A Challenge to the Supremacy of DNA as the Genetic Material
About a month ago, a news release stood out among the many I get every day: “A challenge to the genetic interpretation of biology,” from a physicist and chemist from Finland, Arto Annila and Keith Baverstock. They’d just published “Genes without prominence: a reappraisal of the foundations of biology,” in the Journal of the Royal Society Interface.
One sentence from the news release grabbed me: “The result is evolution from simpler to more complex and diverse organisms in both form and function, without the need to invoke genes.” Instead, Drs. Annila and Baverstock invoke thermodynamics.
I was mesmerized, mostly because I am immersed in writing the 11th edition of my human genetics textbook and a non-DNA-centric view got me thinking. So I read the paper and asked the authors to guest post. Their idea brought me back to pre-1953 thinking that proteins are the genetic material, mostly because we knew more about them than the mysterious goop on soiled bandages that was DNA.
Then last week I posted here about the information from a dozen sequenced human genomes not being all that clinically useful, at the same time that the blogosphere trumpeted the not-very-surprising finding that a gene attached to obesity was actually controlled by another gene. The news last week seemed to validate Drs. Annila and Baverstock’s concern about genome sequencing entering the clinic when we don’t fully understand how genes interact at the level of their products, the proteins.
Dr. Baverstock kindly agreed to post. His impressive bio is here. Most notably, he brought to global attention the increased childhood thyroid cancer incidence in Belarus caused by radioactive iodine from the Chernobyl accident. (I had thyroid cancer although I’ve never been near a leaking reactor.) Here he shares his thoughts, lightly edited, subheads added:
A VIEW FROM PHYSICS
Arto Annila and I are making the seemingly outrageous claim that mainstream biology, since around the 1920s, has pursued a course that is deeply flawed. Critical to that course is the notion that genes are Mendel’s units of inheritance and that their material realization is a DNA base sequence. We propose instead that Mendel’s unit of inheritance is a process involving the interaction of mainly activated proteins contributing to an attractor state that represents the phenotype. Many will find this language of physics unfamiliar. However, cells are complex dissipative systems (CDS) in that they consume energy and thus operate according to the 2nd law of thermodynamics as it applies to open systems.
First, two irrefutable facts in justification of our position:
1. When cells divide they inherit the state of the cell. If this were not the case, cancer and differentiation would have to be one-step processes. The state of the cell cannot be encoded on the DNA base sequence: it is the active proteome.
2. Key biological processes, such as development, growth and aging, are irreversible in time, whereas standard textbook physics describes time reversible deterministic dynamics.
It is very well known that at cell division the cytoplasm is partitioned between the two progeny, but not emphasized, as we propose, that it contains a coherent complex process of interacting proteins. When this state is understood as the unit of inheritance, the epigenetic memory that enables processes, like differentiation, to take place over several cell generations is a natural manifestation. In addition, CDS physics supports the phenomenon of quasi-stability – that is, stability within limits: attractors are quasi-stable states formed by the interacting proteins. This would mean that inheritance at the cellular level is not after all a matter for the nucleus, but rather for the cytoplasm.
NOT JUST THE NUCLEUS
The nucleus/cytoplasm issue was hotly debated around the turn of the century – not the last one but the one before, and eventually resolved in favor of the nucleus by the geneticist T H Morgan in 1926. It’s clear that components of the egg cytoplasm are inherited at fusion, the mitochondria for example, but it has generally been regarded that the sperm delivers only genomic DNA. However, studies on male fertility have revealed that proteins essential for successful fertilization are present in the sperm and some of the chromatin is in a non-condensed state and thus, possibly even active. Therefore, we can assume that the sperm is capable of supporting a protein-based attractor state.
One experimental way to resolve the nucleus/cytoplasm issue is cross species nuclear transfer to enucleated eggs. This has not proved possible with mammals, but has been successful with fish. Enucleated goldfish eggs transplanted with nuclei from carp eggs develop with the outward appearance of the donor carp, but with a vertebral number (26 to 31) consistent with goldfish (26 to 28) rather than the genomic DNA donor carp (33 to 36). We assume that when two dynamic attractors are placed in a common environment, as in the case of the zygote, that they will “synchronize” as, for example, with Huygens’ clocks. Therefore, we argue that biology can explain inheritance on the basis of a sound foundation in the appropriate physics, without resorting to mechanistic narratives involving genes.
Furthermore, work in the 1970s demonstrated that enucleated HPRT-competent (HPRT is an enzyme whose absence causes the awful Lesch-Nyhan syndrome, an inborn error of metabolism-RL) fibroblasts in vitro could correct HPRT deficiency in fibroblasts with an intact nucleus, by transferring molecules via gap junctions, without the need for protein synthesis. In addition, erythrocytes (red blood cells) dispose of their nuclei at the last stage of differentiation, but retain, for example, the circadian rhythm function for their lifetime.
In fact, the evidence clearly points to routine cellular function (apart from cell division) and regulation in somatic cells being a matter for proteins without the intervention of genes. If, for example, the dark/light rhythm changes (travel over a few time zones) then intervention involving new transcription to adjust the circadian rhythm does occur, but otherwise circadian rhythm is taken care of by protein chemistry, as has been demonstrated in vitro.
DID MENDEL PICK CHERRIES, NOT PEAS?
If you have read as far as this, you are no doubt wondering about the plethora of experimental evidence for the action of genes that has accrued since Mendel experimented with pea plants in the monastery garden in the mid 1800s. It is impressive, but how complete is it and what does it really explain?
The American geneticist Richard Lewontin drew attention in 1974, in a book on population genetics, to the fact that all experimental geneticists since Mendel had studied very marked, i.e., easily measured, traits, such as flower color. He identified the following paradox “what is measurable is not interesting and what is interesting is not measurable.” We suggest that these marked traits are rather special and they often do associate with gene sequences, but the association is not causal. A correlation or association as such does not reveal driving forces of ensuing effects. Key here is the thorny issue of protein folding.
THE IMPORTANCE OF PROTEIN FOLDING
An important step in the Central Dogma (DNA encodes RNA encodes protein-RL) is the folding of the peptide to form the protein, which can become biologically activated and contribute, as a component of the attractor, to phenotype.
Anfinsen’s dogma, derived from experiments with the enzyme ribonuclease, says that the amino acid sequence of the peptide dictates the folding. Were that true the “protein folding problem” would have been understood by now. In fact, predicting the folded structure is still an unsolved problem and according to Arto Annila that is because the folding process is a dissipative (energy consuming) non-determinate process. It is non-determinate because of the involvement of the environment in which the folding takes place.
An extreme example is the involvement of chaperone proteins, which provide an environment favoring a specific folding. Therefore, we have the possibility that a single amino acid sequence, as a peptide, dictated by a gene coding sequence, can fold into more than one protein and therefore perform more than one biological activity: the determinate relationship between sequence and biological function, crucial to the Central Dogma, is violated. It is, of course, also violated by the several ways in which a single multi-exon gene sequence can be spliced to produce several peptides.
EMERGENT PROPERTIES
Another aspect of the physics of dissipative systems is the role of symmetry breaking and the consequent emergence of new properties. Symmetry breaking may sound obscure, but it is a simple concept.
Liquid water has perfect symmetry in that no matter from which direction you look at the molecules, the view is the same. A perfect sphere has perfect symmetry for the same reason. If the water freezes to ice, the perfect symmetry is lost or broken and the property of rigidity emerges. In Finland, the lakes freeze over in the winter and roads across the lakes open up, exploiting this emergent property. In this case the symmetry is broken by a phase transition, but any transfer of energy has the potential to break symmetry and therefore to give rise to emergent properties.
We see this all the time in chemistry. If we take a mixture of the harmless and odorless gases, nitrogen and hydrogen, and heat them to a high temperature, exchange of electrons between the two molecules occurs (symmetry breaking) and ammonia is the product with the emergent properties of a noxious and pungent gas. If this reaction had never been performed, there would be no way to predict, from the physical properties of hydrogen and nitrogen, the properties of ammonia – its properties are emergent.
THE PROMINENCE OF PROTEINS
What we believe drives the cell to deliver its phenotype is protein chemistry – chemistry in which information derived from the folding process (not from the amino acid/DNA base sequence) is processed through the attractor to yield the very specific, but emergent, and therefore unpredictable even from knowledge of the proteins, let alone the DNA sequence, properties of the cell. So the sequence information in DNA serves only to specify the amino acid sequences of peptides; the emergent information that underpins the phenotype is not even primarily of the same type as the sequence information.
Sequence information is usually regarded as being composed of “bits,” but the emergent information carried by proteins is physical in character. Consider a notice outside a café in say Tucson, Arizona. It says, in Finnish, that anyone is welcome to visit for a free lunch on Wednesdays. The proportion of Finnish speakers eating lunch in that café on a Wednesday is likely to be far higher than that in any other café in town. The information in the notice can of course be quantified in terms of “bits,” but that is irrelevant to the “physical nature” of the information that only Finnish speakers recognize. Enzymes express their activity by their ability to recognize a specific substrate with which they can react and we are suggesting that this kind of physical recognition process underlies the interactions between cellular proteins and thus, the operation of the attractor and therefore, cellular phenotype.
The attractor is also responsible for the regulation of the cell: that is why enucleated cells retain biological functions and even communicate and initiate functional activities, such as building gap junctions or exhibiting circadian rhythm. This forces us to the conclusion that causality in cells is exercised downwardly from the phenotype to the genotype (for example, to initiate transcription or even modify the genomic sequence), exactly the reverse of the Genotype to Phenotype (G -> P) concept underpinning population genetics.
However, if we think about the origin of life from a non-creationist perspective it is difficult to see how it could have been otherwise: the life process initiated itself and recruited nucleic acids in order to retain the necessary peptides as the cell’s raw materials. Recent evidence shows that in the period from 4.5 to 3.8 billion years ago, a great deal of carbon was delivered to the Earth via meteorites and that the shock of impact was sufficient to synthesize amino acids. Meteorites are also believed to have delivered bases. From the perspective of the physics of complex dissipative systems, it was almost inevitable, given the climatic conditions on Earth, that energy from the Sun, via the second law of thermodynamics, would concoct a form of chemistry we call life.
So as astronomers discover ever-increasing numbers of planets, in and beyond our galaxy, orbiting suns in what is known as the Goldilocks zone, it seems inevitable that Earth is not alone in the Universe in supporting the phenomenon we call life. In the evolution of how we explain that phenomenon, genetics and genes have played a prominent, even dominant, role. Genetics is, however, only a statistical association between something we had to infer and something we could observe.
Now that genome sequencing is routine and we no longer have to infer the genotype, we can see things are not so simple. We are faced with either generating ever more complex genetics-based narrative explanations for biological behavior or looking for a more rational basis for biology: we opted for the latter.
Thanks for this. It was all going brilliantly until the last sentence: how is the proteomic explanation any more or less rational than the genomic one? These things can’t be directly compared, they must both be looked at and conclusions could be drawn from the further study of both. We must be very careful not to speculate too much, although we have plenty of data, we have little computational ability to interpret it all so we shouldn’t jump to conclusions because as we know in biology, anything can happen!
I don’t think any serious geneticist simply thinks that there is a straight line from genotype to phenotype. The role of the environment has long been appreciated. More recently, the transgenerational inheritance of epigenetic information has also started to be elucidated, for example where a mutation that affects chromatin can have an effect many generations hence, after the mutation itself has been bred out. However, none of this disproves the central dogma, for which the evidence is overwhelming. This piece verges on being about as credible as the Duesberg hypothesis.
Ah, yes. Of course. Another physicist who thinks he knows more about biology than several decades of biologists. That always goes over well.
(This is from Keith because it is the middle of the night in Finland)
It is a matter of following the information. The DNA sequence information specifies the peptide sequence, but that cannot specify the information that generates phenotype because that is carried by proteins and is generated on folding of the peptide (as is clearly demonstrated by enzymes, which only recognize their substrate when appropriately folded). Since any given gene coding sequence can generate several peptides (by alternate splicing), each of which may fold into more than one protein there cannot be a causal relationship between a trait and a gene coding sequence. We are left with only the proteins.
FROM KEITH:
I am afraid the central Dogma was discredited sometime ago. It relies on a deterministic chain of events from DNA sequence to peptide sequence, to protein with biological activity. That has not been credible since the discovery of chaperone proteins in the 1980s as they violate the determinism between peptide sequence and protein activity (in theory two or more protein activities can arise from a single gene sequence). A further blow was dealt by the results of the HGP in 2001, where it has to be assumed that each gene coding sequence can produce on average at least 5 peptides by alternate splicing. A single gene coding sequence can produce multiple proteins and therefore multiple traits depending on factors such as which other proteins are active in the cell at a given time and that cannot be deduced from the sequence.
Many thanks,
Keith
Yes, but the first molecular geneticists were physicists.
I think your interpretation of the central dogma is a strict one to which no biologist I know adheres. To say that the central dogma requires one gene encoding one protein, and therefore because that is not true in the strict sense that the central dogma is wrong is frankly preposterous. The central dogma is DNA->RNA->protein. Biologists agree that by and large the phenotype itself is a result of protein action and the environment (non-coding RNAs not withstanding, which are being appreciated as increasingly important).
Surely we are left with more-if we take into account emergent properties, there are many interactions between polynucleotides and polypeptides which take place and affect the proteome in unpredictable ways. What do we gain by seeking a link between observable phenotype and the presence of a group of molecules? I don’t think we can infer a causal relationship right away. Viruses are always on my mind, abundant packaged genomes, their interactions with biological systems are entirely biochemical and dependent on both DNA and protein presence simultaneously.
Keith will reply in the morning, thanks!
Of course, we are not disputing the sequence of events specified by the Central Dogma: what we are disputing is the determinism and consequently its application to predict traits from DNA sequence. The rationale behind sequencing the genome was that it would be possible to predict adverse traits from abnormal sequences (alleles). That requires that each step in the sequence will predict unequivocally the next. Our argument is that the determinism fails on two counts: a) the folding of peptides can yield more than one active protein and b) the original DNA sequence can yield more than one peptide though alternative splicing. For example, the DSCAM gene from fruit flies can, in theory, produce 38,000 peptides by alternative splicing. I hope this clarifies things.
Well, would you agree that biology must be founded on physics: if not what would you propose as its foundation? The only alternative I can think of is vitalism, discredited long ago. The question is “what physics?” would be most appropriate. We think the text book physics tacitly assumed to be the foundation of biology is inappropriate and we propose the physics of complex dissipative (energy consuming) physics.
Regards, Keith
Hello again, I think we agree here. We are criticizing the idea that a base sequence can define a trait. The fact is huge sums of money are spent on research to do this for traits ranging from height, though common disease, cancer, for example, to school attainment and political affiliation. We aimed to show that there is no basis in physics for this research. One of its strongest advocates is Robert Plomin, but even he now admits to being unable to find the alleles that determine the inheritance of height.
Regards, Keith
[…] Locutus #1Just now This forces us to the conclusion that causality in cells is exercised downwardly from the phenotype to the genotype (for example, to initiate transcription or even modify the genomic sequence), exactly the reverse of the Genotype to Phenotype (G -> P) concept underpinning population genetics. A Challenge to the Supremacy of DNA as the Genetic Material – DNA Science Blog […]
I agree these authors 100%. Physics dictates the biologic paradigm. I’ve been writing about the clinical implications for three yrs. http://jackkruse.com/cpc-8-quantum-brain-cancer/
[…] Unless you have access to an academic library, the paper is behind a paywall, but there’s some commentary on it over at PLOS Blogs. […]
I don’t know any geneticists that believe in a simple determinism. In the case of GWAS, which started out looking promising, but which has largely (IMHO) been oversold and under successful, the premise is based on the idea that there are common variants that are IBD, and in linkage disequilibrium with SNPs that are assayed on the common SNP platforms. It is very possible that many of the traits that are being investigated do not vary due to common variants that are IBD, and hence those loci cannot be determined by GWAS, but *may* be identified by genome sequencing. The second reason for the missing explained variance is likely do to gene-gene interactions, where you rapidly become underpowered to identify loci due to the astronomical number of tests that would have to be performed. Epistasis is likely much of the reason that we cannot find simple determinism, even if it is deterministic. Your “new paradigm”, in my opinion, does nothing to push science forward, and doesn’t actually deal with the facts or well known genetic phenomena (such as epistasis). As an evolutionary geneticist, I see mutations in genes driving changes in fitness, and require nothing other simple mendelian genetics and darwinian selection to explain them.
Is this really surprising? Every biologist knows a cell has enormous ‘intertia’ in its behaviour which derives from epigenetic changes, the proteins present in the cell, indeed everything about the shape and form of the cell. You can see this in development of every multicellular organism where identical DNA gives diverse cellular form and function. You can see this in fusion of gametes; you can’t take an X and a Y sperm and fuse them to make a male embryo, there needs to be an egg. You can see this in viruses where the viral DNA is insufficient for replication of the virus, you need the host cell proteome. To be honest this article just sounds like some physicists have just cottoned on to the complexities of modern biochemistry and given a single name to a big mess of biological complexity which modulates expression of genes and modulates genetic changes that result from selection pressures.
I’m not sure if I understand your point, as I’m still an undergrad student. I think the chaperones are a measure to widen a possible proteome (as alternative splicing), and since chaperones and alternative splicing factors are passed on through cytoplasmatic continuity, these should be also considered as an unit of heredity. I agree with this view, but I think it is already a predominant view with, lets say, developmental biologists – who seek out for function of certain genes during morphogenesis, for example. The same gene in different also locations can give rise to different structures – and this is certainly due to different proteomes in these locations.
At risk of sounding overly placating, my reading of Dr. Baverstock’s article and many of the critical responses to it find more common ground than disagreement: everyone agrees there is NO one-to-one correspondence between DNA sequence and phenotype, everyone agrees proteins play a huge role is gene expression, and everyone agrees that understanding how DNA sequences lead to physical disease and disorder will require far more research into both nucleotide and cytoplasmic chemistry. Recent research into understanding how mitochondrial DNA plays a role in gene expression (very possibly by affecting cytoplasmic environment, and hence gene expression in concordance with Dr. Baverstock’s premise) seems to me to be one area of research where Dr. Baverstock’s position is already converging on current genetic “dogma”.
In fact, my instinct is that the approach, data, and premise outlined by Dr. Baverstock is highly testable, and therefore will prove to be fertile grounds for future genetics research. Although I disagree with Dr. Baverstock seemingly “jumped to” conclusions that it is NOT DNA but the cytoplasmic protein environment that is the “unit of inheritance”, I can easily agree that protein chemistry, and more importantly the chemistry behind protean folding, will turn out to be fundamental to understanding genetic disease.
Dr. Baverstock has not turned modern genetics upside down with his approach (as he concluded), no more than Einstein ever disputed Newton’s mathematics: they both have simply added a finer degree of understanding to observed complex phenomena. In my read, Dr. Baverstock is not really refuting current genetics thinking, he is expanding on it.
Well, you are of course are entitled to your beliefs. However, there is much empirical evidence that is not explicable in terms of the kind of genetic explanations you are proposing. We think it is important to develop a theoretical framework that encompasses, rather than ignores, such evidence. We think this is best done from the standpoint of fundamental physics – after all genetics is a statistical interpretation of biology – not biology.
Regards, Keith.
I agree completely with Rick, most of us seem to be in fundamental agreement that DNA encodes polypeptides and then from there gene-gene and gene-environment (epigenetics) interactions contribute to the final phenotype. My only quibble is with the word “belief” — all of the discussion is based on interpretation of evidence, and so much of it. Thanks everyone for the great comments!
We certainly do not claim to have changed everything about biology but I think we have not so much inverted genetics as shown its irrelevance to say evolution – we have tried to put forward something that replaces genetics. This can be seen best from the perspective of information and how the cell deploys information for regulation. The most obvious information is in the DNA sequence, but that cannot be the information from which phenotype is derived and by which the cell is regulated, because a single sequence (unit of information) gives rise to multiple proteins (each units of information) and most of those depend on the presence or not of multiple other proteins, the cellular environment. If it were the case that a single gene sequence contained several “packets of information” that might be different, but the information at the protein level would still be contingent on the (uncontrolled by the DNA) environment provided by other proteins. This leads us to propose that it is the phenotype that regulates the cell – in other words causality acts downwards on the genotype and not upwards from the genotype to the phenotype – the genotype simply provides the raw materials (mRNA, peptides) which the phenotype regulates to produce itself. If we were proposing a genetic model this would be an inversion, but we are not – we are proposing biology based on something other than genetics.
The question then arises – where does the information to regulate the cell come from? Our proposal is that the dissipative process of peptide folding produces information as a component of the entropy. We are familiar with enzymes only being able to recognize their substrates when in the appropriately folded structure and this recognition ability is a form of information – physical information. So yes, protein chemistry is much more interesting: it is chemistry in which energy, matter and information are interchangeable
Yes Richard, biology is messy and complex and what we aimed to do and we think we have done, is to make biology conceptually simpler and provide a foundation based on fundamental and relevant physics, namely the 2nd law of thermodynamics as applied to open systems, from which a better understanding of the life process can ultimately be built.
Decades ago I was a young guest in a class at William & Mary on the origins of life and listened to a distilled lecture regarding the emergence of DNA from the “primordial soup.” Over a decade later I was privileged to take a course with Harold J. Morowitz and learned “the miracle of mayonnaise.” The latter made the earlier concepts possible. This seems to be a similar event.
I would like, by way of thanks, to offer a metaphor.
It seems to me that if genetic researchers were like young students of music, the band conductor is at some point obliged to say “Pay attention to the key signature.”
Simplistic yes, but here the argument has a mirror. The “notes” and sequencing are not changed but their expression clearly is.
In our view genes do not have a function. Function arises from a process entailing the interaction of active and information bearing proteins (mainly) and it is this process that we propose is the “unit of inheritance”. It can be regarded as a unit because it can be encapsulated by a quasi-stable state of the cell and as we said at the outset of the piece: it is the state of the cell that is inherited at cell division. as well as the DNA. I think you are pretty close to the idea. Good luck with your studies.
Thank you: a nice analogy! I like analogies and they have helped me think through these ideas. A good one is a flock of starlings that are so close together they form a dark patch in the sky that moves as a whole. There is here no conductor! Instead, each bird stays a constant distance from its neighbours – obeys a simple rule (information) and creates something that is ordered. This is roughly what I think the proteins in a cell do – obey rules of interaction.
“but I think we have not so much inverted genetics as shown its irrelevance to say evolution” – this is probably the most ridiculous thing I have read in a long time. I look forward to seeing your groundbreaking and exciting experiments that us biologists never thought of that show categorically that DNA is not the unit of heredity. I suggest one:
Deplete a cell of a specific protein (your choice as to how), and then determine how readily a the cell can recover its original phenotype.
Now instead, delete the gene encoding that protein, and see if it can ever recover its phenotype through following a few divisions.
I think you’ll find the gene is kind of important – just a hunch.
Your question is right on: where DOES the baseline information come from that regulates the cell? However, your statement that protein chemistry is one in which “energy, matter and information are interchangeable” is less compelling unless you are suggesting cellular chemistry includes cold nuclear fusion/fission.
Your hypothesis that the information required for cellular function is encoded in peptide folding however is certainly interesting, and testable through experimentation, but it belies the question: where is the information directing peptide folding encoded? You conclude this information is located within the cytoplasm but as yet there is no supporting evidence for this conclusion. One could just as easily hypothesize that the decreased entropy (i.e. increased structure through peptide folding) could come from cytoplasmic components created by additional DNA (nucleotide or mitochondrial) sequences. Either (or both) models could ultimately fall or rise as a result of further experimentation, which is really where we want to go with all this.
I’m not a geneticist and I don’t pretend to understand the physics or the biology, but I have always felt that there’s something too simplistic about the proposed one way street from genotype to phenotype. The studies of the Dutch Hunger Winter never seemed too surprising. (http://www.news.leiden.edu/news/dutch-hunger-winter.html) Equally, if my zaideh and my zaideh’s zaideh and my alter-zaideh’s alter-zaideh spent their days and nights in Kolel learning Torah law, should I be surprised to find myself in law school fascinated by torts? I have assumed that DNA affects behaviour and behaviour affects DNA, and I have a duty to the great grandkids to live a moral life.
The Dutch Hunger Winter opens chapter 11, Gene Expression, of my human genetics textbook. A great story and terrific work by the researchers — I think they are from Columbia if I’m remembering correctly. Thanks for posting!
Yes, that is true, but it is an absurd assumption to think that one can reasonably reduce highly complex systems to their basic physical properties and make predictions. Is it theoretically possible? Yes. But is it is a practical way of doing science, and could it answer any useful questions? No, and probably not.
Like Gavin above, I have a simple question:
Let’s say I want to make a line of HEK-293 cells resistant to some antibiotic. Let’s also say that I microinject the cells in one culture with whatever protein is responsible for resistance, I transfect (oh, how I hate that word) another with a plasmid with a resistance gene. I then add that antibiotic to my RPMI and start culturing the cells. Which flask do you think will still have cells in it in a month (providing one of the undergrads doesn’t infect them both…)?
Say what? Perhaps you need to go back and read what biologists were saying in the 1950s and 1960s. Your version of the central dogma is idiosyncratic and wrong.
Chaperones do not violate the central dogma.
Alternative splicing does not violate the central dogma.
There are bits of what you wrote that I think you’d find most biologists would agree with, because they’ve been saying them for years. But that nonsense about finding a violation of the central dogma, and then listing phenomena do not refer at all to the fact that information does not flow from protein sequence back into nucleotide sequence, tells me that you really do not have enough respect for the discipline of biology to bother examining what we actually say.
Yes, you are right, mass is exchanged only in the sense that the molecules are broken down or agglomerated –thanks for alerting me to the potential misinterpretation. My point is that the cellular chemistry yields products that become incorporated as “bound energy” into the body of the growing organism, while others are excreted from the system. So, overall chemistry increases the mass of the system.
I regard enzyme chemistry as a simplified example of what I mean here. We are saying that active enzymes carry physical information that allows them to recognize their substrate (have an appropriate binding site). That information is contingent on their tertiary structure and their environment, e.g., pH. We are proposing that the cell is regulated by similar kinds of process. That is an area of chemistry, as far as I understand, that has received rather little attention – but I stand to be corrected.
You ask “where is the information directing peptide folding encoded?”. The best way I can answer this is to refer you to our paper entitled “Epigenetic Regulation of the Mammalian Cell (PloS One 2008;3:e2290). Here we formulate the concept of an attractor state based on information bearing proteins and formalize it. Of course, we would not claim this is the only solution for an alternative to the current genetic paradigm. However, where genetics has failed in explanatory power (and some examples are given in that paper and in others referenced in the Interface paper) some light is shed on what types of alternative explanations would be required: we arrived at this point by following the logic and a rather narrow set of options – it seems to us most likely that the cytoplasm is the location of this regulatory process. On the issue you raise about the need for research (I agree with you) – why do think that the results with enucleated cells referred to above were not more thoroughly investigated? That was a lost opportunity? It can of course still be followed up.
You are absolutely correct Phil and there is much more besides the Dutch Hunger Winter. For example the BBC documentary “The Ghost in your Genes” http://www.bbc.co.uk/sn/tvradio/programmes/horizon/ghostgenes.shtml
and experiments with mice run over generations currently in the literature, e.g., http://www.nature.com/news/fearful-memories-haunt-mouse-descendants-1.14272 and work by Roderick Wallace http://hmgsg.org/legacy/Profiles/Wallace-Rodrick.html.
Conventional genetics cannot explain these phenomena and the question is do we continue to try and squeeze explanations out of genetics by making it more and more complex or do we abandon it and look elsewhere?
Yes, antibiotic resistance can be transferred with a single gene coding sequence and as we pointed out there is a huge body of genetic results that look very impressive. But ask the question “what fraction of the total of phenotypic properties (output) can be explained by the genetic input?”. Richard Lewontin gave the answer in 1974 and we refer to it above under Ricki’s brilliant sub-heading “Did Mendel pick cherries not peas?”. As a chemist if I study a reaction, I do a mass balance: I ensure that the mass of my products equals the mass of the reactants. What goes in must come out. That is a lot more difficult with biology (see comment above to Rick Page) and so successful genetic explanations should not be taken as evidence of generic success. There is after all the problem of the “missing heritability” and results, even in bacteria that cannot be explained in terms of genetics. Some of these are discussed in earlier papers. Robert Rosen’s sentiment in his book “Life Itself” is in my view profound: “pleasing as the view from the top of the skyscraper may be it is wise to visit the basement occasionally to check the foundations.”
We will agree to disagree then.
I’m afraid to say that I find your argument here to be somewhat self defeating. If you are trying to argue that phenotype is genotype viewed through the lense of environment and development, we’ve know that for years. I’m afraid I have to agree with PZ, if you actually read some of what we lowly biologists write, you might have a better understanding of the arguments made against your assertion.
[…] das Letras, 2007. Rick Lewis. A challenge to the supremacy of DNA as the genetic material. DNA Science Blog, March 20, […]
My name is Ricki, not Rick. Thanks.
I take your point. I think it depends on the level of abstraction at which you approach the problem. You are right if you looking at fine detail and that would be my criticism of genetics with all the narrative about detailed molecular pathways etc. We are working at a much less detailed (higher abstraction) level and one of our main conclusions is that “everything depends on everything else”. This is bound to set limits on computational biology and it surely must be useful to know that. So, I agree with you if you expect highly detailed predictions but otherwise we think trying to understand how complex systems work is a valid scientific approach..
Sorry this has appeared in the wrong place – see above in response to earlier AR comment. Keith
I take your point. I think it depends on the level of abstraction at which you approach the problem. You are right if you looking at fine detail and that would be my criticism of genetics with all the narrative about detailed molecular pathways etc. We are working at a much less detailed (higher abstraction) level and one of our main conclusions is that “everything depends on everything else”. This is bound to set limits on computational biology and it surely must be useful to know that. So, I agree with you if you expect highly detailed predictions but otherwise we think trying to understand how complex systems work is valid science.
Goodness! I thought we had gotten to this point over a decade ago. In high school the teacher tried to convince me that the there was “junk DNA.” I argued that scientists just hadn’t figured out what it did yet, years later we discovered exons, TATA boxes, and alternative splicing. Then we started in on epigenetics, and I thought that the redundancy of genes along with the histone bundling gave evidence that the DNA really was just a database. (Did the Central Dogma really state that a protein could ONLY have one gene encoding it?) It seemed that using siRNA supported that too. Oscillations in peptides have been well established through evo-devo research.
Ultimately we end up with a chicken and egg argument; did the protein that allowed the DNA transcription come first or did the transcribed DNA? Did the chaperone protein that folded the other protein come first or was it the peptide sequence? And does it really matter whether the protein came from a meteorite?
Where I am getting confused is exactly how the second law of thermodynamics is supposed to be critical to a quasi-stable cellular state. And how does this get affected by a free lunch on Wednesdays?
[…] Genes without prominence: a reappraisal of the foundations of biology reported in the context of A Challenge to the Supremacy of DNA as the Genetic Material and in the context of the 5.5 minute-long video representation of: Nutrient-dependent / […]
PZ Myers decided to tell his minions I am a ‘crank’ based on my detailed model of nutrient-dependent pheromone-controlled epigenetic effects on genome organization in species from microbes to man. Thus, it is appropriate for you to agree to disagree with him, unless you want to be subjected to unceasing attacks from those he has recruited to his blog.
Thank you for bringing biophysical constraints back into what recently became mutation-driven evolution via “constraint-breaking” mutations. Perhaps theorists will now address how mutations lead to species diversity in cases where they do not lead to physical diseases and mental disorders.
The duality of their proposed function(s) still goes far beyond my ability to grasp in the context of biologically-based receptor-mediated cause and effect. But I’m certain that PZ is not going to try to explain anything that, in his world, “just happens.”
http://xkcd.com/793/
And is it really true that none of the properties of ammonia can be predicted from the properties of hydrogen and nitrogen? What have the chemists been wasting their time on?
A single–amino acid change enabled a unicellular pathogen to effect a specific host by disabling an enzyme in the host. The tragic result was the Irish Potato Famine. Although no epigenetic effect of a specific nutrient on a specific base pair that conclusively led to a specific amino acid substitution was demonstrated, nutrient-dependent amino acid differences link algae to cell type differentiation in plants (okay, viruses, too). Thus, the atoms to ecosystems approach continues to be based on some speculation, but it is also based on experimental evidence, which comes from others who also have speculated about the thermodynamics of intercellular signaling, which leads to organism level thermoregulation, in species from microbes to man via amino acid substitutions.
Had I known about this excellent work by Annila and Baverstock, which fills in all, or nearly all the required details of biophysical constraints on ecological adaptations, I would probably violated copyright laws by including too much of what they have accurately represented in an already submitted invited review in an attempt to move evolutionary theorists forward into the 21st century.
The genome codes for molecular machinery that regulates and modulates the RNA and protein output of the genome itself, based on cell state and environmental signals.
It seems that Dr. Baverstock has not explored the avalanche of results generated during the past 25 years of cell biology, molecular genetics and epigenetics.
Further, one particular landmark experiment can hardly be ignored in relation to his central argument that inheritable information starts in the cytoplasm:
Creation of a bacterial cell controlled by a chemically synthesized genome:
http://www.sciencemag.org/content/329/5987/52.long
It seems that some people who are unimpressed with the fact that the de novo creation of cell types is biophysically constrained will continue to think in terms of theory, while all around them others are reporting results in terms of ecological variation and ecological adaptations.
Creation of a cell is nothing like getting one to eat and reproduce via the conserved molecular mechanisms of nutrient-dependent pheromone-controlled physiology of reproduction in species from microbes to man. Watch for more reports of ecological adaptations — even when the researchers think that species diversity results from mutations. By year’s end, I doubt there will be many evolutionary theorists left. The concept of biophysical constraints is a theory-killer because biophysical constraints control ecological adaptations.
http://www.sciencemag.org/content/early/2014/02/12/science.1249998.abstract
http://www.sciencemag.org/content/343/6177/1366.abstract
I think your take on the matter is interesting as an higher level approach, and it can certainly turn out to be useful.
However, you are overselling it. The view that “everything depends on everything else” has been around for decades, including molecular genetics. No one really has the simplistic view that you seem to imply. In fact, you are coming across as very patronizing, even if unintentionaly. Biologists have known for ages about the effects of environment in biochemistry. None of this is new. No one claims that a specific aminoacid sequence determines one single folding independently of the cellular environment. This is a strawman.
More worringly, you seem to completely misunderstand the Central Dogma. All it says it that *sequence* information in DNA gets transcribed to RNA. From there, it can go back to DNA or get translated to aminoacid sequences. *Sequence* information doesn’t get back from protein to nucleic acid. That’s ALL the Central Dogma says. I wonder how many people actually bothered reading Crick’s paper. Alternative splicing, environment-dependent folding, prions, etc, NONE violate the Central Dogma. Claims of overturning the CD are a 100 a dime every year.
‘@ Pedro
Re: “Alternative splicing, environment-dependent folding, prions, etc, NONE violate the Central Dogma.”
Is there anything in the extant literature that indicates biophysical constraints on protein folding have ever been considered in the context of mutations and species diversity? You seem to be saying “We’ve known this all along,” which is what typically occurs after a paradigm shift — as a “face-saving” measure.
For contrast, I noted that Annila and Baverstock cite Noble D. 2013 Physiology is rocking the foundations of evolutionary biology. Exp. Physiol. 98, 1235–1243. The citation and many things they now bring to the attention of others attest to what has either not been known to theorists or to what they have ignored.
Perhaps it is time to credit Annila and Baverstock with a long-awaited advancement, and to also credit Ricki Lewis for bringing the advancement to our attention.
It would be unfair to comment on the merits of the proposition after only a quick perusal but my gut reaction is ‘what else is new’? If we accept the premise that we are relatively perceptually/conceptually limited reporting on such a supercomplex evolving reality as ‘life’ origins and its progression as it unfolds in real time/space before us. This discussion would have made sense many years ago before the information explosion and technology sophistication. Granted that thermodynamic entropy basis is as basic as you can get but to claim it as the exclusive controlling factor determining genotype and phenotype is wishful thinking when all kinds of variables are participating in the final result …a living unit. The enucleated cell (mature red cells, gold fish cells, etc) results say nothing about the presence of nuclear products in the cytoplasm and their necessary absence if a nucleus was always absent. Their experiments on embryonic fibroblasts makes no mention of our own work on the phenotypic transformation and replication of chick embryo fibroblasts cultures when infected with Rous Sarcoma Virus (RSV-RNA). It is naive to ignore how the totipotentiality of genes expression is controlled by the cytoplasmic environment. It does not mean that the gene can be dispensed with or substituted. Our experiments were done in the Biophysics Lab. at Sloan-Kettering Institute’s state of the art facilities in Rye, NY. Rubin and Temin won a Nobel Prize with similar conclusions as it turned out. :-). I will read article again. Dr.d
Thanks James for the warning!
Well leave aside the extent of my reading and look at exactly what the authors of that paper say: “We report the design, synthesis, and assembly of the 1.08–mega–base pair Mycoplasma mycoides JCVI-syn1.0 genome starting from digitized genome sequence information and its transplantation into a M. capricolum recipient cell to create new M. mycoides cells that are controlled only by the synthetic chromosome.” So the “created” bacterium inherited the cytoplasm of the original bacterium. Did they establish that the new bacterium showed none of the phentypic of the original. Look at the section above in the interspecies nuclear transfer experiment.
Well let us resolve the confusion and then may be the other issues will be clearer. As cells are first and foremost energy consuming entities they are governed by the 2nd law of thermodynamics. We are proposing that it is on the efficiency with which organisms can extract that energy from their environment that natural selection acts. However, the physics which best supports this kind of process is not the text book physics taught in schools but the physics of complex dissipative systems and these exhibit quasi-stable states which we suggest is what phenotype is.
If the first pre-life systems were composed of proteins and those proteins coded their amino acid sequences onto RNA and then DNA in the step we would call the origin of life, then there is no chicken and egg situation to be resolved.
On the issue of chromatin marking, which I imagine you refer to as epigenetics, what is missing is the information source for locating the marks on chromatin.
Thank you for your reply, I almost missed it since it was posted at the bottom.
Khol, I don’t work in this specific field, so I need no “face-saving”. What I mean is that the existence of environmental constraints in protein folding is not a new idea, and the view that people working in the field think that amino sequence is all you need to explain folding is false. Ask any microbiologist if he thinks that, say, temperature won’t affect the folding of a given protein in an organism that lives at 30 C versus one that lives at 110 C. The problem here is that it is difficult to take all those constraints into account, not that people don’t know about them. If the authors can contribute to solve that problem, more power to them. Just don’t oversell what you actually have. As I said above, I think Arto Annila and Keith Baverstock may be contributing with a new perspective that has the potential, as an higher-level, less granular approach, to make progress in the field. But they are overselling it as some kind of new theory of evolution that “doesn’t need genes as an explanation”. This is nonsense. What they can certainly do is contribute new perspectives that may translate into new approaches and insight. I’m all for that. They show to be much more reasonable in the comments here than in their initial claims. I whish they had shown that same restraint before.
As for the Central Dogma, I’d like you or Annila to read Crick’s paper and tell me exactely why does alternative splicing or environment-dependent folding violate it. It seems that Annila and Baverstock, like so many before (including some texbook writers), never actually read the paper. They seem to think the Central Dogma is a synonimous term for “modern views on general molecular genetics”. It isn’t. It deals only and solely with the directional flow of *sequence* information. It has nothing whatsoever to do with protein folding or splicing of RNA. The only way to violate the CD is to present evidence that the aminoacid *sequence* information can be transcribed back to nucleic acids. I’m open to the idea, but so far no one has shown any evidence that it occus. Annila and Baverstock should aquaint themselves better with what the CD actually is and isn’t.
“Is there anything in the extant literature that indicates biophysical constraints on protein folding have ever been considered in the context of mutations and species diversity?”
Yes. A simple Google search turned up this:
http://phenomena.nationalgeographic.com/2013/12/12/how-a-fish-unleashed-its-evolutionary-potential-and-went-blind/
It contains the link to the original article.
Thanks for the example of how biophysical constraints on protein folding are bastardized in misrepresentations of biologically-based cause and effect. In this example, the blind Astyanax cave fish and the sighted Astyanax surface fish produce viable offspring because they are the same species.
However, reports of cause and effect move across an evolutionary continuum of eye development and/or regression and explain that eye regression in cave fish is due to increased tactile sensitivity but also that normal eye development in other fish is required for detection of visual perceived physical features important to sexual reproduction.
That’s confusing — if only due to the failure to mention the requirement for conserved molecular mechanisms of species diversity in species from microbes to man. It is also amazing — because there is no mention of the role of olfaction or pheromones that enable the response to food odors and potential mates in other species on the planet, whether or not the species has eyes that evolved, or first evolved and then regressed.
The journalist’s misrepresentations could be addressed by Ricki Lewis, in an intelligent response. However, rather than try to teach anyone like Ed Yong or Carl Zimmer to think about what they are touting, she moves us forward with thoughts about why mutation-driven evolution is not something that just happens. — Zimmer in https://www.simonsfoundation.org/quanta/20130716-the-surprising-origins-of-lifes-complexity/
Ricki Lewis attests to the fact that mutation-driven evolution does not “just happen” by informing us about what she’s learned about biophysical constraints. She’s not like other science journalists, she actually understands that “science” must be reported, not pseudoscientific nonsense.
“Others maintain that as random mutations arise, complexity emerges as a side effect, even without natural selection to help it along. Complexity, they say, is not purely the result of millions of years of fine-tuning through natural selection—the process that Richard Dawkins famously dubbed “the blind watchmaker.” To some extent, it just happens.” — Carl Zimmer
Thanks Pedro.
I spent the last few years of my 38-year career as a medical laboratory scientist in the microbiology lab of a small hospital. I was reminded of what we once called bacterial conjugation, which is nutrient-dependent and pheromone controlled, when others started touting their results on E. coli as examples of mutation-driven evolution.
These are the folks that have retarded scientific progress in the context of antibiotic resistance, which is biophysically constrained by the thermodynamics of intracellular signalling — addressed in Annila and Baverstock (2014). Simply put, increased nutrient-dependent (e.g. fueled) stability of protein folding enables organism-level thermoregulation in microbes that continue to reproduce in their immuno-compromised hosts despite the host’s increased body temperature.
Attributing cause and effect to microbes that have somehow mutated and become resistant to antibiotics is pseudoscientific nonsense. The microbes have simply adapted to higher temperatures, which is why many microbes in human bodies grow better outside human bodies at 37 degrees C.
However, death from evolutionary theory or death from ecological adaptation is never reported on the death certificate. If it were, the public outcry would force theorists to abandon any explanation that did not include experimental evidence of biophysical constraints on ecological adaptations and address the biological facts of what caused their loved-ones to die.
If that sounds harsh, please consider how many times I witnessed death by evolutionary theory despite the best of what current medical practice has to offer. At the end of sepsis, that amounts to keeping the patient “comfortable.”
“It is naive to ignore how the totipotentiality of genes expression is controlled by the cytoplasmic environment.”
That is a gross misrepresentation of the work being discussed. I hope you will comment after reading the article again. Do you still think that they are attributing control to the cytoplasmic environment?
I got the impression they were attributing control to the epigenetic landscape and to biophysical constraints on how it becomes the physical landscape of DNA in the organized genomes of species from microbes to man.
I think it is naive to attribute the totipotentiality of gene expression, which determines cell type differentiation in individuals of different species, to mutations. Is there a model for that?
“Attributing cause and effect to microbes that have somehow mutated and become resistant to antibiotics is pseudoscientific nonsense.”
Well, I think trying to explain all resistence and adaptation with no recourse to mutation is pseudoscientific nonsense too. Anyway, as long your work provides new insight, regardless of what survives later on, I’m all for it.
Thank you for your review, but I wasn’t making the case that the authors are correct in their assessment, only that biophysical constraints on protein folding are considered in the context of mutations and species diversity (we certainly could spend the rest of the day discussing when one should consider two populations as diferent species, but that’s beside the point). I’m personaly not convinced by some of the claims of the article either.
Anyway, time will tell what will come out of all of this. My career doesn’t depend on this venue of research, so I’m fine either way. My only, and final, advice to the authors is simply to:
1) not oversell their product; much water will have to flow before we can see what gets retained as relevant, and
2) get the Central Dogma right, specially before you claim it’s wrong.
Thanks KB. However, I’m afraid that this is what scares evolutionary theorists. You have gone so far beyond what most of them can comprehend because they believe that creation of a cell occurred.
That’s all that matters to most of them. They don’t care that reproduction in yeast (and all other species) is biophysically constrained or how it is biophysically constrained.
They will read: “Genomes isolated from this yeast clone produced 5 to 15 tetracycline-resistant blue colonies…” — and reassert the fact that a functional cell was synthesized. But no theorist stops there.
Once biophysical constraints on the de novo creation of a cell type have been abandoned, anything is possible. The synthetic cell can then somehow mutate into other cells that are somehow naturally selected with a result manifested (or not) in species diversity.
The fact that you leave aside the extent of your reading and accurate representations of cause and biophysically constrained effect to attempt discussion of any experimental result is problematic. Theorists will leave aside from the extend of their readings anything that does not attest to mutation-caused species diversity. They will then barrage you with what they think is evidence that supports their theories — none of which include biophysical constraints on anything.
In fact, Masatoshi Nei has made it a point to exclude ecological factors and also to tout constraint-breaking mutation as “…the ultimate source of all biological innovations and the enormous amount of biodiversity in this world.” (p. 199) http://www.amazon.com/books/dp/0199661731
Therefore, the latest in textbook-based knowledge ignores physics and chemistry at a time when you and AA are trying to say: Stop That! You could attempt to discuss all experimental evidence that should have stopped the pseudoscientific nonsense, and still the theorists will claim: You are wrong! And they will cite Nei’s book or other books that tout the same nonsense.
The forthcoming book by Ricki Lewis may be our only hope. Theorists have observed species diversity and thus it must be explained by mutations because it always has been — until it no longer is.
Thanks again. I think that Ricki Lewis may soon have something to say about mutations and eye regression compared to biophysically constrained fixes in human subjects/patients.
On the other hand, she may wait for the pseudoscientific nonsense to subside, which could take until the end of this year (and I hope, no longer).
Re: Overselling of the products of misconceptions, which have bastardized Darwin’s theory via insemination of self-propagating pseudoscientific nonsense:
I think Denis Noble said it best: “If you learnt evolutionary biology and genetics a decade or more ago you need to be aware that those debates have moved on very considerably, as has the experimental and field work on which they are based (p. 1014).” http://jp.physoc.org/content/589/5/1007.abstract
Thanks everyone for so many great comments. I’m currently buried under mountains of PDFs for 2 forthcoming textbooks and barely have time to sleep. When the deluge lets up I will go over all of these wonderful comments and write more about it. For now, I’ve learned how very important it is to spell out the limitations (and I don’t mean that in a negative sense) of the central dogma — that it in fact leaves plenty of room for influences on the expression of genes. That is its brilliance.
Dr. Lewis:
Thank you for providing an information source that may lead others to acknowledge the importance of how two adjacent nucleotide changes can result in antibiotic resistance sans mutations.
If the change is biophysically constrained by nutrient uptake (as suggested by Annila and Baverstock), and the nutrient sometimes is DNA (as suggested by me), that may change… well, everything.
See for example: DNA as a Nutrient: Novel Role for Bacterial Competence Gene Homologs cited in “Human pheromones and food odors: epigenetic influences on the socioaffective nature of evolved behaviors.” http://www.socioaffectiveneuroscipsychol.net/index.php/snp/article/view/17338/20758
The epigenetic influences (e.g., on the physical landscape of DNA) are obviously biophysically constrained, which suggests that evolved behaviors include only those that could best be consistently described as “ecologically adapted” behaviors. Ecologically adapted behaviors are consistent with Darwin’s ‘conditions of life.’ Constraint-breaking mutation-driven changes in behavior are not!
I think that biological fact is why Annila and Baverstock (2014) cited “Physiology is rocking the foundations of evolutionary biology.” http://ep.physoc.org/content/98/8/1235.long
Like some biologists, some chemists and some physicists, they probably realize that the biophysically constrained physiology of reproduction is nutrient-dependent and pheromone-controlled. However, unlike many theorists, they may not have excluded the role of DNA as a nutrient.
“If the first pre-life systems were composed of proteins and those proteins coded their amino acid sequences onto RNA and then DNA in the step we would call the origin of life, then there is no chicken and egg situation to be resolved.”
Ah yes, that well known process of reverse translation. Let me know when you discover it, and determine its mechanism. All of us biologists who have been fumbling around in the dark for so many decades (presumably waiting for some physicists to turn on the light) will surely see sense once we read that paper (presumably in PLoS Biology).
Gavin sounds embarrassed, which is to be expected. However, it’s good to encourage help from outside specific disciplines and to look at papers published… everywhere. Biologists can then read about: “Evidence that protons act as neurotransmitters at vestibular hair cell–calyx afferent synapses” http://www.pnas.org/content/early/2014/03/24/1319561111.abstract
I’m not sure that biologists can understand the role of protons in intercellular signaling and modulation of ion channels in adjacent cells without the help of physicists and chemists. Gavin may, but when other biologists realize that they cannot understand biologically based cause and effect outside the context of biophysical constraints, they may welcome help rather than try to turn it away with their sarcastic comments.
Embarrassed? I don’t think so. I’m pretty comfortable with my understanding of biology, as well as my publication record, to be confident that I know a thing to two about biology. No matter how many times you try to promote your bogus pheromone site, it is unlikely to convince me. Show me reverse translation, and I’ll be interested.
On Monday this week I set off on travels and it has been increasingly difficult to get INTERNET access in places where it is possible to work properly and respond, so I am aware that some of the recent comments have not received responses. However, I would like to thank everyone who took the trouble to read the blog and especially those who commented – it has been most stimulating and thought provoking. I went down the road I did in an attempt to explain the empirically established phenomenon of radiation induced genomic instability. To the best of my knowledge no genetic solution to this problem has been found, despite quite a significant research efforts in Europe, the US and Japan over the past 2 decades. When one views the successes in terms of explanations, one also has to bear in mind the failures to find convincing explanations for clear empirical results. In my papers cited in the Interface paper, a few examples are addressed. I still need to be convinced that the CD has not been fatally challenged in terms of its determinism and if that was not one very important factor in the decision to expend so much on genome sequencing in the early 90s, then I have missed an important point. So at least the entrepreneur sequencers took it seriously and today those who would advocate personalised healthcare based on predictive whole genome sequencing, those seeking the “missing heritability” and those who would like to base education on genome sequence measured at birth, believe in it – their projects fall without it. Its flaws are not biological but rather logical: the information in the average gene sequence, regarded my most as a unit, is proliferated by the processes of splicing, peptide folding and protein activation into several (unrelated to one another) active proteins each with its own information, the information that determines phenotype. It is this proliferation that negates the determinism. Admittedly, our proposals in place of genetics are speculative – they are hypotheses and of course subject to criticism.
From tomorrow I will be without INTERNET access for the following four weeks, but after that anyone inclined to follow-up with further discussion can find me through my website at: http://www.kbaverstock.org. Once again many thanks for the comments.
I waited to respond again until after Keith Baverstock, who I respect for taking the lead in all this. I expressed similar, albeit somewhat scattered, thoughts on the importance of biophysical constraints on alternative splicings in: “Nutrient-dependent / Pheromone–controlled thermodynamics and thermoregulation”
http://figshare.com/articles/Nutrient_dependent_Pheromone_controlled_thermodynamics_and_thermoregulation_/643393
— published with less details from physics as http://www.socioaffectiveneuroscipsychol.net/index.php/snp/article/view/20553/27989
I failed to recruit someone with biophysics expertise, but decided to submit an invited review on cell type differentiation — anyway. As I wait to see the reviewers comments, it is great to see experts like Annila and Baverstock bring their perspectives into the realm of biology.
I’ve spent two decades attempting to dispense with the pseudoscientific nonsense of mutation-initiated natural selection, which defies the Laws of Physics. That nonsense also prevents anyone from fully establishing Laws of Biology that link the epigenetic landscape to the physical landscape of DNA in the organized genomes of species from microbes to man via conserved molecular mechanism.
With Annila and Bavertock (2014) and with the interest of Ricki Lewis in their paradigm-shifting work, I think we will soon see the end of nonsense touted by folks like PZ Myers and others who have not learned anything about genetics during the past decade or more.
However, as we have seen here, the theorists will continue attacking anyone who presents new knowledge that focuses attention on their lack of experimental evidence. Experimental evidence has always been required to support the scientific theories of others. Only with theories based on population genetics was the need for experimental evidence dismissed.
Vitamin D, for example, obviously stabilizes the genome in areas where the sickle cell hemoglobin variant is attributed to mutations and natural selection. Lead and maganese-contaminated leaves eaten by the larvae of fawn-to-peppered moths caused the color change attributed to natural selection by bird predation.
The obvious links between cause and effect are found in species where the physiology of reproduction is clearly nutrient-dependent and pheromone-controlled — as it is in E. coli, and in every other species on the planet. Theorists should now begin to tell us about species that live their lives outside the biophysical constraints that Annila and Baverstock have detailed — or they should consider becoming serious scientists.
Attacks on physicists, chemists, or on other biologists are as futile as the seemingly futile thermodynamic cycles of nutrient-dependent pheromone-controlled protein biosynthesis and degradation in species from microbes to man. Attacks don’t change the scientific facts!
Re: Gavin says: March 28, 2014 at 5:06 am
“I’m pretty comfortable with my understanding of biology, as well as my publication record, to be confident that I know a thing to two about biology. ”
Hopefully, you are uncomfortable with your lack of understanding of physics and chemistry. That’s the only way you are likely to move forward and begin to incorporate biophysical constraints into whatever you add to your publication record — if anything.
Meanwhile, please point me to any current extant literature that explains how constraint-breaking mutations (or other mutations) are involved in adaptations and species diversity. I would be grateful to learn whether any of the literature you think supports whatever theories you have touted is based on anything other than data from population genetics.
Everything I’ve read in the past decade attests to the importance of protein folding and amino acid substitutions in cell type differentiation in individuals of all species.
But also, I’m not trying to sell any flim flam garbage on the web like you are, so I have no conflict of interest.
I suggest you look at some of the experimental evolution literature, in both yeast and bacteria, such as from Richard Lenski, Maitreya Dunham etc.
Hi James, thank you for your kind words. I have to apologize for not keeping up on these wonderful threads. I am buried under textbook deadlines, and never ever expected this huge a response! Although Keith’s paper did strike an immediate nerve in me.
Anyway, I am a scientist by training, and that is why I am different from the other science writers. Compared to them, I’m a nobody. I don’t get awards. I don’t do TED talks. I don’t have a wikipedia entry. What gets my ATP going is finding the papers and topics that fly beneath the radar of the non-scientist science writers, or to cover the news with fuller perspective, like I did with “mitohype” or the “gene whisperers” of recent weeks. I think if I blogged every day I’d still never run out of ideas and research to connect and comment upon.
Sometimes non-scientist journalists fall prey to the “let’s represent all sides” fallacy, and try to give equal time to ideas that just don’t fly in terms of the science. Thanks everyone for reading DNA Science!
Thanks. I get that a lot from academics who sometimes think that attempting to maintain their positions in the context of new evidence, which refutes their theories, is not a conflict of interest.
Works by Lenski and Dunham are, of course, examples of how evidence from population genetics has confused evolutionary theorists who equate it with experimental evidence of biologically-based cause and effect reported by serious scientists.
Many of the academics have not updated their knowledge base by reading articles on yeasts, like “Signaling Crosstalk: Integrating Nutrient Availability and Sex” http://stke.sciencemag.org/cgi/content/abstract/sigtrans;6/291/pe28
Many theorists have not yet grasped the unicellular nutrient-dependent pheromone-controlled physiology of reproduction connection to “Feedback loops link odor and pheromone signaling with reproduction” http://www.ncbi.nlm.nih.gov/pubmed/16290036
Oddly, many people haven’t become aware of the conserved molecular mechanisms that we detailed in our 1996 Hormones and Behavior review in a section on Molecular Epigenetics. Has it really been more than 17 years? “From Fertilization to Adult Sexual Behavior” http://www.ncbi.nlm.nih.gov/pubmed/9047261
“Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species, Drosophila melanogaster and Caenorhabditis elegans. That similar proteins perform functions in humans suggests the possibility that some human sex differences may arise from alternative splicings of otherwise identical genes.” (p. 337)
Yes, it has been more than 17 years, and your comments are typical of those I have received despite award-winning publications that link cause and effect across species from microbes to man. It’s as if evolutionary theorists have stuck their head in the sand and are afraid to come up and look around — long after Dobzhansky urged them to do so when he wrote: “…the only worthwhile biology is molecular biology. All else is “bird watching” or “butterfly collecting.” Bird watching and butterfly collecting are occupations manifestly unworthy of serious scientists!” (Dobzhansky, 1964) http://icb.oxfordjournals.org/content/4/4/443.citation
Consider that DNA is like a production in a production system. Each production is very simple -a condition action pair. Yet when these productions are combined a nearly infinite number of very complex behaviorial patterns is possible.
So, yes of course, the behavior of a given cell is going to depend on the starting state, such as the cell that is dividing and its surroundings. However, the basic “program” shared by every cell is encoded in the DNA.
Maternal nutrition at conception modulates DNA methylation of human metastable epialleles http://dx.doi.org/10.1038/ncomms4746
and
Genetic Interactions Involving Five or More Genes Contribute to a Complex Trait in Yeast http://dx.doi.org/10.1371%2Fjournal.pgen.1004324
link the nutrient-dependent differentiation of cell types in individuals of all species from ecological variation to pheromone-controlled ecological adaptations via conserved molecular mechanisms of signaling and sensing.
Chemosensory Communication of Gender through Two Human Steroids in a Sexually Dimorphic Manner http://dx.doi.org/10.1016/j.cub.2014.03.035
Love the article, really got the proverbial juices flowing! Hopefully someone can clear this up for me: To the best of my knowledge, cancer or an increase in the likelihood of the growth of a tumor can be hereditary, thus can be linked to genes. How is this so if a tumor is made up of cells which do not function as intended? Secondly, with reference to this statement: “The state of the cell cannot be encoded on the DNA base sequence: it is the active proteome”, a cancerous cell producers cancerous daughter cells through replication, like any normal cell would, is this not an ‘inheritance’ of “the state of the cell”? Still on that point, during the replication process of these cancerous cells, does the replication process run smoothly as in normal cells, or with more defects occur further down the replication chain? IE, will your fourth generation cancerous cell have more defects that your 1st generation cancerous cell? Apologies if I’m completely off track.
Yes, mutations accumulate as a cancer progresses. I often quote one researcher who said “in cancer, the genome is shot to hell.” Hereditary cancers account for only about 5%. The person inherits one susceptibility allele, which is germinal so it is in every cell, and then a second mutation, a somatic one, happens in a cell in the body part where the cancer originates. Most cancers are sporadic, with two somatic mutations occurring in the same gene in the same cell. Cancer cells have mutations in cell cycle genes, so it is a matter of replication happening too frequently — not shutting down. I hope that helps.