Denis Noble Interview

Denis Noble is Emeritus Professor of Cardiovascular Physiology in the Department of Physiology, Anatomy, and Genetics of the Medical Sciences Division of the University of Oxford. A Fellow of the Royal Society and a pioneer of systems biology, Professor Noble held the Burdon Sanderson Chair of Cardiovascular Physiology in that department from 1984 until his retirement in 2004.

Professor Noble, who in 1960 developed the first successful mathematical model simulating the activity of the living heart, is the author of over 450 scientific papers, some of the most important of which are collected in The Selected Papers of Denis Noble CBE FRS: A Journey in Physiology Towards Enlightenment, edited by Denis Noble, et al. (Imperial College Press, 2012). He has also co-edited a volume of essays, The Logic of Life: The Challenge of Integrative Physiology, with C.A.R. Boyd (Oxford UP, 1993), and has authored a well-received book aimed at a general audience, The Music of Life: Biology Beyond the Genome (Oxford UP, 2006).

More information about Professor Noble and his work may be obtained from his academic websites (individual; and team), as well as his personal website.

TheBestSchools

Thank you very much for agreeing to participate in this Interview, as well as in the forthcoming Focused Civil Dialogue on the conceptual foundations of evolutionary theory with David Sloan Wilson, to be published in this same space over the coming weeks.

Before we get to the substance of the Interview—the way in which your groundbreaking work in the physiology of the heart led you to question the reductionist consensus in biology—we would like to ask you to share with us some of your personal story.

When and where were you born? What did your parents do? What is your religious background, if any? Where did you attend school and university? How did you get interested in science? Anything you would like to share with us about your personal journey.

Denis Noble

I am a child of the 1930s, one of the darkest decades of the twentieth century. In 1936 Hitler was already well-ensconced in Nazi Germany and the sinister events that led to the Second World War were rapidly unfolding. These included the Anti-Comintern Pact between Germany and Japan, signed on 25 November just days after I was born. The Spanish Civil War had begun. Mussolini and other fascist dictators all over Europe were queuing up to join with the Nazis. Anti-Jewish propaganda was alarmingly threatening, leading to Kristallnacht in 1938, while one of the last Kindertransporten from Vienna was to bring my future PhD supervisor to Britain.

My father, George, had fought in the First World War, was wounded in the Battle of the Somme, and fought with the fledgling Royal Air Force (RAF). He knew at first-hand the terrible consequences of all-out war, most particularly for working-class people like him. He knew what it was like to be a soldier when 90 percent of your colleagues were defenseless: to be cruelly mown down by machine guns. He was lucky to be only injured. There was a narrow escape during the Second World War, too, but that part of the story comes later.

He and my mother, Ethel, worked as jobbing tailors, making suits to order for rich clients of Saville Row tailoring firms. Some of my earliest recollections are of them listening to the BBC news on the radio during the war. My father would be sewing suits while sitting cross-legged on the huge iron shelter that filled the main room, while my younger brother and I hid underneath in case the bombs fell. We also had a concrete shelter in the small garden at the back. But fortunately he never used that; he couldn’t afford to lose time from his work. That led to the second lucky escape. Hitler’s bomb made a direct hit on the garden shelter. The house was a ruin but we survived. The first photograph of me, and a younger brother, taken shortly afterwards shows two emaciated children with their ribs clearly visible—we resembled the underfed children of war-torn poverty that, sadly, the world still sees today, except for the obvious fact that we look happy. We owe the smiling faces to our parents.

Shortly after the war finished I was sent to Emanuel School in London. In those days, poor children were given state-funded places. I was there from 1947 to 1955. I was hopeless at sports—imagine those wasted arms and legs in the middle of a rugby scrum! But an absolutely dedicated set of masters in chemistry, physics, maths, and biology fired my excitement with science. The outcome was that I went on to study medicine at University College London (UCL).

I was the first member of my family ever to go to university. In those days only five percent of the population benefited from such privilege. It felt like a privilege, too. UCL was packed with household names in the various sciences, philosophy, mathematics, and many other disciplines. The successes of the reductionist approach to biology were also very apparent. I remember seeing the first images using electron microscopy from Hugh Huxley’s work showing the individual protein molecular filaments responsible for muscle contraction. And I could witness the excitement of Bernard Katz’s work showing the quantal nature of neuromuscular transmission.

Sadly, just as I was beginning to experience these heights of intellectual endeavor, we suddenly became much poorer through the relatively early death of my father. We became a single-parent family, and there were three younger brothers to bring up. Paying the family’s electricity bills from what remained of a student grant was not easy. I shared with our mother the weekly anxieties of managing on very tight budgets.

It was impossible after that tragic event to imagine how my own career would eventually develop, and even whether I could continue as a student. We couldn’t see much beyond the end of each week. My life had to focus entirely around the family, the academic work, and the long cycling journeys across London between the two. With no money left over, student social life became an unnecessary luxury, but therefore no longer a distraction.

It was therefore very fortunate that I won a prestigious Bayliss-Starling scholarship providing the full funding for graduate work towards a doctorate. It became possible for me to branch out during my graduate research years. I explored what UCL could offer in physics, in mathematics, and in philosophy. Often enough I was the only biologist in these classes. There was no specifically designed course for such an omnivorously hungry student. I simply made it up as I went along, and somehow UCL gave me the freedom to do that.

This led to my being the only biologist in the whole university to beg for time on a precious early valve computer: one of the first machines used for seriously challenging mathematics, the Ferranti Mercury. They were so expensive that I doubt whether Ferranti ever made more than a dozen or so of those worldwide. I was given the worst time slot each day: 2–4 am! Somehow, in between doing experiments on the heart during the day to obtain the data, I used the evenings and early mornings to develop the mathematical skills to do computer modelling in biology. This experience played havoc with my circadian rhythms and looking back on it I don’t know how it was possible to do that for days on end before crashing out for a long weekend sleep.

TheBestSchools

An amazing story! Thank you very much for sharing it with us.

Next, we would like to hear about your early research on the heart, leading as we understand it to two ground-breaking papers published in Nature in 1960. Could you please describe the nature of this research and the resulting model for us, in terms suitable for a lay audience?

Denis Noble

So, why was I the only biologist working on an early electronic computer? With my supervisor, Otto Hutter (the Kindertransporten boy from Vienna, but now established on the faculty of UCL), I had made an important discovery by measuring electric current flow in heart cells. By manipulating the ions present in the bathing solution, we were able to distinguish two kinds of potassium channels. The first, which we naturally called iK1, resembled the phenomenon of anomalous rectification observed by Bernard Katz in skeletal muscle. ^[1] Instead of being activated during the action potential, the channel is rapidly inactivated. This produces electrical behavior that is best described as a rectifier. Nowadays, we call it inward rectification since the channel can pass potassium ions into the cell much more easily than out of the cell. The other type of channel we called iK2. This type resembles that discovered in nerve axons by Hodgkin & Huxley in 1952^[2] in passing outward current more easily than inward current. But the cardiac channel activates very slowly indeed, around 100 times slower than in nerve.

With these experimental results I could put 2 and 2 together and hope to make 4. I could see that the slow activation would be very important in allowing the action potential in heart to be very long compared to nerve, and the inward rectifier channel would help by reducing the amount of sodium or other ions that would need to enter to maintain the action potential. The question was whether this would work quantitatively. That could be answered only by constructing a mathematical model, just as Hodgkin and Huxley did for nerve. That is what led me to beg the guardians of the Mercury computer to give me time. Initially, they didn’t agree: “You don’t know enough mathematics (totally correct) and you don’t know how to write computer programs.” Wow! I hadn’t realized that would be such a problem; I somehow thought that I would just give them my equations and the computer would do the rest.

The only solution was to ask a maths lecturer to allow me to attend his course and have my assignments marked, and to buy the programming manual to learn how to program. Most of that was in machine code. Those were the days before structured computer languages like Fortran. The first maths lecture was totally incomprehensible and the programming manual was not much better. But I knew I had a great project, so I stuck it out. After a few of the lectures I started getting full marks for the assignments and within a month or two I could see how to write the programs. I went back to the guardians of Mercury. They still shook their heads in disbelief. But they relented and gave me the two hours each night on the machine.

The results exceeded my own expectations, let alone those of my supervisor. Not only was it possible to reproduce the detailed shape of the action potentials in the region of the heart that I was studying. As a bonus, a form of pacemaker rhythm was also reproduced. Some very counterintuitive resistance changes were also explained. The result was the two publications in Nature in 1960, even before my doctoral thesis was submitted.^[3]

I have to admit, though, that while the successes of that work were impressive, there were cracks in the explanations. Many years later cardiac electrophysiology became much more complex. The ways in which that happened are very relevant to how I became involved in evolutionary biology. So I will leave that matter to a later question.

TheBestSchools

You first came to the attention of one of us (James Barham) many years ago as the co-editor of The Logic of Life (Oxford UP, 1993), which contained among many other wonderful papers an important essay entitled “Self-Organizing Systems” by F. Eugene Yates (1927–2015), the longtime President of the American Physiological Society and another pioneer of systems biology.^[4]

One of the reasons why Barham found Yates’s work so fascinating was the latter’s use of the mathematical formalism known as “nonlinear dynamics” (which derives from work by Henri Poincaré at the turn of the twentieth century, but only began to find application within biology in the 1960s). More specifically, the mathematical object called a “nonlinear attractor” seemed like a promising way to model the global teleological (purposive, goal-directed—see below) aspect of biological functions, while fully acknowledging their objective reality (that is, without attempting to “reduce” them to local mechanistic interactions only).

We were very sorry to hear that Yates passed away just last year. Did you know him well? What was he like?

How would you describe the relationship between Yates’s work on “homeodynamics” (the modeling of generalized biological functions via nonlinear dynamics) and your own work on the heart? Do you agree that the concept of a nonlinear attractor is a useful tool for helping us to think about the teleological character of living systems?

Denis Noble

Sadly, I did not know Eugene Yates personally. Someone told me that we should include him as an invited author in The Logic of Life (OUP, 1993), and I was very pleased we did. I was also pleased with the reception of The Logic of Life at the 1993 International Union of Physiological Sciences (IUPS) Congress, for which it was produced. It resulted in full-page articles in The Guardian (PDF) and The Observer.

I believe its effect was largely to reinforce the convictions of the converted. I doubt whether it was widely read outside the domain of the physiological sciences. But it is an important publication for another reason also. My own chapter in the book, written with Richard Boyd, “The Challenge of Integrative Physiology,”^[5] shows that even two decades ago I was seriously doubtful about purely gene-centric explanations of biology. The more dogmatic neo-Darwinists sometimes pretend that I have no track record in the field. Actually, I organized the first debate on Dawkins's The Selfish Gene way back in 1976. I have at least 50 publications in peer-reviewed journals that relate to genome-phenotype relations and to evolutionary biology. The more recent ones (last 10 years) are available as The Music of Life Sourcebook (PDF).

To return to Eugene Yates, the concept of homeodynamics certainly fits my work. The process of heart rhythm is a non-linear attractor. It is an attractor because, within physiological ranges of initial parameters, the system of equations naturally moves towards the limit cycle that describes the rhythm. It is non-linear because perturbations in both directions show threshold behavior in which beyond a certain size they lead to run-away behavior.

I also agree that the concept of a nonlinear attractor is a useful tool for thinking about the teleological character of living systems. What do we mean by “teleology” if not the tendency of a system to move towards the function that serves its interests in the organism as a whole, i.e., to have a goal? As I will argue later in this Dialogue, that does not require us to believe that there was a creator that designed the cardiac pacemaker. The term “final cause” has unfortunately created the impression that there is some ultimate goal in the universe from which all other forms of teleology derive. By contrast it is sufficient in my view to see teleological behavior as emergent during evolution.

TheBestSchools

We rehearsed some of the basics of the standard neo-Darwinian theory of natural selection (i.e., random variation of genes and selective retention of corresponding phenotypes) in our interview with your interlocutor, David Sloan Wilson, so there is no need to repeat that here.

Clearly, most evolutionary biologists feel that natural selection represents the only genuine theory in biology comparable to theories in physics and chemistry, while the sort of work in physiology you have done is mere filling in of details. In short, we suspect they would not see the relevance of your work to theirs.

So, why should a physiologist be concerned about the proper interpretation of the theory of evolution? What possible role could such a scientist play in such discussions?

Denis Noble

This is a good question because the neo-Darwinist Modern Synthesis is almost designed to exclude physiology from any role other than to preserve the “vehicle” that carries the genome from one generation to another. If all inherited change is random with respect to function, and if the genome really is isolated from changes in the phenotype and its environment, then physiology has no role in the evolutionary process other than to express what the genome dictates and to allow natural selection to work on the outcome.

I developed serious doubts about this way of viewing biology as a consequence of my work on cardiac rhythm. The first model I created in 1960 was very simple indeed. Just four kinds of ion channels and no representation of any intracellular controlling processes such as the way in which calcium triggers contraction. I also found that such a model represents the process of rhythm as very fragile. A knockout of any of the genes for those protein channels would cause the rhythm to stop completely.

During the next two decades many more ion channels were discovered experimentally; Dick Tsien and I greatly extended the range of potassium channels^[6]; and Harald Reuter discovered calcium channel,^[7] as well as an exchange mechanism allowing sodium and calcium ions to exchange for each other.^[8] During the 1970s and 1980s, therefore, we needed to incorporate all of these additional mechanisms. Dick Tsien, Eric McAllister, and I first did that for the discoveries up to 1975,^[9] while Dario DiFrancesco and I did so for the discoveries up to 1985.^[10]

Some physiologists even wondered why all of this complexity was necessary when nature could clearly build rhythm mechanisms with much less, as I had shown in 1960. Critics of the methods we were using to record and distinguish between the different channels even proposed that most of them were artefacts of the recording methods. The answer to that problem is far more interesting and significant from a functional point of view. The complexity builds in robustness. Robustness is important in enabling organisms to resist unfavorable changes in their environments or genomes.

In the case of heart rhythm, we demonstrated that robustness in 1992 by showing that a protein mechanism that can contribute up to 80 percent of the ion current flow responsible for generating rhythm in the natural pacemaker of the heart, the sinus node, can be blocked completely with only a 10–15 percent change in frequency.^[11] The rhythm mechanism is therefore highly robust and relatively insensitive to what is happening at the molecular level.

Block of a protein mechanism is equivalent to a gene knockout experiment. What this shows, therefore, is that knockout experiments cannot be relied on to reveal quantitative relationships between genotypes and phenotypes. The difference between 80 percent function and 10 percent function is far too great an error to be ignored. The only way in which accurate quantitative relations can be obtained is by reverse-engineering from physiological models of the interactions between all the proteins (and therefore genes) involved. But that means that we must first understand the physiology in order to build the models with which to reverse-engineer.

That brings physiology back into relevance at least in establishing genome-phenotype relations.

This problem is even more extensive than I demonstrated. In a landmark study in 2008^[12] all 6000 genes in yeast were studied using individual knockouts. Eighty percent of the knockouts were silent in the sense that no change in metabolic or reproductive activity was observed. That does not mean that those genes have no function. It means simply that the organisms are extremely well buffered against changes in their own genomes. Once the organisms were stressed by depriving them of various nutrients, it was possible to reveal that most of the 80 percent have functional roles.

At the least, such experiments and calculations force one to think deeply about the basis of gene-centric views of biology. But they do not, in themselves, challenge the neo-Darwinist view of evolution. For me, they were more a way back into thinking about evolution again, as I have done, on and off, for about 50 years.

What followed was like a falling domino cascade. Once one central issue in gene-centrism comes into question, others inevitably also come under suspicion. I will now list some of the dominoes that fell in the wake of questioning the gene-centric view of genome-phenotype relationships.

1. The Central Dogma of Molecular Biology. The idea of a one-way determinate read-out of genome sequences (if that is taken as the meaning of the Central Dogma^[13]) doesn’t make much sense to a physiologist. The 200 or so cell types in a vertebrate organism all have the same genome. Each cell clearly controls its genome to produce a pattern of gene expression that is unique to that type. Moreover, the environment of each cell type, formed by the tissues and organs the cells find themselves in, also contributes to control of the genome. Within the body, therefore, a form of Lamarckian inheritance of acquired characteristics is rampant.

2. The Weismann Barrier. If that can happen within an organism, why can’t it also happen across generations? In 1998 I interacted with the renowned evolutionary biologist John Maynard Smith (1920–2004) during a Novartis Foundation Symposium on the limits of reductionism.^[14] Though working entirely within the Modern Synthesis framework, he did acknowledge some of its weak points. Two quotes from his book, Evolutionary Genetics (Oxford UP, 1998), suffice to illustrate this.

On Lamarckism, Maynard Smith writes:^[15]

[It] is not so obviously false as is sometimes made out.

On Weismann, he writes:^[16]

[I]t is not clear why he thought it [the germ line is independent of changes in the soma] is true.

I entirely agree with both remarks—but they don’t go nearly far enough.

Weismann’s tail-cutting experiments, in which he showed that no tailless mice were ever born to mice whose tails had been amputated, only tests whether a surgical mutilation can be inherited. Half a century later, Conrad H. Waddington (1905–1975) performed the correct experiment, which was to change the environment. He treated fruit fly embryos with gentle heat or with ether and produced variants from which he bred. After only a few generations it was no longer necessary to give the environmental stimulus. The change had become assimilated into the genome so that the changed phenotype bred true even without the environmental stimulus.^[17] Waddington coined the term “epigenetics.”

3. Transgenerational Epigenetics. Modern biology has greatly extended Waddington’s epigenetic idea to include many processes that were completely unknown to him. In addition to control of gene expression by transcription factors, we now include various chemical processes by which the genome sequences can be marked in a way that modifies gene expression. Both DNA itself and the histone proteins around which it is wrapped can be marked.

Initially, it was thought that these marks are always removed between generations. But we now know that is not always true.^[18] This has led to the creation of the field of transgenerational epigenetics.^[19] Defenders of the Modern Synthesis usually dismiss this evidence by saying that such transmission is rare and that it always dies out after a few generations. I have three answers to that.

First, there are now well-established examples where it does not die out even over many generations.^[20]

Second, even if the process is rare, so is speciation. As a mechanism contributing to the rare process of speciation, rare transgenerational inheritance of epigenetic changes could clearly occur. In a recent study of Darwin’s finches, this is what seems to have happened.^[21] Both epigenetic (meaning DNA marking) and genetic (meaning DNA sequence) changes are correlated with the evolutionary distance between the different species. The authors of the study conclude that both interacted in the process of speciation.

Third, it is important to note that testing whether epigenetic marking dies out after a single generation exposure to the environmental change does not test for what may happen during evolutionary change since, in any realistic case, the environmental stimulus would continue to act over many generations. Waddington’s idea of genetic assimilation can then occur to ensure that the change becomes more permanent.

4. Lateral transfer of DNA. The Modern Synthesis was based on Darwin’s idea of the tree of life, radiating from a common ancestor. We now know that the tree is more like a network, particularly in the early branches. DNA is not just transferred vertically from generation to generation; it can also be transferred laterally between organisms, even between different species.

5. Symbiogenesis. I was given the huge privilege of interacting with Lynn Margulis (1938–2011) on an almost daily basis during the academic year 2008–9, when she was the Eastman Visiting Professor at Oxford University. It so happens that this chair is attached to my own college, Balliol, so we often met at lunch. That led to me chairing a landmark debate between her and Richard Dawkins, together with Martin Brasier (symbiosis in corals) and Stephen Bell (prokaryotes). It lasted four hours and is fully recorded online.

Richard Dawkins was the better debater, judged by some audience reactions. But Lynn had killer lines. I shall never forget this interaction:

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: “Because it's there.”

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

6. Genome reorganization (natural genetic engineering). I have also had the great privilege of interacting over several years with James Shapiro at the University of Chicago. James taught me to understand the significance of the work of Barbara McClintock (1902–1992), the discoverer of mobile genetic elements, for which she received the Nobel Prize in 1983. Neo-Darwinians argue that this is just an example of a large mutation. I argue that if large, already-functional sequences are moved around the genome, then potentially existing or new functions travel with the sequences. The Modern Synthesis was built on the idea of the gradual accumulation of point mutations. I explain the significance of moving large sequences in the next item.

7. Randomness versus functionality of inherited variations. This is perhaps the biggest question of all. How does functionality, and hence teleology, arise in random processes? My short answer is that viewed from the level of molecules we may never see it.

My argument develops in just a few stages.

(a) Randomness and order at different levels in physics. At a molecular level, a gas or a liquid shows random movement as the molecules interact with each other's motions. In an enclosed elastic container the global variables, pressure, volume, and temperature obey predictable laws. In our most basic science, physics, therefore, stochasticity at a low level does not entail stochasticity at a higher level. If we were to visualize a water molecule as the size of a billiard ball, the edge of the biological cell containing it would be one kilometer away. Imagine a billiard table one kilometer across and millions of billiard balls interacting. From their individual behavior we would have no idea where the constraint lies. Without that information we would not be able to work out what is going on. This is the basis of Erwin Schrödinger’s argument in What is Life? (1943) when he said that physics is “order from disorder.”

The great Dutch-Jewish philosopher Baruch (Benedict) Spinoza (1632–1677) recognized this way back in 1665 when he wrote:

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.

—Spinoza, Letter to Henry Oldenburg, secretary of the Royal Society, 20 November 1665^[22]

Demonstrating random behavior of molecules like DNA cannot therefore exclude ordered or functional behavior at a higher level.

(b) Organisms can use stochasticity to evolve new functions. The next stage in my argument is that organisms have been demonstrated to use stochasticity in effective functional ways. The best example is 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. 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. It would not be functional if it was not targeted since it would produce unwanted, potentially damaging sequence changes.

(c) Natural genetic engineering has occurred during evolution. From the Nature paper of 2001 announcing the draft sequence of the human genome,^[23] two classes of proteins were shown to have evolved through transposition of complete functional domains. The details can be found in James A. Shapiro’s book, Evolution: A View from the 21st Century (FT Press, 2011). To appreciate the full significance of these mechanisms by which whole domains can be moved around in the genome, imagine two children playing with a construction kit like Lego. To one child we give a pile of the original simple Lego bricks. To the other we also include many preformed shapes. It is obvious that when asked to make any construction that requires the preformed shapes, the second child will succeed much faster than the first. In the same way, evolution is much more likely to generate successful novel organisms if it can “play” with preformed DNA domains. Existing functionality is transferred into forming new combinations.

TheBestSchools

We understand that your credentials to be participating in these debates at all have indeed been challenged. Without necessarily naming names, could you give us an example of such a case? What exactly did your critics say? How did you respond?

Denis Noble

These examples are almost hilarious, or they would be if they had not been seriously penned by chairholders in major universities:

Here we go again: someone arguing that DARWIN WAS RONG [sic]!

REPLY: I argue that Darwin was (largely) right! He didn’t even read the article.

His most moronic claim by far is the one on mutations not being random . . . What we mean by “random” is that mutations occur regardless of whether they would be good for the organism.

REPLY: The potentially functional nature of some of the variations is the central theme of the articles and lectures. It is hard to miss that theme if one reads the article even cursorily. A much fuller reply is what I have written above about randomness.

Cells are transitory, and DNA is not.

REPLY: This is a common mantra, copied from Dawkins's The Selfish Gene. It is linguistically incoherent and factually incorrect.^[24]

TheBestSchools

As alluded to above, the most striking thing about living things, in comparison with non-living systems, is their teleological organization—meaning the way in which all of the local physical and chemical interactions cohere in such a way as to maintain the overall system in existence. Moreover, it is virtually impossible to speak of living beings for any length of time without using teleological and normative language—words like “goal,” “purpose,” “meaning,” “correct/incorrect,” “success/failure,” etc.

Why do you think this is? We would like you to answer this question in two stages.

First, do you see teleology as objectively there in organisms themselves, or as a kind of illusion projected onto organisms by us? Doesn’t cybernetic theory, together with evolutionary theory (as delineated by Harvard ornithologist and philosopher Ernst Mayr [1904–2005] and others), obviate the need for us to take the apparent teleology in living things at face value?^[25]

Denis Noble

I also originally held that view. It was a debate with the Canadian philosopher Charles Taylor in 1967 that began the process by which I came to a very different view. In the first article,^[26] I demonstrated what Ernst Mayr and others argue, which is that for every high-level description there must exist a valid low-level description. Taylor replied ^[27] that that may be true in any given case but that it would not explain what is happening if one takes a set of cases. They may be ordered only at the high level. I further replied ^[28] that this move makes the issue one of explanation, i.e., conceptual rather than strictly empirical.

I now go much further. My work on heart rhythm taught me that the rhythm simply doesn’t exist at the molecular level. If I placed all the molecular components in a nutrient solution, but without being constrained by a living cell, the rhythm would not exist. By the usual ontological criteria the rhythm doesn't exist at a molecular level but does exist at a cellular level.

TheBestSchools

Second, if we must understand teleology in biology as objectively real, how can we do so without bringing in unwanted theological or similar baggage?

Denis Noble

I will give a brief answer here. I will explain the concepts of biological relativity and the relativity of epistemology later. The brief answer is that explaining purpose in organisms can be complete at any level, without having to go further to higher levels. The rhythm of the heart is explained at a cellular level. Its function is explained at the level of the cardiovascular system. That doesn’t mean that there could not be a theological explanation. It does mean that the theological explanation is not necessary.

TheBestSchools

One way of elucidating the difference between the objective and the mainstream views of teleology is by reference to the notion of a “machine.”

A machine is a goal-directed system (it has a “function”), in which the goal state of the system is determined by an outside observer/agent. In such a system, the physico-chemical properties of the system have been carefully assembled by the outside observer/agent in order to bring about the goal state. There is no inherent, internal, or intrinsic tendency of the component parts and processes of the system, considered just in themselves, to produce the goal state as a distinguished system state. The intentionality and the outside intervention of the observer/agent are constitutive of what it is for something to be a machine.

A living organism is very different. Its goal state is its own continued existence, and all of its component parts spontaneously behave in such a way as to contribute to the realization of that distinguished system state (those individual contributions are then sub-goal-states). The functionality—that is, the teleology—of the system as a whole arises as a result of purely inherent, internal, or intrinsic processes.

Do you agree with this characterization of the essential difference between machines and organisms? That is, do you agree with the proposition that organisms are not machines—that machines and organisms belong to fundamentally different ontological categories?

Denis Noble

I don’t think they arise as a result of “purely inherent, internal, or intrinsic processes.”

They arise because organisms are open systems interacting extensively with their environment, including the behavior of other organisms. Just as such interactions can canalize the behavior of any complex but flexible system (e.g., learning machines) towards effective solutions, so the interaction with other organisms creates new solutions. The social interactions of organisms are critical to their evolution.

TheBestSchools

What is your definition of “neo-Darwinism” (or “Modern Synthesis”)? Isn’t it enough to talk of “extending” it? Why do you speak of its needing to be “replaced”?

Denis Noble

The main ideas in the original formulation of neo-Darwinism are the following:

1. All changes in the genetic material are random, as Weismann first proposed. It is important to note that what is meant is that genetic change is random with respect to function. This is the “blind chance” part of the theory with no room for teleology.
2. The germ line cells are completely isolated from the rest of the organism. Dawkins encapsulated this view in The Selfish Gene: “Sealed off from the outside world.”

There are also some negative statements. Most important is the exclusion of Lamarckian forms of inheritance, which is implied by 2. Some modern defenders of neo-Darwinism claim to accommodate the Lamarckian forms that have now been discovered, but this seems to me to be contrary to common sense.^[29] The central assumption of neo-Darwinism is that the inheritance of acquired characteristics is impossible. But if inheritable variations are not always random with respect to physiological function, then it seems to me to be more honest to say so.

I am very sympathetic to the extension idea in science. But when neo-Darwinism goes so far as to accept the inheritance of acquired characteristics and of non-random functional variations, I think we are talking more about a replacement. Note, however, that even replaced theories still have ranges of validity. Newtonian mechanics was replaced by quantum mechanics and relativity theory, but we still use Newton’s equations for many ranges of applications.

I am not saying that all the equations of, e.g. population genetics, suddenly become invalid. In their range of application they still work. I am saying that neo-Darwinism is incomplete.

TheBestSchools

You have written that “Darwin was not a neo-Darwinist.”^[29] We assume you mean by this something more than the obvious fact that Darwin was unacquainted with modern genetics. What exactly did you mean?

Denis Noble

If neo-Darwinism excludes the inheritance of acquired characteristics, then Darwin was clearly not a neo-Darwinist. There are many places in On the Origin of Species (1859) where Darwin assumes such mechanisms and in a later book, The Variation of Animals and Plants under Domestication (1868), he even spelt out his theory of “gemmules” to explain them. The theory of gemmules is that chemicals pass through the blood stream to influence the germ line. We now know that RNAs do precisely that.

TheBestSchools

What about the role of genes in life? Nowadays, many people are saying that the word “gene” has acquired so many senses as to be almost meaningless.^[30] What is your own working definition of a “gene”?

Denis Noble

I agree that we now have so many definitions of “gene” that some even question the utility of the concept. Wilhelm Johanssen (1857–1927) introduced the word (“Gen,” in German) in 1909 as essentially a Mendelian factor. Anything (“ein etwas”) that determines the phenotype. That was an interpretation of Mendel’s discoveries that meant that a “gene” necessarily exists when a phenotype trait obeys Mendel’s laws. Of course it was assumed that it was to be found somewhere in the organism.

The modern definition is a particular DNA sequence with start and stop codons. These definitions have very different consequences for evolutionary biology.^[31] Many evolutionary biologists slip easily between the two. That doesn’t work. To take just one example, I may be selfish at a phenotype level, but my selfishness would depend on my genes (and their products, proteins and RNAs) being cooperative. I try to distinguish clearly between the various definitions to avoid the pitfalls of confusing them.

TheBestSchools

How has your work in physiology led you to challenge the “genocentrism” of mainstream biology and evolutionary theory? What is the best way to think about the relationship between genes and organisms?

Denis Noble

Yes, that is how I got back into working on evolutionary theory. The sequencing of the genomes of many species has greatly illuminated our understanding of evolutionary biology. But it has not led to much success in enabling the development of new therapies. Even the leaders of the Project admit that the outcome has been disappointing.^[32] In fact it has been disastrous. The output of the pharmaceutical industry has declined to become pitifully small while the investment has ballooned enormously.^[33]

The reason why it all went wrong is that genes do not fit what was expected of them. Very few ailments indeed depend on a single gene. Most are complex interactions involving many components in networks that extend in the body well beyond the genome. Moreover, the correlations of illness with life-style and family history are far stronger than any correlations with the genome. People thinking of buying into commercial organizations that promise the advantages of genome sequencing should reflect on that fact. You can get better prediction at far lower cost.

TheBestSchools

We have all read about the recent “epigenetic” revolution in our understanding of the workings of gene expression and inheritance. Another similar development is the flowering of the field known as “evolutionary developmental systems theory” (“evo-devo,” for short), in which evolutionary changes are derived from changes in the trajectories of the developing embryo.

These developments are widely seen as “extending” the neo-Darwinian synthesis, rather than rivalling it or overthrowing it.

What is your view of epigenetics and evo-devo? How do your own ideas relate to these new bodies of research? Just how radical do you think they really are?

Denis Noble

It depends on the trans-generational inheritance of epigenetic changes. Since that underpins new forms of Lamarckian evolution (function influencing variation), it is clearly incompatible with neo-Darwinism and is therefore a radical change. There are neo-Darwinists who claim that it is compatible,^[34] but I think that is going too far from the original definition.^[35]

TheBestSchools

Would you say that your criticism of neo-Darwinism (the Modern Synthesis) is primarily conceptual, as in for example your recent paper in the Journal of Experimental Biology?^[36] Or would you say it is primarily empirical? And how do those two things relate to each other?

Denis Noble

They necessarily go together. As an example, if the Weismann Barrier were really shown to be watertight, it wouldn't even make sense to talk about the genome as “an organ of the cell” responding to the environment, to quote Barbara McClintock.^[37] One of the problems with the hardening of the Modern Synthesis during the mid-twentieth century is that it made it difficult both to think that certain experiments (e.g., on Lamarckian forms of inheritance) were worth doing and, even if one thought they were, there wouldn’t be funding to do so. Many of the problems with neo-Darwinism arise from the misuse of language and the influence that has on our thought patterns. That is why I wrote the J Exp Biol paper. But many of my other papers deal with the empirical evidence for changing our ideas on evolutionary biology.

TheBestSchools

You recently co-edited a special issue of Interface Focus,^[38] a journal dedicated to exploring the “interface” between physics and biology (according to one dictionary definition, an “interface” is “a point where two systems, subjects, organizations, etc., meet and interact”).

One of your co-editors was George Ellis, a well-known physicist specializing in cosmology and complexity theory. You obviously represented the other—the biology—side of the “interface.” But there was also a third co-editor, namely Timothy O’Connor, a distinguished analytical philosopher specializing in philosophy of mind, the philosophy of action, and the philosophy of religion.

We are very curious about how this collaboration went. Do you find it fruitful to interact with philosophers? What do you think they have to bring to the table in important scientific disputes like the one surrounding the adequacy of the neo-Darwinian explanatory framework? Would you recommend more collaborations of this sort between scientists and philosophers?

Denis Noble

I have been interacting with professional philosophers ever since I gatecrashed Stuart Hampshire’s graduate philosophy class at University College London 57 years ago. I first published in a professional philosophy journal 49 years ago. The professional philosophers I have seriously interacted with since include R.M. Hare, Charles Taylor, Bernard Williams, Alan Montefiore, Anthony Kenny, Peter Hacker, Bryan Magee, Daniel Dennett, and Jos de Mul. There are many more. One highly respected British philosopher acknowledges me as a philosopher of science, in addition to being a practicing scientist, while another recently completely mistook me for being only a professional philosopher. It seems to run in the family. Like my brother, Raymond Noble, with whom I share many views on evolution, I am an academic chameleon.

Such interaction used to be much more common. The world of science today makes it very difficult. This is unfortunate. As the great French physicist and polymath Henri Poincaré (1854–1912) remarked a century ago, those who claim they are not philosophers make the worst conceptual errors.^[39] They don’t even see the conceptual holes into which they fall.

TheBestSchools

Why do you think the interpretation of evolutionary biology raises such passion, and even anger?

Denis Noble

Two opposing sides became entrenched into dogmatism: the creationists on one side and the neo-Darwinists on the other. It is as simple as that, a kind of war of religion, since dogmatic science shouldn’t exist. When it does it becomes a faith rather than a science. Faith wars almost invariably engender anger and cruelty. Remember the cruelty of the Crusades.

TheBestSchools

We see from your website that you have been traveling the world (including China) giving lectures about your anti-reductionist view of life. We are curious to know what sort of reception you’ve been having.

Are you finding that your audiences are more open to your message than they used to be? What about the Chinese, in particular—how willing are they to entertain new ideas about the nature of life?

Denis Noble

In many parts of the world the clash between creationism and dogmatic neo-Darwinism doesn’t have anything like as much impact. Many religious traditions find evolutionary biology to be no challenge to them. Buddhism in Tibet, Japan, China, Korea, Thailand, Burma, Vietnam, Sri Lanka, as well as the original religions, such as Shinto, simply don’t have a problem. The only times I have encountered problems with discussing ideas of evolution in those parts of the world has been where strongly fundamentalist forms of western religions have penetrated South and East Asia.

I have argued elsewhere ^[40] that part of the reason is that these are religions in which ritual and practice are much more important than belief systems. It is for that reason that many Buddhists, for example, argue that their tradition is not a religion. I have also found that in my interactions with the Dalai Lama and other leading Buddhists they are wide open to the findings of empirical science.

TheBestSchools

Recently, you have been involved with a number of like-minded scientists in launching a website devoted to spreading anti-reductionist ideas about the nature of life. It is called the Third Way of Evolution.

Could you tell us a bit about how this project came into being? What was your role in it? Besides you, who else was involved in founding the website? What does your group hope to achieve?

Denis Noble

I have interacted with many evolutionary biologists, representing both old and new views, and over many decades. A recurring theme amongst those who question aspects of neo-Darwinism, whether proposing extension or replacement, is that they often experience frankly insulting remarks from some of the more dogmatic neo-Darwinists (I emphasise that this is not true of all neo-Darwinists by any means) and that they have much greater difficulty getting articles published.

When James Shapiro and Raju Pookottil told me of their idea to launch a Third Way of Evolution website, I readily agreed. I therefore became one of the three founders. When I meet with those (more than 50 now) who have joined it, I find that they are very pleased that we took this initiative.

It also establishes a very important point. Criticism of neo-Darwinism should not be taken to mean support for creationism or intelligent design. We have put a marker down. It is now much easier to dissent, without being accused of supporting creationism or intelligent design. That alone makes the initiative worthwhile.

TheBestSchools

On the homepage of the Third Way website is the following statement:

It has come to our attention that THE THIRD WAY web site is wrongly being referenced by proponents of Intelligent Design and creationist ideas as support for their arguments. We intend to make it clear that the website and scientists listed on the web site do not support or subscribe to any proposals that resort to inscrutable divine forces or supernatural intervention, whether they are called Creationism, Intelligent Design, or anything else.

I would like to play Devil’s Advocate for a moment, and ask you to support this claim further. After all, in the minds of a great many people, “teleology,” “intelligence,” and “design,” as they are manifested in biology, are pretty nearly three names for the same thing.

Therefore, could you please expand on the difference, as you see it, between your approach to teleology in biology and that of the Intelligent Design people?

Denis Noble

This naturally follows on from the previous answer. My view is that teleology is alive and well in biology because organisms clearly have goals, including feeding and reproduction, and the natural intelligence to realize them. Moreover, it is just as easy for biologists to test theories about goals in organisms as it is for engineers to test such behavior on man-made systems.

The work of English physiologist William Harvey (1578–1657) on the circulation of the blood made it possible to understand the purpose of the heart and circulation and led to the search for capillaries. Good teleological theories have precisely such valuable outcomes in experimental science.

The difference from creationism and intelligent design is that we think that evolution has produced organisms with purpose.

TheBestSchools

You have spoken of the “beguiling” nature of the mainstream, reductionistic interpretation of evolution that we find in neo-Darwinism.”^[29] You have also said that “it is almost impossible to stand outside it.”^[29] We have two questions for you in this connection.

First, why do you think the neo-Darwinian view is so beguiling? Why are so many people so attached to the notion that they are “nothing but” animals, and that living things are “nothing but” the atoms and molecules that compose them?

We would have thought this view of things would be depressing, but we have the impression that many people would rather undergo any degree of intellectual contortion than relinquish their cherished adherence to the mechanistic and reductionist neo-Darwinian worldview.

Denis Noble

Neo-Darwinism is beguiling and convincing because it was developed by some of the best biological minds of the twentieth century and has been popularized by extremely clever writers who, themselves, felt that they were on a mission to convince the world of the insights of their science. They succeeded. Their theories thoroughly permeate the social sciences (sociobiology, and game theory models in economics and sociology), politics (neo-conservatism), literature (which freely uses their colorful metaphors), politics (the Cold War divide was partly buttressed by polarization over Lysenkoism—in my view a very bad version of Lamarckism), and so it goes on. I simply don’t know of an area of human endeavor that has not been influenced.

Is it depressing? I quote the ending of a review of The Music of Life (PDF) by the distiguished Dutch philosopher, Jos de Mul:

Noble offers a powerful antidote to the nihilism of Dawkins. Although Dawkins writes on the last pages of The Selfish Gene that man is the only creature to rebel against the selfish genes, how [would that] be possible in the light of the reductionist determinism which permeates the preceding two hundred pages of his book [and] remains completely unresolved[?]

That reassuring incantation is not always received by Dawkins's readers. I had to think about it when I read the interview that the well-known Dutch author Joost Zwagerman gave to HP/De Tijd four days before his self-chosen death. Referring to a statement by Nietzsche, he says that the thought of suicide for a long time gave him consolation during bad times in his life. But that comforting character completely disappeared when his father undertook an attempt to take his own life. From that moment his life was dominated by the fear that he and his children and future grandchildren would be genetically predisposed to commit suicide.

Of course, I do not claim that the neo-Darwinian view of man alone drove Zwagerman to suicide. The failure of his marriage, the incurable, very discomfiting and painful ankylosing spondylitis, and recurrent depression will undoubtedly have also played an important role. Again, it is always a combination of elements in life. But the idea of genetic predestination found in books like The Selfish Gene seems to me very likely to have played a role.

I don't think I need add anything to Jos de Mul’s remarks.

TheBestSchools

Second, what does it take to break the charm?

This issue is of enormous public significance, especially for the way we view moral and legal responsibility, but also in medicine, in politics, and in other domains of public life.

What is the best way to help the public to see that the mainstream reductionist view of life, however beguiling, is not nearly so well supported scientifically as they think?

Denis Noble

My belief is that those of us who think differently need to try at least to emulate the literary skills of the popularizing neo-Darwinists. That is why I wrote The Music of Life, and why I have written a new book that goes much further than the earlier one: Dance to the Tune of Life: Biological Relativity, in the process of production by Cambridge University Press.

TheBestSchools

One of the terms you use to describe your own alternative position is “biological relativity.” Could you explain to us, briefly and in non-technical terms if at all possible, what you mean by this phrase?

Denis Noble

This is one of the themes of the new book referred to above. Briefly, the central problem with neo-Darwinism, as with reductionist biology in general, is that it makes some (usually hidden) metaphysical assumptions. To quote James D. Watson:^[41]

There are only molecules—everything else is sociology.

To many people, not only scientists, this now seems almost obvious.

I was not myself immune from this feeling. When I first read Dawkins's The Selfish Gene I thought, “Wow, are we really determined by a set of molecular sequences that work inside us like viruses?” It feels almost creepy until you get to the last chapter, when Richard makes some important and revealing disclaimers. You get drawn in by the colorful metaphors, greatly helped by the ease with which the reductionist story can be told. Complexity is much more difficult to expound to a general audience.

The more I thought about this, the more I realized that it would take a root-and-branch approach to counter it. 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. By doing so, neo-Darwinism automatically excludes teleology, because there is no form of life at that level. DNA alone is dead. The Theory of Biological Relativity also challenges a metaphysical assumption in the gene-centric approach. This is that, because there can be no purpose at the molecular level, there can be no purpose anywhere. Blind chance is seen here as the “real” underlying nature of the universe. That view is supported by the feeling that, at the lowest scale, the fundamental particles cannot conceivably have goals or intentions. But there is also a further assumption, which is usually unspoken. This is that if the elements cannot have goals, then nothing else in the universe can do so. There is no room in this interpretation for purpose.

Purposive behavior arises precisely because evolution enables it to do so. The nihilist version of neo-Darwinism therefore denies evolution’s own major achievement, the creation of purpose!!

And, by the way, instead it attributes (metaphorically?) the missing purposiveness to genes. They alone are allowed to have a goal: to be selfish. The rest is a throwaway.

TheBestSchools

Nonlinear dynamical models of biofunctions have been dismissed by some observers as “phenomenological,” meaning they may simulate aspects of the behavior of biological systems more or less well, but they do not make contact with the underlying causal processes—i.e., the chemistry and physics—and thus ultimately have only limited explanatory value.

Others, like Stuart A. Kauffman,^[42] Gerald H. Pollack,^[43] the late Mae-Wan Ho,^[44] Alexei Kurakin,^[45] and others have counseled a far more radical approach based on “collective phenomena” arising out of the condensed-matter-physics properties of “the living state of matter.”

What do you make of such proposals? Do you see them as a promising avenue of research? Or is all of this a bridge too far, in your opinion?

Denis Noble

I think that challenging the idea of privileging the molecular level is enough. Everything else in my work flows from that.

TheBestSchools

In closing, we would like you to tell us—in bulleted list format, if you like—what you consider to be the five strongest arguments in support of your view that “neo-Darwinian is not enough,” as well as the five weakest arguments that supporters of neo-Darwinism commonly advance.

Denis Noble

Neo-Darwinism is not enough because:

1. 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.

2. It doesn’t 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.

3. It has had profoundly damaging (even if not intended) consequences in sociology, economics, politics, and many other areas of the humanities and social sciences.

4. It 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.

5. Its claim to parsimony. Nature simply isn’t parsimonious.

I believe that those five points answer both questions. But let’s try to formulate the other five:

1. 

   Crest of Royal Society of London (founded 1660), showing motto

   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.
2. 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.

3. 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.

4. Neo-Darwinism is obvious and necessarily true (often advanced by Dawkins, as in the debate with Margulis). If it were, it would become a tautology and not open to experimental verification. Not much good as a scientific theory.
5. It was formulated by some of the greatest scientists of the twentieth century, so it must be right. Nullius in Verba! ^[46]

TheBestSchools

Finally, what are your plans? We take it you are still actively engaged in research: What can share with us about your current projects? May we look forward to another book for a general audience, at some point?

Denis Noble

As to active research, I am trying to lead the way back into investigating natural products in healthcare. The failure of the Human Genome Project to produce more than a handful of successful medications compels us to look elsewhere. Remember, too, that about half of the drugs in Western pharmacopeias came from natural products. The latest Nobel Prize for Physiology and Medicine was awarded for this kind of work—to Tu Youyou, in China.^[47]

The new book for a general readership, Dance to the Tune of Life: Biological Relativity, is already with the publisher!!

TheBestSchools

We look forward very much to reading it!

In the meantime, on behalf of ourselves and our readers, we would like to thank you for sharing your time and your thoughts with us. We also look forward eagerly to the Focused Civil Dialogue between you and David Sloan Wilson, to appear in this space over the next several weeks.

Notes