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Replace the Modern Synthesis (Neo-Darwinism): An Interview With Denis Noble

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In a search for the more colorful side of physiologist and systems biologist Denis Noble, I was drawn to his Oxford Trobadors page of Occitan music (medieval songs of love and chivalry from the south of France, Italy and Catalonia), featuring videos of the group mixing it up with modern infusions of jazz, etc. Noble, a classical guitarist, doubles as troubadour and maestro in the clips -- with impressive stage presence. He says, "No one needs to be just a scientist."

Denis Noble's understanding of music is clearly reflected in the elegance with which he communicates science. Maybe that's partly why he was invited to China to talk about evolution and the need to move beyond neo-Darwinism. (Noble prefers the term "modern synthesis.") He reports in our interview (below) that "youngish" scientists came up to him after his address to the Chinese Association of Physiological Sciences describing their struggles trying to get published in Western journals.

Denis Noble is Emeritus Professor of Cardiovascular Physiology and Co-Director of Computational Physiology at Balliol College at Oxford University. He also serves as the president of the International Union of Physiological Sciences (he was IUPS Secretary-General for almost a decade) and is currently the editor-in-chief of the Royal Society's bimonthly journalInterface, which features articles at the crossroads of the physical and life sciences. Noble is the author of The Music of Life and 10 other books as well as 500 scientific papers.

It was Denis Noble's discovery, more than 50 years ago at University College London, of the "electrical mechanisms in the proteins and cells that generate the rhythm of the heart" -- the basis of his Ph.D. thesis -- and his mathematical model that first attracted international attention to his work. He and his colleagues at Oxford are now making computer simulations for the rest of the organs of the body.

Noble has received several honorary Ph.D.s and numerous other awards, including the British Cardiovasculal Society's Mackenzie Prize, the Russian Academy of Sciences' Pavlov Medal, the Pierre Rijlant Prize from the Belgian Royal Academy of Medicine, the British Heart Foundation Gold Medal and the Baby Medal from the Royal College of Physicians in London. He is a fellow of the Royal Society and an honorary member of both the American and Japanese Physiological Society

My interview with Denis Noble follows.

Suzan Mazur: In recent years the modern synthesis has been declared extended by major evolutionary thinkers (e.g., "the Altenberg 16" and others), as well as dead by major evolutionary thinkers, the late Lynn Margulis and Francisco Ayala among them. Ditto for the public discourse on the Internet. My understanding is that you are now calling for the modern synthesis to be replaced.

Denis Noble: I would say that it needs replacing. Yes.

The reasons I think we're talking about replacement rather than extension are several. The first is that the exclusion of any form of acquired characteristics being inherited was a central feature of the modern synthesis. In other words, to exclude any form of inheritance that was non-Mendelian, that was Lamarckian-like, was an essential part of the modern synthesis. What we are now discovering is that there are mechanisms by which some acquired characteristics can be inherited, and inherited robustly. So it's a bit odd to describe adding something like that to the synthesis ( i.e., extending the synthesis). A more honest statement is that the synthesis needs to be replaced.

By "replacement" I don't mean to say that the mechanism of random change followed by selection does not exist as a possible mechanism. But it becomes one mechanism amongst many others, and those mechanisms must interact. So my argument for saying this is a matter of replacement rather than extension is simply that it was a direct intention of those who formulated the modern synthesis to exclude the inheritance of acquired characteristics. That would be my first and perhaps the main reason for saying we're talking about replacement rather than extension.

The second reason is a much more conceptual issue. I think that as a gene-centric view of evolution, the modern synthesis has got causality in biology wrong. Genes, after all, if they're defined as DNA sequences, are purely passive. DNA on its own does absolutely nothing until activated by the rest of the system through transcription factors, markers of one kind or another, interactions with the proteins. So on its own, DNA is not a cause in an active sense. I think it is better described as a passive data base which is used by the organism to enable it to make the proteins that it requires.

The third is an experimental reason. The experimental evidence now exists for various forms and various mechanisms by which an acquired characteristic can be transmitted.

So I think the reasons for replacing the modern synthesis are the experimental, that certain forms of inheritance of acquired characteristics have now been both demonstrated and their mechanism worked out, and the more philosophical point about the nature of causality. I believe that the modern synthesis, and indeed very many aspects of the interpretation of molecular biology generally, got the question of causality in biological systems muddled up.

Suzan Mazur: Lynn Margulis told me the following in 2009:

[W]hat Haldane, Fisher, Sewell Wright, Hardy, Weinberg et al. did was invent.... The anglophone tradition was taught. I was taught, and so were my contemporaries, and so were the younger scientists. Evolution was defined as "changes in gene frequencies in natural populations." The accumulation of genetic mutations was touted to be enough to change one species to another.... No, it wasn't dishonesty. I think it was wish fulfillment and social momentum. Assumptions, made but not verified, were taught as fact.

Margulis addded that "people are always more loyal to their tribal group than to any abstract notion of truth. Scientists especially tend to be loyal to the tribe instead of the truth."

Would you comment?

Denis Noble: I would certainly go along with the view that gradual mutation followed by selection has not, as a matter of fact, been demonstrated to be necessarily a cause of speciation. Many of those who defend the modern synthesis would say, "Well, it has been." But what you find when you look at the examples modern synthesists give is that they are for the gradual transition of one species into another in the historical record.

Just to take an example of that: the so-calledring warbler example. With the ring warbler you can watch the process, work back the historical process of how these birds developed into various subspecies around the southern areas of the world, south of the Himalayas and eventually creeping around to meet again at the north of the Himalayas. What you find is that each of the varieties can breed with each other all the way through the various branches that lead from the south to east and west. When they meet in the north, they no longer interbreed. What that tells us is there clearly was a historical development in which these warblers developed first into subspecies and then eventually into different species in the sense that they don't any longer interbreed. That tells us that that process of speciation occurred, but it does not tell us the mechanism by which speciation occurred.

Regarding wish fulfillment, what I find is that the modern synthesists tend to quote such ring warbler examples as though it is obvious that they must have occurred by gradual mutation followed by selection, when it isn't certain that that can be the mechanism if other mechanisms exist. You have to prove it. So I go along with the view that there has been no really clear proof that speciation occurred via gradual mutation followed by selection.

Suzan Mazur: Do you think scientists are anywhere near an agreed-upon definition of what life is?

Denis Noble: That's an enormous question. No, I don't think so, actually. First of all, molecules are dead. There's no sense in which individual molecules can be said to exhibit the phenomenon of life. You need a process among many, many components -- molecular components, of course, included -- of an organism in order to have something which has some of the characteristics we would want to regard as living.

You can produce a list, and physiologists do this a lot, of the obvious characteristics of a living organism: It grows, it divides, it reproduces, it metabolizes. But one can find examples where some of those properties would not necessarily be present in all the examples that one would want to take of a living organism. That's why we have difficulties with organisms like viruses, which clearly can't reproduce on their own. Are they or are they not living? It's obviously a very difficult question to ask.

I'm not sure that we need to bother about a precise definition. It's pretty clear that DNA on its own, proteins on their own, metabolites on their own, lipids on their own, are not alive. It's the network of system interaction that can be said to have living characteristics, however one defines those.

Suzan Mazur: University of Chicago microbiologist Jim Shapiro, whose work you cite, told me in our 2012 interview that he no longer uses the word "gene," saying:

[I]t's misleading. There was a time when we were studying the rules of Mendelian heredity when it could be useful, but that time was almost a hundred years ago now. The way I like to think of cells and genomes is that there are no "units"; there are just systems all the way down.

New York Medical College cell biologist Stuart Newman said he thinks the gene is "down but not out."

But only a week or so ago the science section of The New York Times ran a piece touting "de novo genes" and their appearance and disappearance.

What is the status now of the gene in your view?

Denis Noble: First of all, I go along largely with Jim Shapiro's view of the difficulty of the definition of a gene. I think it's actually even more difficult than Jim says. My argument is very simple. Wilhelm Johannsen in 1909 introduced the definition of "gene." He was the first person to use that word, although he was introducing a concept that existed ever since Mendel. What he was actually referring to was a phenotype trait, not a piece of DNA. He didn't know about DNA in those days. We now define a gene, when we attempt to define it, as a particular sequence with "start" and "stop" codons, etc., in a strip of DNA. My point is that the first definition of a gene -- Johansen's definition as a trait, as an inheritable phenotype -- was necessarily the cause of a phenotype, because that's how it was defined. It was, if you like, a catch-all definition of a gene. Anything that contributed to that particular trait -- inheritable, according to Mendelian laws -- would be the gene, whether it is a piece of DNA or some other aspect of the functioning of the cell. That we define "gene" as a sequence of DNA becomes an empirical question, not a conceptual necessity. It becomes an empirical question whether that particular strip of DNA has a function within the phenotype. Some do and some don't.

It's interesting that many knockout experiments don't actually reveal the function of the knocked-out gene. In yeast, for example, there's a study that 80 percent of knockouts don't have an obvious phenotypic effect until you stress the organism. What that tells me is that we have progressively moved from a definition of a gene which made it a conceptual necessity that the defined object was the cause of the phenotype -- that's how it was defined -- to a matter which is an empirical discovery to be made, which is whether a particular sequence of DNA plays a functional role or not. Those are very, very different definitions of a gene.

So I go further than Jim. Not only is it difficult, as he says in his book, to now define what a gene is; one should be thinking more of networks of interactions than single and fatalistic genes at the DNA level. It's also true that the concept of a gene has changed in a very subtle way, and in a way that makes a big difference to how the concept of a gene should be used in evolutionary biology.

The reason for that is very simple. It is that many of the definitions used by modern synthesists, including Richard Dawkins, are actually the Johannsen definition of a gene -- that is, the trait as the phenotypic characteristic.

[Note: While many consider Dawkins a Darwinist rather than a neo-Darwinist, Noble says that neo-Darwinists tend to encourage people to think they are following Darwin when, in fact, they're not. Noble points out that Darwin did not exclude the inheritance of acquired characteristics: "He even praised Larmarck, in the preface to the fourth edition of The Origin of Species."]

Suzan Mazur: There's also natural selection, which became a catch-all term. As Richard Lewontin has pointed out, it was intended as a metaphor not to be taken literally by generations of scientists. The range of views about what natural selection is is staggering -- a brand, a political term, a political and scientific term, failure to reach biotic potential, physicists are seeing it as part of a larger process now, etc. etc. Things are being majorly redefined.

Denis Noble: You're putting your finger on a very important point here. And what I just said about the definition of a gene is only one example where I think some philosophical clarity is needed.

Suzan Mazur: Is it the case that there are all sorts of mechanisms at play, some of which have now been identified, that have been previously considered part of natural selection? It seems natural selection is used as a catch-all for a failure to identify what the mechanisms are.

Denis Noble: I think that's right. In principle, Darwin didn't refer to any mechanisms. It was simply what we now regard as a fairly obvious statement, which is if there is variation and no definition -- not in Darwin's books, anyway -- as to what the cause of that variation might be, if there is variation, then there can be selection. If there can be selection on variants, then some will survive and some won't. In some sense this is a necessary truth, isn't it?

Suzan Mazur: Congratulations on your lecture on evolution at the Chinese Association of Physiological Sciences. What was the response to your talk there in China?

Denis Noble: Very interesting. I had similar responses in India. A lot of scientists came up to me afterwards and said, "Thank goodness somebody from either Oxford or Harvard said what you said." I asked them, "What do you mean by that? I mean, it shouldn't matter where somebody comes from whether what they're saying is correct or not." They said they were working on various epigenetic forms of inheritance, in some cases on cross-species cloning between different species.

Suzan Mazur: Are you referring to scientists in China or India?

Denis Noble: Actually, I'm thinking of both, but China is certainly where the cross-species cloning work occurred. It was India where the epigenetic work was occurring. And the comment was, "We can't get our papers published." They said they simply have been told that their theory is wrong.

Suzan Mazur: This is fascinating because Lynn Margulis mentioned to me just a few years ago that the Chinese lack any tradition in evolution, although they enjoy "superb" traditional healing medicine. It was wonderful that you gave this address in Suzhou. Seems like a real breakthrough.

Denis Noble: I do think there is a different overall approach, which has a lot to do with the integrative aspects of traditional Chinese medicine. But that is also true of India. Ayurveda, which is the Indian equivalent of traditional Chinese medicine, has more or less similar kinds of characteristics -- that is, emphasis on the integrative whole, how the past contributes to the whole, but also understanding the whole. So I'm not too surprised by the reactions in both China and India.

Suzan Mazur: Can you tell me who some of the key evolutionary thinkers are in China?

Denis Noble: Now, there I don't really know. The people who came up to me were youngish scientists telling me that they tried to get their work published and had great difficulty finding places to publish it.

Suzan Mazur: You said some of the papers focused on hybridization.

Denis Noble: Yes, that I do know. That is the work of Yong Hua Sun and his colleagues at Wuhan at the Chinese Fish Institute. I referred to their work in my lecture. What Yong Hua Sun et al. did was take the nucleus of one species of fish and insert it into the denucleated but fertilized egg cell of a different species. What they got as an adult -- it's very rare that you get an adult from such a cross-species clone -- but what they got as an adult is intermediate between the two, whereas, of course, in a gene-centric view you should -- and assuming the genes are defined as DNA -- you should get the animal from which the nucleus was taken. That doesn't happen in Yong Hua Sun's experiment.

Suzan Mazur: Where was Yong Hua Sun trying to get published and was rejected?

Denis Noble: In the end they got their work published in a journal called the Biology of Reproduction. That's not an evolutionary journal. I think they were fortunate in having an outlet, because, after all, this could be said to have to do with reproduction and mechanisms of reproduction -- the mixed nucleus and egg, nucleus from sperm and egg from the mother. It was fairly obvious to them to publish their work in Biology of Reproduction, which they did six or seven years ago. There's an article by Yong Hua Sun in the Journal of Physiology at the end of this month.

Suzan Mazur: Are you aware of any other cutting-edge evolutionary research that China is doing aside from the work on hybridization?

Denis Noble: No.

Suzan Mazur: China is clearly doing interesting work on stem cells.

Denis Noble: Unfortunately, I didn't take notes in China or India on who approached me with their stories of difficulties in getting things published.

Suzan Mazur: Are the Chinese investing in origin-of-life research, including protocell development?

Denis Noble: I would be very surprised if they are not, but I don't know for certain whether that is the case.

Suzan Mazur: What is your view as to whether or not we are alone in the universe?

Denis Noble: I find it very hard to imagine that we are alone. There's absolutely no reason why the conditions that enabled life and living systems to emerge on Earth shouldn't occur in many other places in the universe, given its immensity and the rapidity with which we're finding that systems similar to the Solar System must exist in many other star systems. It would be utterly remarkable if we were alone in that sense.

Now, whether life on many other locations -- planets, if you like -- necessarily evolved into being what we are is a rather different question, of course, because remember we're the last few seconds, if you think of it in terms of a speeded-up process where a billion years becomes a year or something like that. We humans are just the last few seconds of life on Earth, and there's no guarantee that anywhere else there's going to be something that is really at all similar to us. I say "no guarantee," but that doesn't say that it couldn't exist. What I suppose I'm saying is that it is extremely unlikely that we are alone in the sense that the evolution of life only occurred on Earth. I think that's most unlikely. It must have occurred elsewhere.