Denis Noble's Statement: Gene-Centric Neo-Darwinism Has Failed

Are you ready to discover your college program?

Search Colleges
TheBestSchools.org is an advertising-supported site. Featured programs and school search results are for schools that compensate us. This compensation does not influence our school rankings, resource guides, or other information published on this site.

At the end of the Interview I proposed that neo-Darwinism is not enough for 10 reasons. I will now explain why I listed each of those reasons.

1. Major diseases still plague humanity.

The gene-centric view has failed in one of its major claims, i.e., that it would result, through sequencing genes, in curing the major diseases that plague humanity.

The genome is often described as the “Book of Life” by biologists favoring gene-centric views. This was one of the colorful metaphors used when projecting the idea of sequencing the complete human genome towards the end of the twentieth century. It was of course a brilliant public relations move. Who could not be intrigued by reading the Book of Life and unraveling its secrets? And who could resist the promise that, within about a decade of establishing the full draft sequence of the human genome in 2000—i.e., by around 2010—reading this “book” would reveal how to treat cancer, heart disease, nervous diseases, diabetes, and many others through the discovery of many new pharmaceutical targets?

As we all know, it simply didn't happen.[1] An editorial in Nature in 2010 [2] (which inspired a similar editorial in Prospect [3]) spelled this out:

But for all the intellectual ferment of the past decade, has human health truly benefited from the sequencing of the human genome? A startlingly honest response can be found on pages 674 and 676, where the leaders of the public and private efforts, Francis Collins and Craig Venter, both say “not much.”

The targets were identified all right. At least 200 new possible pharmaceutical targets are now known and there may be more to come, but we simply do not understand how to use them. The problem does not therefore lie in absence of knowledge about the sequences. The problem is that we neglected to do the relevant physiology. The chase to sequence everything as quickly as possible at any cost distorted the balance of health care research so much that major areas of integrative physiology are now in a very fragile state. The transmission of knowledge and skills to the next generations of researchers has become the big problem. And it requires urgent attention if we are to rescue those skills.

The “Book of Life” represents the high-water mark of the enthusiasm with which the medical application of gene-centric Neo-Darwinism was developed. Its failure to deliver the promised advances in healthcare speaks volumes.[4]

I feel sad about this for two reasons.

First, before the shift towards genomic approaches to pharmacology, we did in fact have reasonably adequate methods for developing new drugs against specific diseases. The method was to work initially at a phenotype level to identify possible active compounds, and then to drill down towards individual protein or other molecular targets. This was the approach used so successfully by Sir James Black (above), the Nobel-laureate discoverer of beta-blockers and H2 receptor blockers.[5] It is the method by which the work of collaborators in my laboratory eventually led to the successful heart drug, ivabradine.[6] But the consequence of diverting large-scale funding towards the search for new drugs via genomics has been that the Black approach is now much less common and that the pharmaceutical industry is producing fewer new medications at vastly greater cost.

Of course, the Black approach could and should be complemented by genomics, and there are successful cases where protein targets found by classical methods were later also identified as coded by particular genes. A good example is Duchenne muscular dystrophy, where the gene for the protein utrophin that can substitute, in mice at least, to cure the disease was discovered before the DNA sequence was identified.[7]

Second, although the results for healthcare are disappointing, there were very good scientific reasons for sequencing whole genomes of various species. The benefits to evolutionary and comparative biology in particular have been immense. I wish that had been the main justification for the Project. There would then have been little risk of a backlash as people come to understand the limitations in relation to healthcare. The sequencing of genomes may well eventually contribute to healthcare when the sequences can be better understood in the context of other essential aspects of physiological function. But the promise of a peep into the Book of Life leading rapidly to a cure for all diseases was an expensive mistake. Without equally strong effort at the phenotype level, we will not reap the rewards of genome sequencing.

The evidence for the poor predictive health impact of genome sequencing compared to standard medical and physiological tests is compelling. See, for example, this lecture by Professor Michael Joyner from the Mayo Clinic:

The whole lecture is well worth watching. I will just illustrate two of the slides. The first compares the variance in human height that correlates with genomic profile, which is around 4–6%, while the variance that correlates with mid-parental height is as much as 40%.

The second illustrates the age-dependent variation of blood pressure in two populations living in island and city environments in Panama. City-dwellers develop age-related hypertension. Island-dwellers do not.

Phenotypic and Genetic Variance for Blood Pressure: Blood Pressure & The Kuna, presentation slide
Figure 2. Phenotypic versus Genetic Variance - Blood pressure

These kinds of comparisons apply also to many diseases in humans. A few phenotype measurements give much more reliable prediction of disease states than do GWAS correlations. More details can be found in the videoed lecture.

2. Privileging any one level in biological systems cannot be justified.

The gene-centric view does not have a sound metaphysical basis. There is no justification for privileging any one level in biological systems. No one has ever produced such a justification.

James Watson had a go at a justification when he famously quipped “There are only molecules—everything else is sociology,” which I have already referred to in the Interview. To quote my own response in the Interview:

The central idea (“there are only molecules”) is what needs challenging. That is clearly not true. Why not say “there are only strings,” or whatever physicists now identify as the most fundamental (note the force of this word) entities? But more importantly, why should we think that the universe cares about any particular level?

The Theory of Biological Relativity answers that question by showing that there is no justifiable basis for privileging the molecular level. I arrived at the germs of a Theory of Biological Relativity[8] from a strongly reductionist position. So I know the strengths and attraction of reductionism. But my early research forced me to rethink.

When I was working as a research student at University College London, I studied ion channels in the heart, as described in the Interview. At that time such work was about as reductionist as you could get in physiology. It was also a field of physiology to which mathematics could be readily applied with great success. I was able to construct the first useful mathematical model of heart rhythm. But it was precisely the use of mathematics that led to my abandoning the hard reductionist viewpoint. I was forced to admit that reductionism had to be softened by respect for multilevel causation.

The way in which that happened depended on an insight of Alan Hodgkin. When solving the differential equations that he developed with Andrew Huxley to study the nerve impulse, he realized that those equations necessarily require downward causation from the level of the whole cell, as well as upward causation from the level of molecules. This is what we now call the “Hodgkin Cycle.” My work showed that the same cycle must operate in the heart, and indeed in all electrically excitable cells.

The Hodgkin Cycle, cell voltage, protein channels
Figure 3. The Hodgkin Cycle. Cell voltage (a global property of the whole cell) controls the protein ion channels, which at the same time conduct ionic current that changes the cell voltage. This is circular causality between the two levels.

Now, you might think that this is just a feature of excitable cells. In fact, it is a feature of all biological processes that can be described by differential equation models. It is hard to think of any biological processes that could not be described by such equations since processes (i.e., how components change with time or space or any other dimension that allows derivatives to quantify those changes) are precisely what differential equation models are designed for.

Differential Equations as Models of Biological Processes, biological system model, boundary conditions
Figure 4. Many models of biological systems consist of differential equations for the kinetics of each component. These equations cannot give a solution (the output) without setting the initial conditions (the state of the components at the time at which the simulation begins) and the boundary conditions. The boundary conditions define what constraints are imposed on the system by its environment and can therefore be considered as a form of contextual causation from a higher scale. The arrows are not really unidirectional. The dotted arrows complete the diagram to show that the output contributes to the boundary conditions (although not uniquely), and they determine the initial conditions for the next integration step.[9]

Now I come to a key point. Even a Laplacian determinist would have to admit the existence of this contextual dependence of biological processes described by such models. That point was realized by the philosopher Benedict de Spinoza in 1665. I was introduced to Spinoza's work by Stuart Hampshire—the philosopher whose seminars I gate-crashed at University College London nearly 60 years ago. Much later I found that, well before Laplace, Spinoza correctly described such contextual dependence of biological processes. The evidence is in a letter that the great Dutch-Jewish philosopher Baruch (Benedict) Spinoza wrote in Latin to Henry Oldenburg, the first secretary of the Royal Society, which is still kept in the Royal Society archives.

Spinoza manuscript, scan, parchment
Figure 5. Part of a letter from Baruch Spinoza to Henry Oldenburg, the Royal Society secretary, 1665.[10]

The Latin text of the section translated into English here begins “ concipiamus jam, si placet,…” (Let us imagine, with your permission,…). The full English translation of the relevant section is:

Let us imagine, with your permission, a little worm, living in the blood, able to distinguish by sight the particles of blood, lymph, etc., and to reflect on the manner in which each particle, on meeting with another particle, either is repulsed, or communicates a portion of its own motion. This little worm would live in the blood, in the same way as we live in a part of the universe, and would consider each particle of blood, not as a part, but as a whole. He would be unable to determine, how all the parts are modified by the general nature of blood, and are compelled by it to adapt themselves, so as to stand in a fixed relation to one another.

This paragraph could stand even today as a succinct statement of one of the main ideas of Biological Relativity. He doesn't use a mathematical format to express his idea (this was before the development of Newton's mechanics), but as I have shown, the idea is beautifully expressed by the mathematics of differential equations. The reason is that, without the initial and boundary conditions, such equations cannot be solved.

Now, Spinoza was a strict determinist, so strict that he did not even distinguish reasons from causes. Everything in the universe envisaged by Spinoza was part of a giant piece of clockwork. The Theory of Biological Relativity therefore requires two more facts to be added. The first is that the universe is not a massive piece of clockwork. Stochasticity rules everywhere, and it most certainly rules in biological organisms. This is true, for example, of all forms of expression of individual proteins. If you take a cultured cell population and measure the expression level of any protein, you find that it can vary between 10- and 1000-fold between different cells in the population.

Stochasticity in Protein Expression, bimodal and monomodal cell populations
Figure 6. Diagram illustrating two forms of stochasticity in protein expression in cell populations, bimodal (left) and mono-modal (right). Experiments show that if you select cells from one of the two distributions, or from outliers in a mono-modal set, the new population initially expresses the distribution of the mother cells. But after a few days the whole population reverts to the original distribution. Thus, the population (not individual cells) determines the distribution. From the work of Sui Huang.[11]

Not only is the stochasticity extensive, it is itself controlled by the cell population as a whole. If a new population of cells is cultured from outliers in the original population, the new population reverts after a few days to the distribution displayed by the original population. This is therefore an attractor; moreover, the attractor is a property of the whole population, not of individual cells. This is yet another example of the contextual dependence of biological systems.

Huang's experiments show the control of stochasticity in cultured cell populations. Does this control of stochasticity also occur across generations of intact organisms? Surprisingly, perhaps, this was demonstrated by the great Danish botanist Wilhelm Johannsen as long ago as 1911. The images below come from the lecture by Michael Joyner referred to above.

Stochasticity in Whole-Organism Populations, Wilhelm Johannsen experiment on beans, presentation slide
Figure 7. Images from Joyner lecture, showing Johannsen's 1911 experiment on beans. The same normal distribution occurs whether one breeds from small or large bean plants.[12]

If cell populations can manipulate stochasticity to this degree, then they can also use it functionally. I will give just one example of that, and it is one that is highly relevant to evolutionary biology since it concerns the way in which organisms can change their own genomes in a directed, functional way.

The example is from the immune system. The germ line has only a finite amount of DNA. In order to react to many different antigens, lymphocytes “evolve” quickly to generate extensive antigen-binding variability. There can be as many as 1012 different antibody specificities in the mammalian immune system, and the detailed mechanisms for achieving this have been known for many years. The mechanism is directed, because the binding of the antigen to the antibody itself activates the proliferation process. The antigen activates special lymphocytes (cells in the blood stream) called B-cells, which evolve rapidly to generate a huge range of antigen-binding variability.[13] Targeted speeding-up of change is therefore one mechanism by which functional change can occur. That is true even if the individual changes at that location are random. The functionality lies in the targeting of the location. That targeting is not random.

This example should warn us that the simple idea that random changes necessarily exclude functional changes is incorrect. Organisms can use random changes to exploit their world and develop their own inheritance in a functional way. The example from the immune system concerns inheritance of cells within a single generation of a multicellular organism. Later, I will give examples of such inheritance across generations. Yet strict neo-Darwinism excludes these processes. This is how it excludes Lamarckian (i.e., functionally directed) forms of inheritance.

So far, I have outlined two essential features leading to the Theory of Biological Relativity: (1) downward as well as upward causation, meaning that molecules are constrained by their context in biological systems, and (2) stochasticity, which is itself under control by the organism.

Image: Symbiogenesis
Symbiogenesis

There is a third requirement for the full theory, which is (3) the creation of novelty, often at new levels of selection. A multi-level theory of organisms could not exist, after all, if evolution did not create novel levels of activity and selection. Evolution has done that many times, for example in the creation of cells, the formation of eukaryotes, and many other forms of symbiosis and symbiogenesis, and the emergence of population levels of selection. The creation of novelty itself then changes the dynamics of evolution since organisms actively change their environment. In all these processes the equations often favored in evolutionary biology, which involve equilibrium dynamics and similar agents, will not capture what is happening. The dynamic creation of novelty leads to dynamic changes in the environment and the creation of new niches.

When nature tells us that our mathematical models are too restrictive, we should listen carefully. We now need ideas and models that respect what nature is telling us, loud and clear, about the imitations of our existing models.

Full details on the Theory of Biological Relativity will appear in my new book, Dance to the Tune of Life: Biological Relativity (Cambridge UP, in press). The account given here is necessarily brief.

3. The gene-centric view has damaging consequences.

The gene-centric view has had profoundly damaging (even if not intended) consequences in sociology, economics, politics, and many other areas of the humanities and social sciences.

I am not a social historian, so I tread here very lightly. My impression is that Social Darwinism, the eugenics movement, and many evolution-based theories of economics, finance, and politics were greatly influenced by the standard gene-centric theory of evolutionary biology that dominated the twentieth century. In economics and management, that is still true.[14] It is also clear that some of these social developments were disastrous.

In noting this, I am not of course apportioning any blame. Nor am I by any means the only biologist to have this impression. Conrad Waddington wrote way back in 1957 that:[15]

Many humanist and religious authors… have drawn attention to its [Neo-Darwinism's] damaging effects on man's spiritual life.

He specifically referred to non-religious, as well as religious, authors, so he was clearly not using the word “spiritual” in a purely religious context. On the contrary, he viewed ethics and other aspects of spirituality as a secular matter in the context of evolutionary progress.[16]

Moreover, leading neo-Darwinians have also acknowledged the danger, explicitly or implicitly. Consider, for example, this quotation from Richard Dawkins:[17]

Let us try to teach generosity and altruism, because we are born selfish. Let us understand what our own selfish genes are up to, because we may then at least have the chance to upset their designs, something that no other species has ever aspired to.

This is a fairly explicit acknowledgement of the need to “upset their designs.” I will leave to a later section whether selfish-gene theory really can mean that “we are born selfish.”

4. The gene-centric view resists new findings.

The gene-centric view has had to gyrate in a contorted way to accommodate one new finding after another. The final straw for me was a supporter of neo-Darwinism purporting to accept the inheritance of acquired characteristics. This is like eating your own tail.

The gene-centric view has had to gyrate in a contorted way to accommodate one new finding after another. The final straw for me was a supporter of neo-Darwinism purporting to accept the inheritance of acquired characteristics. This is like eating your own tail.

First, we need to ask what we are talking about. Neo-Darwinism is significantly different from Darwinism, in the sense of Charles Darwin's own thought, although many neo-Darwinists give the impression that they can be conflated. In his On the Origin of Species (1859) and in his later books, Darwin presented a much more nuanced position. Natural Selection was argued to be the most important—but not the only—mechanism of evolution.[18]

Specifically, Darwin, like Lamarck before him, accepted the idea of the inheritance of acquired characteristics. Ernst Mayr notes about 12 places in On the Origin of Species where Darwin does this.[19] Even more significant, in The Variation of Animals and Plants under Domestication (1868), Darwin takes the idea so seriously that he formulated a theory for how it might happen. He realized of course that in multicellular organisms with separate germ lines it would be necessary for some information about changes in the organism to be transmitted to the germ line for it to be possible for acquired characteristics to be inherited. His tentative solution was his theory of “gemmules,” small particles travelling in the blood to transmit this information. We now know that small RNAs can play just such a role. I will return to that comparison later.

By contrast, neo-Darwinism can be seen, historically at least, as specifically excluding this process. For its founder, August Weismann, this was an absolutely central feature of the theory. He wrote:[20]

When these deviations only affect the soma, they give rise to temporary non-hereditary variations; but when they occur in the germ-plasm, they are transmitted to the next generation and cause corresponding hereditary variations in the body.

Regarding the sufficiency of the genome, Ernst Mayr wrote:[21]

All of the directions, controls and constraints of the developmental machinery are laid down in the blueprint of the DNA genotype as instructions or potentialities.

Richard Dawkins summed it up when he wrote that genes are “sealed off from the outside world.”[22]

But, if we accept that environmentally induced phenotypes can be inherited, as recent observations show and which I will discuss in a later section, then we have broken the Weismann barrier, because the germline is no longer isolated from the environment and the organism's response to it. We have also automatically broken the other neo-Darwinian assumption of random variation because phenotype changes can then guide inheritable variation, at least to some degree, as we have seen in item 2, above. The honest response to this situation is to say that the central tenets of neo-Darwinism are simply no longer valid.[23] We then return to a modern version of Darwinism, in the sense of Darwin's original thinking. The reason for distinguishing neo-Darwinism from Darwinism disappears.

Randomness, dice, redThe other key feature of neo-Darwinism was that all genetic change is random with respect to function, which would exclude any other way in which acquired characteristics could be inherited. This assumption was also first introduced by August Weismann. It is worth noting though that some neo-Darwinists have questioned the basis of that assumption. An example is John Maynard Smith's statement in his book Evolutionary Genetics:[24]

…it is not clear why he thought it [Weismann's claim that the germ line is independent of the soma] was true.

Neo-Darwinism therefore led to an unjustified narrowing-down of the mechanisms supposed to have been involved in the origin of different species. Moreover, the motivation for the development of neo-Darwinism was clearly a move to exclude Lamarckism. Despite Darwin's acceptance of the idea, the inheritance of acquired characteristics was deemed impossible. Natural selection working on chance variations in genetic material was thought to be entirely sufficient to explain all evolutionary change. The experimental evidence for this was flimsy, as John Maynard Smith acknowledged.

I believe that it was this unnecessary insistence on the two central assumptions of Weismann, combined with the apparent strength of support from molecular biology and the Central Dogma, that created the conditions that required some contorted gyrations to accommodate all the findings that could be regarded as challenging either of the basic assumptions. The consequence though was unfortunate since some very important discoveries were side-lined or reinterpreted in ways that closed off lines of research that should have been followed up. I will briefly list here some of the examples.

Spalding, Baldwin, and the adaptability driver. This is a phenomenon usually known as the “Baldwin effect,”[25] or “adaptability driver”—which is the term I prefer.[26] Organisms can choose new niches for themselves and their descendants.[27] Moving to a new niche can change the course of evolution even with no mutations whatsoever. That choice is a physiological characteristic of the phenotype, not a change in DNA. So how can it change the course of evolution? The answer is surprisingly simple. In a wild population in which individual genomes are not identical, the combinations of alleles in the adventurous organisms discovering new niches will be favored. That is an evolution of the genome by combinatorial selection, not selection of new random mutations. Such selection can lead to inherited novelty, as Waddington showed so clearly in his work on fruit flies.

Conrad Waddington and genetic assimilation. The Weismann Barrier was based on some experiments in which the amputation of tails in mice did not lead to mice being born with no tails. But surgical mutilation is not a test for Lamarckian forms of inheritance. Waddington performed the experiments that more successfully tested for the inheritance of acquired characteristics by using environmental manipulations that played into natural plasticity in fruit fly populations. But orthodox neo-Darwinists dismissed Waddington's findings as merely an example of the evolution of phenotype plasticity. That is what you will find in many of the biology textbooks. I think that is to misrepresent what Waddington showed. Of course, plasticity can evolve, and that itself could be by a neo-Darwinist or Darwinist or any other mechanism. But Waddington was not simply showing the evolution of plasticity in general; he was showing how it could be exploited to enable a particular acquired characteristic in response to an environmental change to be inherited and become assimilated into the genome.

Barbara McClintock and “jumping genes.” Barbara McClintock won a Nobel Prize in 1983 for her discovery in the 1940s of mobile genetic elements, often called “jumping genes.” She correctly saw that this meant that the genetic material is under some form of control by the organism, i.e., that—as she put it:[28]

the genome… [is] a highly sensitive organ of the cell.

Yet, by 1957 McClintock (right) was completely discouraged from publishing further work on the subject—until she received the Nobel Prize at the age of 81.

As James Shapiro has shown in his book Evolution: A view from the 21st century (FT Press, 2011), large-scale re-organization of genomes has occurred during evolution. These changes are sometimes represented in standard theory as “large mutations.” The problem with that designation is that, unlike the gradual accumulation of point mutations, the domains that shift around can carry functionality with them.

Carl Woese and the discovery of archaea. Carl Woese was described by Science in 1997 as “microbiology's scarred revolutionary” because his discovery of archaea as a separate domain [29] was rubbished by neo-Darwinists like Ernst Mayr.[30] Another great contribution to the study of the prokaryotes was also made by Carl Woese, which is that archaea share the bacterial propensity for promiscuous sharing of DNA. Horizontal gene transfer has occurred and still occurs frequently amongst prokaryotes, and also occurs to some degree amongst eukaryotes. The whole field of microbiology is a problem for neo-Darwinism, since there is no separate germ line, and there is rampant exchange of DNA between species. Evolution is as much dependent on horizontal transfer of DNA as on vertical inheritance. Even the concept of species is a problem.

Lynn Margulis and symbiogenesis. I will discuss this example in the next section.

What precisely has been disproved by these and other developments that challenge neo-Darwinism? This is an important question.

First, I want to note that the standard neo-Darwinist mechanism, i.e., the accumulation of gradual mutations followed by natural selection, has not been disproved. What has been disproved is the idea that this is the only way in which evolutionary change can happen. For example, the equations of population genetics, which are based on neo-Darwinist mechanisms, could still be valid as descriptions of the particular conditions and processes they were designed to describe, though we should note that those conditions are highly idealized. A rough analogy is the way in which Newtonian mechanics has been replaced by quantum mechanics. That does not invalidate the use of Newton's equations in many situations to which they apply well enough. But, as with the move in physics to acknowledge what nature tells us by developing new models, we should move on to new mathematics when it becomes clear that our existing maths is inadequate for the job.

This last point is important because some evolutionary biologists seem to fear replacement of neo-Darwinism by a more nuanced, multi-process view of evolution. Some of the arguments about whether neo-Darwinism has been extended or replaced seem to me to be largely a matter of viewpoint. I find myself more comfortable with a replacement view. Others feel more comfortable with an extension view. It is as simple as that. Even those who favor a replacement view can acknowledge, as I do, the continued existence of ranges of application for which the neo-Darwinist mechanism is valid.

5. The gene-centric view claims parsimony.

Nature simply isn't parsimonious.

The appeal to parsimony was inherent in Weismann's reactions to the nineteenth-century neo-Lamarckians. His 1893 response to Herbert Spencer, for example, was entitled Die Allmacht der Naturzüchtung (the all-sufficiency of natural selection). He wrote:[31]

We accept it [Allmacht]… simply because we must, because it is the only plausible explanation that we can conceive.

He admitted that it was not possible to observe the process in detail, so there could be no experimental proof, but continued:

It does not matter whether I am able to do so or not, or whether I could do it well or ill; once it is established that natural selection is the only principle which has to be considered, it necessarily follows that the facts can be correctly explained by natural selection.

He doesn't fully explain what is meant by “the only principle which has to be considered,” but he does admit that it doesn't depend on any experimental proof. It was seen as just “necessary.”

We encounter a similar approach in a 2009 debate between Richard Dawkins and Lynn Margulis. In this debate, the following exchange occurred:

Evolutionary theorist, Lynn Margulis
Evolutionary theorist Lynn Margulis, 1938–2011

Dawkins: “It [neo-Darwinism] is highly plausible, it's economical, it's parsimonious, why on earth would you want to drag in symbiogenesis when it's such an unparsimonious, uneconomical [theory]?”

Margulis (right): “Because it's there.”

That's it in a nutshell. What is there, what exists, is the starting point of all science.

Symbiogenesis is indeed more complex, but nature has clearly used it many times over.

In 2014, I and my colleagues wrote an editorial in an issue of the Journal of Physiology devoted to evolutionary biology. We concluded:[32]

Nature is even more wondrous than the architects of the Modern Synthesis thought, and involves processes we thought were impossible.

We are still absorbing the immense implications of these developments in biology, and many other disciplines. Whole areas of economics, sociology, and philosophy are based on interpretations of selfish gene viewpoints. No field of human endeavor will remain untouched since the implications affect even our concept of humanity.

6. The gene-centric view claims to settle the question of Lamarckism.

The claim that the Weismann Barrier and the Central Dogma have settled the question whether Lamarckism is possible. But Weismann's experiments were not a test for Lamarckism and the Central Dogma does not counter the fact that the organism controls the genome.

August Weismann performed his tail amputation experiments in 1890. They were designed to counter rather wild claims of nineteenth-century neo-Lamarckians who thought that surgical changes could be inherited. Some even claimed that the practice of circumcision could reduce or eliminate the foreskin in the offspring.

But this was not Lamarck's idea. His idea was that inheritance may occur in a functional interaction between the organisms and their environment, through use and disuse of the organism's structures. The question is not whether the non-functional results of surgery can be inherited. Darwin must have known already that such inheritance did not occur from the work of animal breeders. Tail amputation in dogs for aesthetic reasons does not result in stunted tails in the offspring, no matter how many generations are bred from the animals.

The real question—to put it in a more modern form—is whether the germ-line is or is not isolated from environmental influences. The relevant way to do a tail-cutting experiment or any other experiment to answer that question would be to change the environment in a way that makes taillessness a functional advantage. Quite apart from the obvious question why a surgical change should be inherited, even a standard Lamarckian would notice that the environment, apart from the surgery, is not different. Furthermore, even if there were environments that would favor taillessness, the experiment would not test for that. Weismann's test for Lamarckism simply would not pass the elementary tests for a scientific experiment today.

Conrad H. Waddington, black and white
Developmental biologist Conrad H. Waddington, 1905–1975

The work of Conrad H. Waddington (right) showed the more successful way forward for such experiments. The way to test for the inheritance of acquired characteristics is first to discover what forms of developmental plasticity already exist in a population, or which the population could be persuaded to demonstrate with a little nudging from the environment. This approach is more finely nuanced than using surgery since it is playing into plasticity that is already present.

Waddington used the word “canalized” for this kind of persuasion since he represented the developmental process as a series of “decisions” that could be represented as “valleys” and “forks” in a developmental landscape. He knew from his developmental studies that embryo fruit flies could be persuaded to show different wing structure simply by changing the environmental temperature or by a chemical stimulus. In the developmental landscape this could be represented as a small manipulation in slope that would lead to favoring one channel in the landscape rather than another, so that the adult could show a different phenotype starting from the same genotype.

The next step in his experiment was to select for and breed from the animals that displayed the new characteristic. Exposed to the same environmental stimulus, these gave rise to progeny with an even higher proportion of adults displaying the new character. After around 14 generations Waddington found that he could then breed from the animals and obtain robust inheritance of the new phenotype characteristics even without applying the environmental stimulus.[33] The characteristics had therefore become locked into the genetics of the animal. He called this process “genetic assimilation.” Since the plasticity being exploited already existed, it is likely that what happened is that all the gene variants (alleles) for the characteristic already existed in the population, so that selection could bring that set of variants together in an individual.

Waddington's work was largely sidelined by most evolutionary biologists. It did not become part of the mainstream. So, an opportunity to develop a more inclusive, systems, and multi-scale approach to evolutionary biology was lost. A plausible explanation is that this was the period when molecular biology was rapidly developing and had already become dominant. Francis Crick's so-called “Central Dogma” of molecular biology was published in 1956,[34] just before Waddington published his book The Strategy of the Genes (George Allen & Unwin, 1957). There is no doubt which has had the largest and longest impact. Sadly, Waddington was largely forgotten. So, also, were many lessons from integrative physiology.

Part of the reason lies in the way in which Crick's Central Dogma was greeted by neo-Darwinists as welcome and impressive support for the Weismann Barrier idea. The two reinforced each other. The isolation of the germ-line seemed to be confirmed spectacularly by the finding that DNA codes for proteins through the intermediate of RNA, whereas protein sequences do not code for DNA or RNA. This is represented by the shaded downward-pointing arrows below.

The Central Dogma of Molecular Biology, DNA, RNA, proteign
Figure 8. The so-called “Central Dogma” of molecular biology, original and revised versions

The actual situation is much more complex and has been widely misunderstood.

First, the 1956 version of the Central Dogma had to be substantially revised in 1970 when it was discovered that the step from DNA to RNA is in fact reversible (upward white arrow). This is one of the processes that enable whole domains of DNA sequence to move around the genome, with very important consequences in evolutionary history.

Second, the way in which Crick formulated the Dogma makes it clear that it actually refers only to transmission of sequence information. That is only one half of the story on the interactions between an organism, its genome, and the environment. Crick wrote:[35]

The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred back from protein to either protein or nucleic acid.

I have italicized “such information” and “from protein” since it is evident that the statement does not say that no information can pass from the organism to the genome. Crick must have known that absolute isolation of the genome from control information could not be true. How else could the same genome be used by the many different cells, tissue, and organs of the body to generate very different phenotypes? Note also that the statement refers to transfer back from proteins. The information that regulates gene expression via transcription factors and epigenetic marks comes, of course, from the networks as a whole, not from individual proteins, although the final message is conveyed by proteins called “transcription factors.” It is the pattern of such factors that is important and that it is a global property of the cells, tissues, and organs involved. There are many possible patterns of transcription factors, each of which corresponds to a different phenotype outcome. The information that passes from the system to the genome is of a different kind from that involved in coding. It is not a property of individual molecular sequences, but rather a property of an ensemble.

The more we learn about DNA and the chromosomes, the more we find that they are more like a database used by the rest of the organism, and that Barbara McClintock was right when she wrote that the genome is an “organ of the cell.” We have come a long way since Descartes fired the first shot in the reductionist-mechanist agenda with this statement in his treatise on the fetus:[36]

If one had a proper knowledge of all the parts of the semen of some species of animal in particular, for example of man, one might be able to deduce the whole form and configuration of each of its members from this alone, by means of entirely mathematical and certain arguments, the complete figure and the conformation of its members.

I wonder what Descartes would think of the modern experiments on cross-species clones. If Descartes, Weismann, and Crick were right, then transferring the nucleus of one species into the fertilized egg cell of another species to replace its removed nucleus should unambiguously lead to an organism that matches the blueprint of the nucleus. So, what do we find? First, they would be shocked to find that for most cross-species clones, the experiment doesn't even work. Usually, the embryonic development freezes at some point. There is therefore an incompatibility between the genetic material of the donor nucleus and the recipient egg cell. Second, in the rare cases where the experiment works, we obtain an organism intermediate between the two species.

The most spectacular example of this kind of experiment comes from work done at the Wuhan Fish Institute in China by Yonghua Sun and his colleagues in 2005 using two different species of fish, where the nucleus of one species was used to replace the nucleus in a fertilized egg cell of the other species. The outcome in the anatomy of the adult that resulted from this cross was determined by the cytoplasmic structures and expression patterns of the egg cells, as well as the transferred DNA. The basic features of structural organization both of cells and of multicellular organisms must have been determined by physical constraints before the relevant genomic information was developed.

Cross-Species dlones, carp, cyprinus carpio, carassius auratus, goldfish
Figure 9. Cross-species clone. The nucleus of a common carp, Cyprinus carpio (middle), was transferred into the enucleated egg cell of a goldfish, Carassius auratus (left). The result is a cross-species clone (right) with a vertebral number closer to that of a goldfish (26–28) than of a carp (33–36) and with a more rounded body than a carp. The bottom illustrations are X-ray images of the animals in the top illustration. Figure kindly provided by Professor Yonghua Sun.[37]

7. The gene-centric view claims that epigenetic inheritance is short-lived.

The claim that epigenetic inheritance always dies out after a generation or two. There are clear examples where it doesn't, and in any case no one supposes that an evolutionary change initiated by epigenetic effects would be the consequence of a single-generation exposure to the changed environment. Multiple-generation exposures can be assimilated into the genome.

Epigenetics includes a variety of ways in which the genome is controlled by the organism. The word “epigenetics” was introduced by Waddington to refer to what he called the “canalization” of development leading to different possible outcomes using the same genome. There are many different cell types in multicellular organisms. They differ in the expression patterns of their proteins. Waddington clearly saw that the complex cell networks are responsible for enabling that to happen. That should have been a signal to biologists that studying those networks was just as important as studying genes.

More recently, the concept of epigenetics has been greatly extended to include processes by which DNA itself and the chromatin proteins can be marked by chemicals that alter the probability of gene expression. The existence of these marking processes has made it easier to understand how the genome is controlled to become “an organ of the cell.” Inevitably, this development has also raised an important question in evolutionary biology: Since these marks are inherited within cell populations in a single generation, can they also be inherited across generations?

The initial reaction of neo-Darwinists was to propose that any such inheritance of genome marking was either impossible or, if it did happen, it would be found to be only transitory, dying out after a generation or two.

Before I come to the question whether this is always true and whether such marking can become more permanent, I want to acknowledge an important respect in which transient DNA marking could be very important in evolution. The ability of a population to experiment with transient changes would enable it to explore options in a reversible way that may be critical to survival in times of environmental stress. Warren Burggren has recently reviewed this question and concludes:[38]

…when environments are dynamic (e.g., climate change effects), there may be an “epigenetic advantage” to phenotypic switching by epigenetic inheritance, rather than by gene mutation. An epigenetically-inherited trait can arise simultaneously in many individuals, as opposed to a single individual with a gene mutation. Moreover, a transient epigenetically-modified phenotype can be quickly “sunsetted,” with individuals reverting to the original phenotype. Thus, epigenetic phenotype switching is dynamic and temporary and can help bridge periods of environmental stress. Epigenetic inheritance likely contributes to evolution both directly and indirectly.

This could work the other way, also. If the environment change is more long-term, there need not be a switch-back. The process of genetic assimilation could then make the change permanent, just as happened in Waddington's experiments.

Evidence that this may have happened in evolutionary history has come from the study of one of the icons of Darwinian evolution: the finches of the Galápagos Islands. Michael Skinner and his team have investigated both the genetic and epigenetic changes that have occurred in these finches. The answer is that both have occurred and that the epigenetic changes correlate rather better with phylogenetic distance than do the genetic changes. The evolution of these species has almost certainly involved both changes and interactions between them.

Epigenetics and the Evolution of Darwin's Finches,chart, diagram
Figure 10. Epigenetics and the Evolution of Darwin's Finches.

One of the criticisms neo-Darwinists raise when the role of epigenetics in transgenerational change is proposed is that such changes always die out. That may well be true in most cases for a single-generation exposure in a laboratory experiment, but Burggren's idea clearly envisages environmental exposure for multiple generations. Moreover, there are examples of epigenetic changes persisting for many generations in laboratory experiments. I will give just two examples here.

C. elegans, Caenorhabditis elegans, nematode, worm
Caenorhabditis elegans

The tiny planarian worm, C. elegans (left), is a favorite organism for genetic and molecular biological studies. It can be infected with a particular virus. Organisms that possess the correct DNA can react to this environmental stimulus by making an RNA that silences the virus, preventing it from using the host mechanisms for reproduction. By breeding these worms with others that do not have the relevant DNA, Oded Rechavi and his colleagues obtained worms in subsequent generations that do not have the relevant DNA. Yet, they still inherit the acquired resistance to the virus.[39] They do so by small quantities of the viral-silencing RNA passing through the male germ line to be amplified in each generation by an enzyme called RNA polymerase. The acquired characteristic is transmitted in this way through at least 100 generations. This example shows that the idea that an acquired characteristic will necessarily die out after a few generations is not correct. It also reveals that RNAs can also be transmitted through the germ line. DNA is not the only inherited material.

This is also a good example of how modern epigenetic research is confirming Darwin's idea of “gemmules.” RNAs can clearly play a role very similar to his explanation for Lamarckian inheritance.

white lab mouse, gloveRobust inheritance of an acquired epigenetic characteristic has been demonstrated in mice by Joe Nadeau's group in Seattle. They worked on a family of proteins that can insert mutations in DNA and RNA to show inheritance of epigenetic marking. This shows that the genome is not completely wiped clean of the marks in the germ line. On the contrary, Nadeau's work shows that such inheritance can be just as robust as standard genetic inheritance and can persist for many generations.[40] Epigenetic marking of the chromosome proteins has also been shown to be inherited.[41] The transmission of epigenetic marking has recently been shown to play a role in the inheritance of obesity in humans,[42] while the transmission of RNAs in sperm mediate the transmission of obesity in mice.[43]

Now I come to the question of rarity. As Burggren notes[44] (see also Tollefsbol[45]), the examples of transgenerational epigenetic inheritance are fairly few, and long-term examples of the kind I show here are even rarer. These are early days in such research, so we don't yet know how rare the phenomena may be. All I will do here is to note that speciation is also rare. The rarity of long-term transgenerational epigenetic effects would not exclude their contributing to rare speciation.

8. The gene-centric view claims genetic change is always random with respect to function.

The claim that genetic change is always random with respect to function. It is almost certain that it would be, since randomness at the molecular level is what you would expect even if functionality exists at other levels.

I have already described the extent and possible role of stochasticity in item 2, above. There are several lessons to be learned from the experiments I described there:

  1. At the molecular level, stochasticity is inevitable in organisms, just as it is in purely physical, non-living systems.
  2. The extent of stochasticity in gene expression is controlled by the organism in a way that is inheritable.
  3. Such inheritance can be transgenerational.

To these points I now add another:

Erwin Schrödinger, black and white
Physicist Erwin Alexander Schrödinger, 1887–1961

The idea that there might be one-way, fully determinate causation between the genome and the phenotype goes back as far as Max Delbrück and Erwin Schrödinger (left). They proposed that the genetic molecular structure would be that of a determinate, aperiodic crystal. If we regard a polymer as a linear crystal, this is a good description of the genome. I think, therefore, that they were influenced by crystallography, which gives a determinate “read-out” of the atomic structure of a crystal. This led Schrödinger to propose that, while physics may be the generation of order (e.g., in thermodynamics) from disorder (random movements of gas molecules), biology would turn out to be the generation of order (phenotype) from order (genotype). As we have seen, that cannot be true. There is no way in which the molecules in living systems can be immune from molecular stochasticity. In his 1944 Dublin lectures, What is Life?, Schrödinger was clearly struggling to find a way around this problem:[46]

We seem to arrive at the ridiculous conclusion that the clue to understanding of life is that it is based on a pure mechanism, a “clock-work” in the sense of Planck's paper.[47] The conclusion is not ridiculous and is, in my opinion, not entirely wrong, but it has to be taken “with a very big grain of salt.”

He then explains the “very big grain of salt” by showing that even clockwork is, “after all statistical).”[48] My reading of these last pages of Schrödinger's book is that he realizes that something is not quite right, but is struggling to identify what it might be. We would now say that the molecules involved (DNA) are subject to statistical variation (copying errors, chemical and radiation damage, etc.), which are then corrected by the protein machinery that enables DNA to be a highly reproducible molecule. This is a three-stage process that reduces the error rate from 1 in 104 to around 1 in 1010, which is an astonishing degree of accuracy. The order at the molecular scale is therefore actually created by the system as a whole. This requires energy, of course, which Schrödinger called “negative entropy.” Perhaps, therefore, this is what Schrödinger was struggling towards, but we can only see this more clearly in retrospect. He could not have known how much the genetic molecular material experiences stochasticity and is constrained to be highly reproducible by the organism itself.

This resolution of Schrödinger's problem is very important. As we have seen in discussing the interpretation of the Central Dogma (see item 6, above), a determinate, one-way coding does not guarantee that information determining the patterns of gene expression cannot be passed from the organism to its genome. In fact, this is happening all the time.

Organisms, therefore, can be seen to control stochasticity, and even to impose order, when it is necessary to do so.

In transmitting DNA sequences from one generation to another, this is necessary and organisms employ whole armies of networks to ensure nearly faultless transmission of sequences. But there is no need for organisms to ensure determinate behavior at the molecular level for any other transmission of information. In particular, functionality at the higher levels does not require the imposition of order at lower levels. Randomness is then what we would expect to see. But it would be wrong to assume that this means that goal-directed functionality cannot be consistent with non-functional randomness at a molecular level. Indeed, organisms not only live with such randomness, they actually control its extent and distribution.

9. The gene-centric view claims neo-Darwinism is obvious and necessarily true.

The claim that neo-Darwinism is obvious and necessarily true (often advanced by Dawkins, as in the debate with Margulis). If that were the case, it would become a tautology and not open to experimental verification—and therefore not much good as a scientific theory.

I discussed the issue of parsimony in item 5, above. The claim that neo-Darwinism is necessary is usually not far behind the claim that it is parsimonious. When Weismann wrote,[49]

…once it is established that natural selection is the only principle which has to be considered, it necessarily follows that the facts can be correctly explained by natural selection[,]

he was close to claiming explicitly that this is a necessary statement. The second phrase necessarily follows if the assumption in the first phrase is correct. The problem with necessary statements is that they are no longer open to experimental verification, unless, of course, some error of logic has crept it—in which case the statement is either not necessary (and might be falsified) or meaningless (which is even worse).

I don't myself think that the main original thesis of neo-Darwinism is a necessary statement since it must be open to experimentation whether variation really is random with respect to function. As we have seen, the experimental proof of that is at least questionable since randomness at a molecular level does not entail randomness at a higher level.

The more serious way in which the theory gets close to being unfalsifiable is the continuous process of extension. Some of the claims for the theory being extensible seem to me to be based on forgetting what the theory originally stated. If we go back to the original definitions of neo-Darwinism, it is fairly easy to see how it could be falsified.

Jean-Baptiste Lamarck, pen-and-ink, illustration
Naturalist Jean-Baptiste Lamarck, 1744–1829

At the top of this list is the absolute exclusion of the inheritance of acquired characteristics as championed by Darwin's great French predecessor, Jean-Baptiste Lamarck (right). It is impossible to read Weismann, Mayr, Dawkins, and many others in any other way. Moreover, reintroducing Lamarckian inheritance would take us back to Darwin. Neo-Darwinism would not then be necessary to distinguish the theory from Darwinism.

This is the central issue in an exchange published recently in the Journal of Experimental Biology. My reply was:[50]

If, as the commentator seems to imply, we make Neo-Darwinism so flexible as an idea that it can accept even those findings that the originators intended to be excluded by the theory it is then incumbent on modern Neo-Darwinists to specify what would now falsify the theory. If nothing can do this then it is not a scientific theory.

I think, therefore, that the ball is in the other court. What would an extended version of neo-Darwinism accept as falsification? Following all the extensions that have now been proposed, it is not clear to me whether there is any agreed definition of what the theory allows and doesn't allow. Different neo-Darwinists see this question differently.

10. The gene-centric view appeals to authority.

The claim was formulated by some of the greatest scientists of the twentieth century, so it must be right. Nullius in Verba!

The neo-Darwinist Modern Synthesis was developed by very major figures in twentieth-century biology. No one can doubt that. The scientists who developed the Modern Synthesis were brilliant and they were among the most influential scientists of the twentieth century. They formulated the best hypothesis they could that would combine the observations and insights of Darwin and Wallace on the role of natural selection with the discoveries of Mendel and the idea of the Weismann Barrier on genetics. As a hypothesis, it was very successful. The study of the genetics of populations was transformed and became a rigorously mathematical discipline.

It is perfectly possible to acknowledge these achievements of neo-Darwinism while dissenting from the view that the theory encompasses all the processes that can contribute to evolutionary change. The distinction and authority of the formulators of a theory are not what matter.

Royal Society Motto, nullias in verba, “On the word of no one” or “Take nobody’s word for it”
(“On the word of no one”)

In the U.K., the Royal Society, which is the equivalent of the National Academy of Sciences in the U.S., has a Latin motto, NULLIUS IN VERBA [visible on its official seal, left—eds.], which can be roughly translated as “don't take anyone's word for it.”[51]

It is evidence that counts. My view is that the evidence strongly suggests that the time has come for a rethink. That view is what I develop more fully in my forthcoming book, Dance to the Tune of Life: Biological Relativity (Cambridge University Press, in press).

Afterword: The Language of Neo-Darwinism

This item was not in the original 10 items at the end of the interview, but I think it is important to conclude this statement of my position with some comments on the language of neo-Darwinism since the problems the theory faces in accommodating many experimental findings have their origin in neo-Darwinist metaphors and other forms of representation, rather than in experimental biology itself.

These colorful metaphors have been responsible for, and express, the way in which twentieth-century biology has most frequently been interpreted and presented to the public. In addition, therefore, to the need to accommodate unanticipated experimental findings, we need to review the way in which we interpret and communicate experimental biology. The language of neo-Darwinism and twentieth-century biology reflects highly reductionist philosophical viewpoints, the concepts of which are not required by the scientific discoveries themselves. In fact, it can be shown that, in the case some of the central concepts of neo-Darwinism, such as “selfish genes” or “genetic program,” no biological experiment could possibly distinguish even between completely opposite conceptual interpretations of the same experimental findings.[52] The concepts, therefore, form a biased interpretive veneer that can hide those discoveries in a web of interpretation.

I refer to a “web of interpretation” since it is the whole conceptual scheme of neo-Darwinism that creates the difficulty. Each concept and metaphor reinforces the overall mind-set until it is almost impossible to stand outside it and to appreciate how beguiling it is.

Since neo-Darwinism has dominated biological science for over half a century, its viewpoint is now so embedded in the scientific literature, including standard school and university textbooks, that many biological scientists may themselves not recognize its conceptual nature, let alone question incoherencies or identify flaws. Many see it as merely a description of what experimental work has shown: the idea in a nutshell is that genes code for proteins that form organisms via a genetic program inherited from preceding generations and which defines and determines the organism and its future offspring.

What is wrong with that? The problem is that the conceptual scheme is neither required by, nor any longer productive for, the experimental science itself. Nor is it consistent with the principle of relativity applied to multi-scale biology. That is why many scientists in the physiological sciences have great difficulty reconciling their science with neo-Darwinism[53] and see the need for a new conceptual framework.[54]

As Waddington saw very clearly in his book The Strategy of the Genes (see the quote from this book in item 3, above), the language of neo-Darwinism leads to questionable ideas on what it is to be human. So, I finish by repeating this quote from The Selfish Gene:[55]

Let us try to teach generosity and altruism, because we are born selfish. Let us understand what our own selfish genes are up to, because we may then at least have the chance to upset their designs, something that no other species has ever aspired to.

The empirical discoveries of biological science do not show that we are born selfish. The idea that we are formed of “selfish” DNA, even if it were correct, could not justify attributions of selfish or cooperative behavior at the level of the organism. My selfish or cooperative behavior (like all humans, I exhibit both) depends on my genes (or, rather, the gene products: proteins and RNAs) cooperating in vast biological networks in interaction with the contextual logic of my environment. It is a category mistake to confuse attributions at a molecular level with those at the level of the whole organism.

Descartes had the same problem when he saw the need to argue that humans are not just mechanisms. Like Dawkins, he also was compelled to consider that humans are unique, that they have a capacity “that no other species has ever aspired to.” I cannot see how an evolutionary biologist can possibly accept this view since we evolved from animals. The abilities to empathize and love are clearly seen in animals other than humans.

Organism as Machine, digesting duck, Duck of Vaucanson, line art, black and white
(Duck of Vaucanso)

The mistake lies in regarding animals as pure mechanisms. That is what leads to special pleading by Dawkins, as much as by Descartes, to somehow regard humans as the only exceptions.

The Czech novelist Milan Kundera expressed the connection between a mechanistic view of animals and the consequent difficulties for our concept of humanity when he wrote this passage in his brilliant book, The Unbearable Lightness of Being:[56]

That is why it is so dangerous to turn an animal into a machina animata, a cow into an automaton for the production of milk. By so doing, man cuts the thread binding him to paradise and has nothing left to hold or comfort him on his flight through the emptiness of time.

Acknowledgments

This text reflects some of my articles published over the last 10 years (see The Music of Life Sourcebook [PDF]) and my forthcoming book, Dance to the Tune of Life: Biological Relativity. Where sections of text have been borrowed from those publications, they have been extensively rewritten for this Dialogue.

Join the Dialogue!

Share your thoughts in the comments section below …while the comments are still open!


Notes

1.  D. Noble, “The Emperor's New Genes” (HuffPost Tech UK website, 2016).

2.  See Editorial, “The human genome at ten,” Nature, 2010, 464: 649–650, p. 649; see, also, M.J. Joyner and F.G. Prendergast, “Chasing Mendel: five questions for personalized medicine,” Journal of Physiology, 2014, 592: 2381–2388.

3.  Philip Ball, “Too Much Information” (Prospect Magazine website, 2010).

4.  See, for example, D.G. Clayton, “Prediction and Interaction in Complex Disease Genetics: Experience in Type 1 Diabetes,” PLoS Genetics, 2009, 5(7): e1000540. (doi:10.1371/journal.pgen.1000540)

5.  “James Black (pharmacologist)” (Wikipedia).

6.  D. DiFrancesco and J.A. Camm, “Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease,” Drugs, 2004, 64: 1757–1765.

7.  R.J. Fairclough, M.J. Wood, and K.E. Davies, “Therapy for Duchenne muscular dystrophy: renewed optimism from genetic approaches,” Nature Reviews Genetics, 2013, 14: 373–378. See, also, this video interview.

8.  The sense in which the statement that “there is no privileged level of causation” is a relativity statement is that it follows the general principle of relativity, which is to distance ourselves from privileging frames of reference for which there is no justification. Einstein's theories of relativity also follow this general principle. For more details on this issue, see D. Noble, Dance to the Tune of Life: Biological Relativity. (Cambridge UP, in press).

9.  The legend and diagram are from D. Noble, “A theory of biological relativity: no privileged level of causation,” Interface Focus, 2012, 2: 55–64. This diagram is highly simplified to represent what we actually solve mathematically. In reality, boundary conditions are also involved in determining initial conditions and the output parameters can also influence the boundary conditions, while they in turn are also the initial conditions for a further period of integration of the equations. There are also important differences between ordinary differential equation models and partial differential equation models. The boundary conditions in partial differential equations become incorporated into the parameters in equivalent ordinary differential equation models.

10. See B. Spinoza, The Letters, tr. S. Shirley. Indianapolis: Hackett Publishing Co., 1995; Letter #32, pp. 192–198. (Note that the text cited is from an earlier translation of the Letters by R.H.M. Elwes.)

11. S. Huang, “Non-genetic heterogeneity of cells in development: more than just noise,” Development, 2009, 136: 3853–3862; H.H. Chang, M. Hemberg, M. Barahona, D.E. Ingber, and S. Huang, “Transcriptome-wide noise controls lineage choice in mammalian progenitor cells,” Nature, 2008, 453: 544–548.

12. W. Johannsen, “The Genotype Conception of Heredity,” American Naturalist, 1911, 45: 129–159.

13. For further details see J.A. Shapiro, Evolution: A View from the 21st Century, Upper Saddle River, NJ: FT Press, 2011; pp 66–68.

14. See, for example, Journal of Economic Behavior & Organisation, volume 53, 2004, which is devoted to articles in this cross-disciplinary area.

15. C.H. Waddington, The Strategy of the Genes. London: George Allen & Unwin, 1957.

16. See Peter J. Bowler, Reconciling Science and Religion. Chicago: University of Chicago Press, 2001; p. 80: “Waddington had no interest in encouraging scientists to revive an interest in religion.” This is also clear from Waddington's 1942 book, Science and Ethics. His concern was for scientists to be involved in the social process. To quote Bowler again: “…his approach to ethics was more in line with Huxley's vision of humanity continuing the course of evolutionary progress by more efficient means.”

17. R. Dawkins, The Selfish Gene. Oxford: Oxford University Press, 1976; p. 3.

18. Darwin wrote in the first edition of On the Origin of Species: “I am convinced that natural selection has been the main, but not the exclusive means of modification,” a statement he reiterated with increased force in the sixth edition (1872).

19. E. Mayr, “Introduction,” in C. Darwin, On the Origin of Species. Cambridge, MA: Harvard University Press, 1964; pp. xxv–xxvi. Mayr writes: “Curiously few evolutionists have noted that, in addition to natural selection, Darwin admits use and disuse as an important evolutionary mechanism. In this he is perfectly clear.”

20. A. Weismann, Das Keimplasma; eine Theorie der Vererbung. Jena: Fischer, 1892. (Published in English as The Germ-Plasm: A Theory of Heredity. New York: Scribner, 1893).

21. E. Mayr, “The triumph of the evolutionary synthesis,” Times Literary Supplement, November 2, 1984, p. 126.

22. R. Dawkins, The Selfish Gene. Oxford: Oxford University Press, 1976; p. 21.

23. D. Noble, “Central tenets of neo-Darwinism broken. Response to ‘Neo-Darwinism is just fine,'” Journal of Experimental Biology, 2015, 218: 2659.

24. J. Maynard Smith, Evolutionary Genetics. Oxford: Oxford University Press, 1998; p 9.

25. James Mark Baldwin, “A new factor in evolution,” American Naturalist, 1896, 30: 441–451.

Many biologists today regard the Baldwin effect as perfectly compatible with the neo-Darwinian Modern Synthesis. This can be done by taking a purely gene-centric view of what is happening. That viewpoint conceals the fact that the process depends on an active choice of environment at the level of the phenotype. Baldwin was a psychologist and described the phenomenon as the effect of learned behavior on evolution. The important point is that it is organisms that choose to behave in a particular way, not genes. The active role here occurs at the phenotype level. Genes then follow by the process of assimilation. The Baldwin effect is as much an assimilation of a character into the gene pool as Waddington's experiments were.

26. This is the term favored by Patrick Bateson, who has carefully researched the literature on the “Baldwin Effect:” see P. Bateson, “The Adaptability Driver: Links between Behavior and Evolution,” Biological Theory, 2006, 1: 342–345. He makes two points. First, that this process was first identified by Douglas Spalding in 1873, so predating Baldwin. Second, that a behavioral driver dependent on the adaptability of the phenotype could drive evolution more rapidly in a direction that would be extremely unlikely to occur by combinations of chance mutations. Both of these conclusions are convincing.

27. The mechanisms by which animals make such choices (sometimes known as “niche construction”) is now an active field of study; see, for example, the work of Daniel Rubenstein.

28. B. McClintock, “The Significance of Responses of the Genome to Challenge,” Science, 1984, 226: 792–801; p. 800.

29. C.R. Woese and G.E. Fox, “Phylogenetic structure of the prokaryotic domain: the primary kingdoms,” Proceedings of the National Academy of Sciences, USA, 1977, 74: 5088–5090. (doi:10.1073/pnas.74.11.5088)

30. E. Mayr, “Two empires or three?,” Proceedings of the National Academy of Sciences, USA, 1998, 95: 9720–9723

31. A. Weismann, Die Allmacht der Naturzüchtung; eine Erwiderung an Herbert Spencer. Jena: Fischer, 1893. [This “rejoinder” to Herbert Spencer's criticisms of Darwin's theory sparked a lively exchange in the pages of the Contemporary Review: see Herbert Spencer, “The Inadequacy of Natural Selection: Professor Weismann's Theories: A Rejoinder to Professor Weismann,” Contemporary Review, 1893, vol. 64 (Feb., Mar., May, and Dec.); and A. Weismann, “The All-Sufficiency of Natural Selection,” Contemporary Review, 1893, vol. 64 (Aug. and Sep.). The passages cited in the main text of this Statement are taken from Weissman's contribution to the Contemporary Review exchange (p. 336), and are quoted by S.J. Gould, The Structure of Evolutionary Theory, Cambridge, MA: Harvard University Press, 2002; p. 202—eds.]

32. D. Noble, E. Jablonka, M.J. Joyner, G.B. Müller, and S.W. Omholt, “Evolution evolves: physiology returns to centre stage,” Journal of Physiology, 2014, 592: 2237–2244.

33. C.H. Waddington, “The genetic assimilation of the bithorax phenotype,” Evolution, 1956, 10: 1–13; see, also, D. Noble, “Conrad Waddington and the origin of epigenetics,” Journal of Experimental Biology, 2015, 218: 816–818.

34. F. Crick,“On Protein synthesis,” Symposia of the Society for Experimental Biology, 1956, 12: 139–163.

35. F. Crick, “The Central Dogma of Molecular Biology,” Nature, 1970, 227: 561–563.

36. R. Descartes, La formation du foetus (Paris, 1664). The French text reads:

“Si on connoissoit quelles sont toutes les parties de la semence de quelque espece d'Animal en particulier, par exemple de l'homme, on pourroit déduire de la seul, par des raisons entierement Mathematiques et certaines, toute la figure & conformation de ses membres…” (paragraph LXVI; p. 146).

[Note that La formation du foetus was first published posthumously, bound together in one volume with L'homme. We have respected the seventeenth-century spelling and punctuation of the original. The English translation is by Denis Noble and Anthony Kenny and has not been previously published—eds.]

37. Y.H. Sun, S.P. Chen, Y.P. Wang, W. Hu, and Z.Y. Zhu, “Cytoplasmic impact on cross-genus cloned fish derived from transgenic common carp (Cyprinus carpio) nuclei and goldfish (Carassius auratus) enucleated eggs,” Biology of Reproduction, 2005, 72: 510–515.

38. W. Burggren, “Epigenetic Inheritance and its Role in Evolutionary Biology: Re-Evaluation and New Perspectives,” Biology, 2016, 5(2): 24. (doi: 10.3390/biology5020024)

39. O. Rechavi, G. Minevich, and O. Hobert, “Transgenerational Inheritance of an Acquired Small RNA-Based Antiviral Response in C. elegans,” Cell, 2011, 147: 1248–1256.

40. V.R. Nelson, J.D. Heaney, P.J. Tesar, N.O. Davidson, and J.H. Nadeau, “Transgenerational epigenetic effects of the Apobec1 cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability,” Proceedings of the National Academy of Sciences, USA, 2012, 109: E2766–E2773. (doi: 10.1073/pnas.1207169109)

41. J.R. McCarrey, “The epigenome—a family affair,” Science, 2015, 350: 634–635; and K. Siklenka, et al., “Disruption of histone methylation in developing sperm impairs offspring health transgenerationally,” Science, 2015, 350(6261): aab2006. (doi: 10.1126/science.aab2006)

42. I. Donkin, et al., “Obesity and bariatric surgery drive epigenetic variation of spermatozoa in humans,” Cell Metabolism, 2016, 23: 369–378. (http://dx.doi.org/10.1016/j.cmet.2015.11.004)

43. Q. Chen, et al., “Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder,” Science, 2016, 351(6271): 397–400 (DOI: 10.1126/science.aad7977); and U. Sharma, et al., “Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals,” Science, 2016, 351(6271): 391–396 (DOI: 10.1126/science.aad6780).

44. W. Burggren, “Epigenetic Inheritance and its Role in Evolutionary Biology: Re-Evaluation and New Perspectives,” Biology, 2016, 5(2): 24. (doi: 10.3390/biology5020024)

45. T. Tollefsbol, ed., Transgenerational Epigenetics: Evidence and Debate. Waltham, MA: Academic Press, 2014.

46. E. Schrödinger, What is Life? (with Mind and Matter and Autobiographical Sketches). Cambridge: Cambridge University Press, 2012; p. 82.

47. Schrödinger is here referring to Max Planck's article, “Dynamische und statistische Gesetzmäßigkeit” ( Zeitschrift für Elektrochemie und angewandte physikalische Chemie, 1917, 23: 63).

48. E. Schrödinger, What is Life? (with Mind and Matter and Autobiographical Sketches). Cambridge: Cambridge University Press, 2012; p. 83.

49. A. Weismann, “The All-Sufficiency of Natural Selection: A Reply to Herbert Spencer,” Contemporary Review, 1893, 64: 309–338; p. 337.

50. D. Noble, “Central tenets of neo-Darwinism broken. Response to ‘Neo-Darwinism is just fine,'” Journal of Experimental Biology, 2015, 218: 2659. (doi: 10.1242/jeb.125526)

51. [Literally, “on the word of no one”—eds.]

52. As an example, consider the following two paragraphs:

“Now they swarm in huge colonies, safe inside gigantic lumbering robots, sealed off from the outside world, communicating with it by tortuous indirect routes, manipulating it by remote control. They are in you and me; they created us body and mind; and their preservation is the ultimate rationale for our existence.” (R. Dawkins, The Selfish Gene [Oxford UP, 1976]; p. 21.)

“Now they are trapped in huge colonies, locked inside highly intelligent beings, molded by the outside world, communicating with it by complex processes, through which, blindly, as if by magic, function emerges. They are in you and me; we are the system that allows their code to be read; and their preservation is totally dependent on the joy we experience in reproducing ourselves. We are the ultimate rationale for their existence.” (D. Noble, The Music of Life [Oxford UP, 2006]; p. 12.)

Apart from the obviously true statement “they are in you and me,” the statements are diametrically opposed. Yet no conceivable experiment could distinguish between them. See D. Noble, “Neo-Darwinism, the Modern Synthesis, and selfish genes: are they of use in physiology?,” Journal of Physiology, 2011, 589: 1007–1015.

53. D. Noble, “Neo-Darwinism, the Modern Synthesis, and selfish genes: are they of use in physiology?,” Journal of Physiology, 2011, 589: 1007–1015.

54. D. Noble, “Evolution beyond neo-Darwinism: a new conceptual framework,” Journal of Experimental Biology, 2015, 218: 7–13.

55. R. Dawkins, The Selfish Gene. Oxford: Oxford University Press, 1976; p. 3.

56. M. Kundera, The Unbearable Lightness of Being. New York: Harper & Row, 1984; p. 297. [Written in Czech in 1982, but originally published in French in 1984—eds.)

Take the next step towards your future with online learning.

Discover schools with the programs and courses you’re interested in, and start learning today.

Search Colleges
TheBestSchools.org is an advertising-supported site. Featured programs and school search results are for schools that compensate us. This compensation does not influence our school rankings, resource guides, or other information published on this site.
Woman working at desk