I will not discuss the
> enormous scientific work that followed the establishment of prions as pathogens, but will instead concentrate on the more recent discovery
> of prions as genetic elements that store and transmit information in various organisms, mainly yeast, the fungi /Podospora/ and the sea
> hare Aplysia/ (Fig 1 <javascript:
> popupWindow('embor/journal/v6/n8/fig_tab/7400497_f1.html','fig_hires','630','600')>;
> Shorter & Lindquist, 2005 <#B23>). 
> Figure 1 <javascript: popupWindow('/embor/journal/v6/n8/fig_tab/7400497_f1.html','fig_hires','650','600')>
> Figure 1 <javascript:
> popupWindow('embor/journal/v6/n8/fig_tab/7400497_f1.html','fig_hires','650','600')>
> Eric Kandel used this model organism to show that prion elements control long-term memory formation. Image reproduced with permission
> from Columbia University, New York, NY, USA 
> In science, the introduction of a new technical tool commonly opens new avenues of knowledge. Yeast quickly became a model organism for
> molecular biologists because it is a very simple eukaryote with a growth cycle of 80 minutes, which allows a large amount of material
> for biochemical analysis to be collected in a few hours. It was in yeast that researchers found the first evidence of non-mendelian
> transmission of phenotypic traits (Cox, 1965 <#B6>; Lacroute, 1971 <#B15>). These phenomena baffled scientists for more than 40 years
> before they could be attributed to prions: [PS1+] suppresses nonsense codons in translation, and [URE3] inhibits nitrogen catabolite
> repression (Wickner, 1994 <#B28>). Both are caused by self-replicating conformational changes--to the translation
> suppressor sup35 in the case of [PS1+], and the Ure2 protein, an antagonist of the transcriptional activators Gln3 and Gat1, in the
> case of [URE3]. Another prion, [Het-s] in Podospora anserina/, was
> found to be involved in programmed cell death when two fungal strains with different genotypes fuse (Coustou /et al/, 1997 <#B5>; Maddelein
> et al/, 2002 <#B18>). In addition, work by Kandel showed that a
> prion has an important role in the formation and maintenance of long-term memory (Si /et al/, 2003 <#B24>).
> Much of this evidence relies on Lindquist's work on yeast prions. Not
> only did she show that prion domains in some proteins act as molecular switches that activate or deactivate the protein (True &
> Lindquist, 2000 <#B26>), she also showed that prions are non-mendelian genetic elements that have an important evolutionary
> role by producing new phenotypes, which are often beneficial. Her work on sup35 revealed that the protein switches to its prion state
> [PS1+] when the environmental conditions for yeast deteriorate, which decreases translation fidelity and causes the ribosome to read beyond
> nonsense codons (Liebman & Sherman, 1979 <#B17>). This in turn enables the expression of formerly silent genes and gene variants,
> and creates new phenotypes. [PS1+] is passed on to daughter cells in which it self-replicates by imposing its conformation on normal sup35
> proteins, until a new phenotype eventually emerges that is better adapted to the new environment (True & Lindquist, 2000 <#B26>). In
> another elegant experiment, Li and Lindquist showed the generality of this mechanism for controlling protein activity by fusing a yeast
> prion domain to a rat protein (Li & Lindquist, 2000 <#B16>). ...some now wonder about reviving Lamarck's idea that the environment
> triggers adaptive structural and physiological changes in the organism 
> Another physiological role for prions emerged through work by Kandel on the molecular basis of long-term memory in /Aplysia/. Kandel's
> group investigated how neurons maintain learning-related synaptic growth and stability over long periods as biological molecules have a
> very short life of hours to days compared with the permanently altered molecular composition of a memory synapse. They found that
> the cytoplasmic polyadenylation element protein (CPEB), which activates dormant mRNAs through the elongation of their poly(A) tail,
> seems to enhance long-term synaptic stability. Surprisingly, the neuronal isoform of CPEB shares properties with prion-like proteins
> (Si et al/, 2003 <#B24>). It seems to exist in two functionally
> distinct and stable forms with the ability to self-perpetuate in a dominant epigenetic fashion when in the prion state. CPEB is active
> in this state and is capable of activating dormant mRNAs (Bailey et
> al, 2004 <#B2>).
> The fascinating aspect of this discovery is that by proposing a
> prion-based mechanism to regulate long-term memory, we have entered the domain of neurology. Apart from the importance of this new
> concept in neurophysiology, the discovery establishes the universality of the prion system in life. A recent summary in
> Nature/ (Krishnan & Lindquist, 2005 <#B12>) on the structure of the
> yeast prion and its existence as a 'protein-only' inheritable element further supports a non-mendelian hereditary mechanism, which
> obviously will have a major impact on biology. The system used by the authors allows a biochemical analysis of protein folding during
> nucleation and assembly of the molecule, and provides a major step forwards for understanding the molecular changes involved in prion
> synthesis. To highlight the growing interest in and importance of prions, the same issue of /Nature/ published two more papers on the
> molecular structure of amyloid-like fibrils (Nelson et al/, 2005
> <#B19>; Ritter et al/, 2005 <#B22>), which will help scientists who
> study the amyloid fibrils in the brains of patients with Alzheimer's. Biologists need to get used to the idea that there is no end in sight
> when it comes to new insights and scientific breakthroughs... 
> 
> The famous motto "one gene, one enzyme" has been dead and buried for some time. Now we may have to abandon another concept, spelled out at
> the above-mentioned Cold Spring Harbor Symposium by Jerne (1967) <#B11>, namely that the primary structure of a protein determines its
> tertiary structure. For all of my working life in molecular biology, this was an 'act of faith'. It will be interesting to see if the
> prion anomaly can shatter some basic concepts in immunology and revive, at least in part, the template theory--obviously the tertiary
> structure and function of a protein is not determined solely by its amino-acid sequence (Bussard, 2003 <#B3>).
> Similarly, Lindquist's work on the role of [PS1+] in adapting to new
> environmental conditions poses some important questions on the nature of evolution. As inherited variance is apparently not restricted to
> DNA but could also be caused by protein-based genetic elements, some now wonder about reviving Lamarck's idea that the environment
> triggers adaptive structural and physiological changes in the organism. "This suggests a possible mechanism for the inheritance of
> acquired traits, postulated in the lamarckian theory of evolution. The prion model also puts in doubt the notion that cloned animals are
> genetically identical to their genome donors, and suggests that genome sequence would not provide a complete information about the
> genetic makeup of an organism" (Chernoff, 2001 <#B4>). It reminds me again of the 1967 Cold Spring Harbor Symposium, during which my
> friend Stephen Fazekas de St Groth sent me a little scribbled note saying "a Lamarckian always sleeps in the heart of a Frenchman."
> In his last book, /The Road Since Structure/ (2000) <#B14>, Kuhn
> devotes a long chapter to what he calls "commensurability, comparability and communicability". Scientific revolutions concern
> the replacement of an old paradigm by a new incommensurable one. However, the conflict of paradigms often does not necessarily 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. Take, for example, Newton's laws of
> mechanics, Einstein's general theory of relativity, and quantum physics, first proposed by Nils Bohr and Werner Heisenberg. At
> relatively low speeds, such as a satellite orbiting Earth, Newton's classic laws are sufficient for a technician to calculate how to
> launch a rocket that will send the satellite into the correct orbit. However, close to the speed of light, Newton's mechanics no longer
> apply and Einstein's law takes over. Similarly, Newtonian mechanics aptly describe the behaviour of objects larger than a molecule. Only
> when we reach the level of atoms, electrons or quarks do the laws of quantum mechanics apply. It seems to me that we are in a similar
> situation with regard to the anomalies presented by prions. The large corpus of existing knowledge will continue to hold true, but may have
> to be expanded into a more general theory to incorporate the increasing evidence that inheritance is not solely governed by
> nucleic acids. 
> During the recent euphoria surrounding molecular biology, it was common to find scientists who believed that the "secret of life" had
> been deciphered. This was the view expressed by Gunther Stent (1969) <#B25> in his book /The Coming of the Golden Age/, and his naive
> thought was shared by many biologists. A few years ago I was amused to see the same idea used in general history, in Francis Fukuyama's
> The End of History/ (1992) <#B8>. Biologists need to get used to the
> idea that there is no end in sight when it comes to new insights and scientific breakthroughs; this idea has long been abandoned 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.
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Sekcje

Narzędzia osobiste

Alain E. Bussard, "A scientific revolution?: The prion anomaly may challenge the central dogma of molecular biology" (2005)

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