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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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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