Shadowing Practice: "What is life"-lecture: Denis Noble - Learn English Speaking with Video

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Well, thank you very much, Peter, for that introduction.

And let me say what a huge pleasure it is to come back to the Karolinska Institute.

The last time I was here I think was about three years ago for a meeting on systems, biology and cancer.

You know, I'm always asked to talk about subjects about which I have no right to claim any knowledge whatsoever.

Interestingly enough at that meeting I think quite a lot of other people thought exactly the same.

We had a very interesting meeting.

What I'm going to do today is to address Schrodinger's question,

which of course was the question, what is life?

those

lectures were given in 1943 at the Dublin Institute of Advanced Studies

and they were of course the lectures in

which Schrodinger first made his famous prediction that the genetic material would be what he called a non-periodic crystal

I still, and I think many others do too, still think that's an extremely good description,

of course, of what was eventually found in the DNA.

He also, though, drew a comparison between, on the one hand, physics, and on the other hand, biology.

And his idea in that book was that they were really very different.

because physics deals with order emerging from disorder.

You have the disorder of the random movements of the molecules of a gas, but you also have the order of the gas laws and of thermodynamics.

By contrast, he argued, biology is about order from order, because where is the order down at the low level,

it is in that aperiodic crystal.

And I think his idea gave rise, of course, later on, or helped to give rise,

to the interpretations that were made of the early results in molecular biology of DNA

when the double helix was discovered and when people began to work out what the coding was between DNA and proteins,

which was to lead to the idea that there was, in a sense, in the DNA, a determinant program.

So unlike physics, you would go from particular events in molecules to particular events in the global property of the organism,

that is, the phenotype.

Now, of course, it's a hard thing to say that perhaps Scherzinger was wrong, but I think he was.

And I would like to substitute that, the view that I and many others now express about biology,

and it's certainly expressed in the book The Music of Life,

which is that indeed physics deals with order from disorder,

but biology also must most of the time do the same

because what do we find down at the level of the individual gene expressions?

We find stochasticity.

If I take the gene expression levels in the ventricular cells of one region of the heart

and compare them to the expression levels of those genes in an adjacent region of the heart,

I will find that they vary.

Now, of course, they vary to some extent according to the anatomy of the heart, and that is both well known and is also important in the functioning of the heart.

but they also vary stochastically, even between neighboring cells.

Stochasticity, therefore, has to be a feature of biology as well as order.

Of course, we have a little bit of a dilemma, which I'll refer to a little bit later on,

which is that we know well that there are certain changes that occur down at the molecular level,

particular mutations which will produce or be the cause of a major change in function at the level of the phenotype.

But what has emerged in the research that's been done over the last decades is that those cases are actually quite rare.

I find that in my work on the heart.

There are certain modifications, certain mutations of particular ion channels that can produce a catastrophic situation predisposing towards arrhythmia.

But most of the time, the heart works perfectly well, just as the pancreas does, just as the brain does,

despite all the variations that occur at the lower levels.

So why should a physiologist be concerned about the question, what is life?

First of all, to be concerned with that, you have got to be concerned with the central theory of biology

or the central story of biology because I think that what we call evolutionary theory is actually a story,

it's a history, which of course is the central idea

without which any form of discussion of the question of what is life can't make sense.

moreover the dominant theory of evolution over most of the 20th century and into this century was of course the modern synthesis

sometimes called neo-Darwinism and

that of course was a gene-centered theory of evolution with its determinate idea of there being a program

that leads to the development of the organism

but in fact organisms are extremely good at immunizing themselves from

variations in their genomes we're going to look at a few examples of

that in just a moment and some of the examples are discussed in

that article in the Royal Society's new journal Interface Focus

let's just give a little bit of background from my own work

as the introducer said I was responsible for working on some

of the early discoveries of ion channels in the heart and

that led me to put this model of rhythm in the heart together in 1960.

Here's the electrical potential showing rhythm that emerges as a cell property not a molecular property from the interactions

between the various ion channels.

In those days, we actually thought there weren't many more channels than there are in nerve.

A sodium channel, two potassium channels, and a background leak.

We now know there are many more.

And in fact, later on, if we go now through to about 25 years later,

in work that I did with Dario Di Francesco, we found there were many, many more potassium channels than we thought initially.

And of course, by that time, Harold Reuter had made his great discoveries of calcium channels and of sodium-calcium exchange.

We were also responsible in the work with Dario Di Francesco at discovering a new non-specific cation channel,

which is responsible for this phase of the rhythm, and also for clarifying the role of the sodium-calcium exchange.

Now, that's all technical detail and I don't want to dwell on that.

What I want to do is to use that model to perform a very interesting experiment.

So what we're going to do is to use a version of

that model that was developed for the natural rhythm generator of the heart, which is the sinus node.

and I'm just plotting two of the channel properties,

a background sodium channel and the non-specific cation channel that I referred to earlier.

This one normally contributes about 80% of the depolarizing current.

It is therefore the rhythm generator, if you like.

And as you knock it down, you can notice 20%, 40% all the way to complete knockout.

You might expect a very large change in frequency.

In fact, the change in frequency is very modest, only about 10%.

And what is happening, of course, is the system is allowing this other mechanism to kick in and to keep the rhythm buffered,

as it were, from the change at the lower level.

And you can even use the physiological interpretation of what is going on to work out what is happening

because if you draw a line along those voltage traces,

you can see that the traces at this end are moving into a more negative range of electrical potential.

And it's precisely that that activates the other channel to kick in and to keep the rhythm fairly constant.

And that is a general property of cardiac rhythm.

It's a general property of other rhythm generators too, for example, of circadian rhythm.

There are backup mechanisms.

Many more examples of what you might call knockout that don't actually succeed in producing a very large phenotypic effect.

This is from some work, again fairly technical detail, but I won't dwell on the technical detail other than to say

that a targeted knockout done in experiments first and then by simulation reproducing the experiments of Ken Philipson,

targeted knockout of the sodium calcium exchange produces almost no change in overall electrical function.

Now, is this a specific property of some of Dennis Noble's work on the heart or is it general?

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I was delighted therefore when I saw this systematic study by Hillenmayer and his colleagues in yeast working

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through the 6,000 genes and producing what they called a chemical genomic portrait of yeast.

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What did they find?

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Genetic buffering is general.

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80% of the knockouts are silent under normal physiological conditions.

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That doesn't mean to say that those genes don't have a function far from it.

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They do code for a protein.

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That protein is produced.

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of course what you have to do if you want to reveal that function is to stress the organism

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for example with metabolic stress

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and then you can begin to reveal the function there are many more examples I won't dwell on

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that other than to say that if you want to understand regulators in biological systems

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which is part of an answer to the question what is life life is a regulated process

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then you don't get that most of the time from knockout experiments.

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As I said earlier on, sometimes you do.

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Biology therefore is a mix.

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Occasionally it is order from order

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but often it is also order from disorder in a sense

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just like physics though I think there are some important differences as well.

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For those who want to follow up on that question and this lovely article in bio-essays is worth reading.

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So what is going on?

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And here I want to also digress a little bit on the concept of a gene, because I think two things are going on here.

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First of all, extensive buffering of organisms against genomic change.

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that's now documented I think sufficiently well to say that it's a fairly general phenomenon

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but there's another major concept that I want to introduce

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which is that the concept of a gene has changed

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and changed in a very significant way indeed

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and it's central to understanding what is wrong with current evolutionary biology theory that is the neo-Darwinist theory.

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The way I explain this is to say that we have DNA, obviously, we have a phenotype.

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Of course, it's a bit artificial to draw complete distinctions between the two.

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As I will quote with Barbara McClintock later on, the DNA is also, after all, a part of the phenotype.

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But I think we all know what we're saying here.

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Here's the genetic material in the sense that the molecular biologists would use that term today.

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Here's the interaction with the environment.

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Here is, if you like, the complete phenotype.

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And what we know is, of course, that all of these interact in bidirectional ways.

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That's also important with the biological networks, the signaling pathways, the filters, the conditioners, and so on,

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which actually generate the function.

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If we want an answer to the question, therefore, what is life?

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it's inside here.

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If I take the DNA out of a cell, if I could do just that and put it into a Petri dish,

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I could keep it for 10,000 years and it would do nothing.

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It's the rest of the system of course that tells the genome when it wants to make particular proteins.

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It's the rest of the system that gives the dynamism.

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Now I come to the point about the definition of genes When Johansson in 1909 first introduced the word gene,

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of course following in the footsteps of Mendel, who didn't use that word but he had exactly the concept,

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what he actually meant was a discrete inheritable phenotype.

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What we now mean of course by a gene is a particular stretch of DNA.

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Now the important point I want to make is that not only are those two definitions not the same,

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that's obvious from the fact that this only includes this part of the diagram, whereas this includes the whole diagram,

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they are conceptually different too.

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Because Johansson's definition is all-inclusive.

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He actually says that in his article.

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He says, it's a something.

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it doesn't really matter whether it was DNA or not of course they did not know about DNA at that time

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incidentally Richard Dawkins uses exactly the same definition most of the time as Johansson

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he also says it is as it were a general concept it is if you like a catch-all concept

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but of course the problem with catch-all concepts that say and include everything is that they can't be tested

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it is a necessary truth

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a conceptually necessary truth that a gene defined in this way as the cause of a particular phenotype characteristic is just that,

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it is the cause you don't ask the question, is it a cause it is so by definition now, the situation of course with the definition of a gene

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that is done in terms of a DNA sequence is that precisely that question can be asked

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There is an empirical question to be settled, which is, does that particular piece of DNA have a big effect on the phenotype?

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You can perform that experiment with the kinds of knockout experiments that I've already described.

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So the difference is fundamental.

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Now, where is the deep problem in the neo-Darwinist thesis,

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particularly as expressed by people like Richard Dawkins in popularizing it.

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The problem lies here, that if you want to distinguish clearly and unambiguously between the replicator,

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which is of course the DNA, and the vehicle, which of course is the organism that carries the DNA,

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then you must use this definition of the gene.

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If you use this one, the one that Johansson first introduced then it doesn't make sense to draw a distinction between the replicator

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and the vehicle because this definition includes much more than the DNA and I don't think that point has been properly appreciated.

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In relation to knockout experiments of course to represent the fact

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that most knockouts and mutations are buffered

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but knocking out just one gene may not get through to the phenotype

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because it gets absorbed as I showed in those computations

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but also in the experiments on which they're based a bit earlier

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but two of course may be enough to get through

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or you may need to do three who knows that's a matter open to empirical investigation

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so I want to turn now to a few other aspects in which the answer to the question what is life

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taking particularly evolutionary biology as absolutely central to that question and to answering it properly

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poses today some very big problems

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but what we need to do is to first go through a very brief history of evolutionary biology

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And I start by going back just over 200 years to Jean-Baptiste Lamarck, who published the Zoologie Philosophique,

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his great work in 1809, exactly 50 years incidentally before Darwin's Origin of Species.

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Jean-Baptiste Lamarck actually invented the term biology he was one of

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those who first as it were therefore defined our subject as a separate subject from other natural science subjects

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but he also did something else which is very famous he certainly espoused and popularized and used

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the theory that there was inheritance of acquired characteristics.

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And many of you will know that, of course, it is a clear feature of the modern synthesis

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or of neo-Darwinism that that process is excluded for reasons I'll come on to a little bit later.

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Darwin, of course, published his Origin of Species in 1859, proposed, of course, the theory of natural selection.

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of course neither he nor Lamarck or anybody else at

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that time had a theory of genetics and heredity in

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that sense they didn't know of Mendel's work until it was rediscovered later now an important point to make

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Darwin also assumed the presence

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and function of the inheritance of acquired characteristics it's present in the origin of species in 12 different places unambiguous,

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all documented incidentally by Ernst Mayer many years ago in his great book Biological Thought in 1982

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further Charles Darwin in I think it's the fourth edition of

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The Origin of Species specifically praises Lamarck as this great biologist who championed the idea

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that there was transformation of species originating from a common ancestor

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Darwin was not a neo-Darwinist that's a very important message we'll come on to the significance of

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that a bit later on so what gave rise to neo-Darwinism?

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what gave rise to neo-Darwinism was of course the work of Weissman who introduced the idea

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which we now call the Weissman barrier that is the specific exclusion of the inheritance of acquired characteristics.

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And the idea was, of course, that the inherited material, wherever it was, and of course he didn't know where it was at that time,

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is immune from the rest of the system.

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The rest of the system, however it develops in the lifetime of an individual, cannot influence the genome, as we would now call it.

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And of course that later became encapsulated in Francis Crick's idea of the central dogma of molecular biology.

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let me just also make a brief explanation at this point in the paper in

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which he defines the central dogma in 1970

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Crick was actually very careful he referred to the fact

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that of course DNA sequences code for protein amino acid sequences

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but amino acid sequences do not code for DNA sequences In that sense, there is a unidirectional flow of information.

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But he did not make the mistake, which was made later by Dawkins and many others,

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of assuming that that meant that no information passes in the other direction.

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And of course, if you ask the question, what makes your heart cell different from your pancreatic cell, different from your liver cell,

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It is precisely the passage of information from the system onto the genome

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to tell the genome to make a completely different pattern of gene expression in a heart cell, a pancreatic cell, a liver cell, a bone cell, and so on.

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So we know already, even just from that observation alone, that there must be information passing the other way.

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We'll come on to the significance of that also a little bit later.

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all of this was put together by Julian Huxley, Fisher, Haldane, Sewell Wright and others

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to form what was called the modern synthesis and it's the modern synthesis

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that is often also called neo-Dawinism now let's look at the popularisation of it in the selfish gene

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I should say that I've interacted with Richard Dawkins on these issues now, ever since he published The Selfish Gene.

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In fact, I've interacted with Richard Dawkins even before he published The Selfish Gene.

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What is it?

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It is, of course, a gene-centered view of natural selection.

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That is what the modern synthesis is.

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Accumulation of random mutations.

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By random here is meant not related to function.

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Random compared to function then followed by selection.

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That means, incidentally, that physiological science has nothing to say about the variation in genetic material.

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Very important, because we'll see that that view is actually wrong.

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Then the impossibility of the inheritance of acquired characteristics, a view, of course, inherited initially from Weissman and the Weissman barrier,

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and then later on buttressed and supported by the more popular interpretations of the central dogma of molecular biology.

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Now, I say that's miscalled Lamarckism because actually,

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if you look at the history of the idea of the acquisition of characteristics that can be inherited,

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that idea was not Lamarck's invention.

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Many others before Lamarck had said the same thing.

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Lamarck, like Darwin himself, just simply assumed it.

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They didn't invent it.

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Neither of them did.

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The other point that I've emphasized earlier on is the distinction between the replicator genes and the vehicle, the phenotype.

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And notice what I said earlier on, I'll just repeat it now.

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The only way in which that distinction can be clear is if the gene is defined as DNA, as what we would now today call the replicator.

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So the vehicle is separate from the replicator.

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If, as Richard also does,

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you see, you define gene to be the original definition by Johansson and implied, of course, by Mendel, though he didn't use that word,

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then you cannot make that distinction.

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There's no way of having it both ways.

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You either define genes in terms of the DNA replicator, and then you have a clear distinction between replicator and vehicle,

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or you define genes in the way that Johansson originally did in terms of phenotype

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and then you can't have such a clear distinction.

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And as I said earlier, these ideas were buttressed by what I would call misinterpretations because I don't think they were intended by Francis Crick,

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misinterpretations, the central dogma of molecular biology.

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Now, the main point of my talk today on the question, what is life, is that to answer that question we have to realize

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that all of these rules have now been broken in ways that I'll just go through.

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First of all, are mutations random?

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The answer is no, and by a very long way.

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In his book recently published, the book by Jim Shapiro in Chicago, Evolution of You from the 21st Century,

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writes it's difficult if not impossible to find a genome change operator that is truly random

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in its action within the DNA of the cell where it works.

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But I want to go a bit further than Jim does.

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Jim documents with very, very many examples from the empirical literature,

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scientific literature, the non-random nature in the sense that there are hot spots in the genome,

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there are great big reorganizations of the genome whole domains as we'll see in a moment

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that have shifted around in the course of evolution

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but I think he fails to make an important distinction

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which has to be added to this which is the big question

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the big question that should worry the neo-darwinists is some of

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that non-randomness functional in other words can the functional state of the organism influence the DNA

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and we'll see in a moment that it can

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he also makes the point which I want to emphasize that

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if you look at what emerged from the first sequencing of

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the human genome you find a very interesting fact for two major classes of proteins transcription factors

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and chromatin binding proteins the evidence is

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that they could not have evolved one mutation at a time in a gradual way as the

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is in accord with the spirit at least of the modern synthesis or neo-Darwinism.

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This diagram is a little bit technical so I'll just go through it very, very quickly.

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All you need to know is

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that these are representations of particular proteins in different organisms all

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the way from yeast through worm through to the human and the stars that I'm going to put up now

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are whole domains, that is long stretches of DNA that have clearly moved around in the course of evolution as whole domains,

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not gradual accumulation of mutations, point mutations or small mutations.

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And as you can see, there are many of them.

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And the same is true for the other class of proteins that they studied.

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So proteins, not all of them anyway, did not evolve just via gradual mutation.

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Something is enabling the system to reorganize the genome.

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So the question I'm going to ask now is what happens in this view to selfish genes.

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And again, I come now to a deep conceptual error.

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the problem with the selfish gene is very simple

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the book is written beautifully

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anybody who's read Richard Dawkins books must admire the skill

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that he has in expressing the view that he expresses and the way in which he uses language

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they're brilliant books but when he was asked the question is selfish,

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in the title of the selfish gene, metaphor by the philosopher Mary Mitchley.

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He wrote back, that was no metaphor.

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I believe it is the literal truth.

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But then he went on to write this very significant qualification.

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Provided certain key words are defined in the particular ways favoured by biologists

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and if you've been thinking about the question what is a metaphor?

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A metaphor is precisely taking a word from one context and changing it and making it perform a new function.

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It is a way, if you like, of redefining a word.

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Clearly, in writing this, he didn't understand the question that Mary Midgley was putting to him, was it a metaphor?

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It clearly is.

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He didn't think it was.

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I wrote about this more recently in an article published in the Journal of Physiology just three years ago, and a quote from it is

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that a metaphor does not cease to be a metaphor simply

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because one defines a word to mean something other than its normal meaning.

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It indeed is the function of metaphor to do precisely this.

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and so at the heart of the neo-Darwinist synthesis at the heart of its popularization

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there are a number of major conceptual mistakes

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first of all a mistake about what is the real definition of a gene

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and it slips between the two according to what the question is

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and you can't do that you can't do that and be logical

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and second because as I show in that article

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but I don't have the time to go through all of

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that in the lecture it's actually impossible to demonstrate any biological experiment that would distinguish the selfish gene theory from any alternative

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and incidentally, curiously enough, Richard Dawkins agrees with that in Extended Phenotype,

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he writes specifically I doubt whether there is any experiment to prove my case.

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So that aspect, at least, of the neo-Darwinist approach to the question, what is life, is simply not falsifiable.

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Now we come to the big question, and the difficult one, can acquired characteristics be inherited?

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I discussed this a number of years ago with John Maynard Smith.

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We were both at the Novartis Foundation Symposium.

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He published a lovely book called Evolutionary Genetics in 1998, and he made a very interesting statement.

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he said John Maynard Smith although he was working totally within

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the neo-Darwinist view he was I think a great thinker and he said in that book specifically

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you know Lamarckism is not so obviously false as it's sometimes made out let's have a look, he was absolutely right although he didn't know

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that at the time there are many examples now those who

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want to go to my Music of Life website will find a page devoted to what are called answers,

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answers to very common questions on this central issue, the theory of evolution and the question, what is life?

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And although I'm just going to give a few examples in this slide, there are many more on that page.

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Weaver's work looking at the way in which you can mark the genome by behavior in each generation.

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and that can work even if nothing goes down through the germline.

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Anway and his colleagues looking at endocrine disruptors where the process does go down through the germline

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and we think probably through inherited RNAs.

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This paper also showing male transgenerational responses in the human.

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Beautiful paper by Yunhua Sun and his colleagues at the Fish Institute in Wuhan in China.

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doing cross-species cloning.

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I'll show that in a moment in another slide.

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And an extraordinary study by Harry Harvey and his colleagues in Cell, published around three years ago,

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showing not only transgenerational inheritance of an acquired RNA-based response,

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but also that it persists for a hundred generations.

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They followed it in C elegans for a whole year.

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the usual reply of neo-Darwinists to these examples is to say the effects die out

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well they don't always die out

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and then they will say well it's rare indeed it is as far as we know at the moment

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but remember also that speciation is rare

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it doesn't have to happen very often it hasn't happened in our lifetimes it hasn't happened in the lifetime of humans

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in fact we've tried very hard with artificial selection of dogs, cats, fish and so on we've produced new varieties but never new species

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so environmentally induced changes can be inherited I think the evidence for

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that as I said is now growing very rapidly go to the answers page on the Music of Life website

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if you want more details I said I'd say what happens in cross species clones

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and then we come towards the end of the lecture

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what Jung Ha Sun and his colleagues did in Wuhan was to take a carp which is this one,

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a goldfish and proceeded to take the nucleus from a carp

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and insert it into the fertilized

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but then enucleated egg cell as the goldfish you should get unambiguously a carp

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if the neo-Darwinist view is correct what you get is intermediate

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this is the result it's one of the few examples where a cross species works in the sense

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that you produce an adult and what it produces is an adult whose anatomy is intermediate between the two

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you can even quantify that if you look at the total number of vertebrae in the goldfish it's about 26

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there is up or down 1 or 2 and the carp is about 33

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in the cross species clone you get a figure in between but it's closer marginally to that of the goldfish.

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There are other respects also in which what they call the inheritance of cytoplasmic information is clearly occurring.

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And I want to come now to one of the greatest thinkers about genetics and their relation to the phenotype.

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I have a lovely picture in my office in Oxford of

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Barbara McClintock at the age of about 81 I think receiving

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the Nobel Prize here in precisely this lecture theatre standing exactly where I'm standing at the moment

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and she was giving of course her Nobel Prize lecture which she received in 1983

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She was of course the person who discovered what we sometimes call jumping genes or mobile genetic elements but she went much,

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much further than that until she was, I'm sorry to say, prevented from publishing.

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From 1953 onwards she no longer published on this issue until, as far as I can recall,

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she was awarded the Nobel Prize in 1983.

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She wrote in that lecture, in the future attention will undoubtedly be centered on the genome

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and with greater appreciation of its significance as a highly sensitive organ of the cell.

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The result of her work on maize was to show her just how labile the material is,

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the genetic material is in response to environmental events.

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And she wrote, responding to those often by restructuring the genome.

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Here we come back to what Jim Shapiro was drawing attention to, that clearly during evolution there have been major restructurings of genomes,

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movements of whole domains corresponding to various proteins.

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So cytoplasmic changes can be inherited,

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and I'll deal, I think I'll jump straight to the next slide just to give one example of how strong

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that inheritance can be.

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This is the article I would recommend reading if you want what I would regard now as the best example of that,

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published by Joe Nadeau's lab at that time in Seattle in PNAS at the end of 2012.

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They write, I won't go through the full details,

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the heritable epigenetic changes persisted for multiple generations and were fully reversed after consecutive crosses through the alternative germline image.

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So my main conclusion, environmentally induced changes can be inherited to the question, are they fairly rare?

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I would give the response I gave earlier on, so is speciation. so

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when we ask the question do we know what the precise

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mechanisms of speciation were I think the honest answer is that we don't know

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not yet anyway

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now I come to my final conclusion

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if functional changes in the adult can be inherited and therefore a target for natural selection

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then the analysis of function is highly relevant to evolution and of course highly relevant to defining the question

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or an answer to the question, what is life?

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Because as I said earlier on, this area of biology is central to understanding the answer to that question.

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I think what I want to do is to leave time for discussion.

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I'll just jump the remaining slides.

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They just simply summarize what I've already just said.

402

And the synthesis that I would propose is shown here that we have to recognize that selection is multi-level,

403

that acquired characteristics can be inherited to quote Barbara McClintock the

404

genome is an organ of the cell not its dictator and that genomes are not isolated from the organism and environment

405

those who want to listen to another version of this lecture it's on the Music of Life website and on YouTube

406

and the article there published just last year

407

in experimental physiology also gives chapter and verse on almost everything that I've presented today.

408

And I finish with this lovely picture that I used right at the beginning.

409

Some of you will recognise the left-hand picture as Conrad Waddington's beautiful picture from the strategy of the genes

410

in which he tried to explain the way in which there is plasticity at the developmental level in the phenotype,

411

which is representing by a landscape here,

412

as a consequence of various gene products interacting in networks that,

413

as it were, are situated between the genome level and the phenotype level.

414

I know that's a bit artificial.

415

We can argue about the exact definition of a phenotype and so on.

416

But he's got the message.

417

He's got exactly the system's approach to it.

418

What happened to Conrad Waddington, he was largely ignored, pushed to one side,

419

just as Barbara McClintock was until she received the Nobel Prize.

420

So my final question is, who pulls strings?

421

In any multi-level set of interactions in any biological organism,

422

the answer is, everything can.

423

if you take a three dimensional network just put together some knitting

424

and make a three dimensional knitting structure you pull any bit of it the whole network changes all networks do that

425

so it doesn't make sense to isolate one part and say

426

that is the cause if you have networks as part of the definition

427

and processes in those networks as part of the definition of an organism

428

then the answer to the question what is life is it lies in those processes in the networks.

429

There is no privileged level of causation.

430

And with that, thank you very much.

431

The end of the lecture.

432

Thank you.

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Vocabulary and speaking notes for this lesson

This C2 speaking lesson is built on the video “"What is life"-lecture: Denis Noble”. This video has 432 sentences and 5866 words to shadow. The speech runs for 43:56. The speaker talks at a steady 134 words per minute, a comfortable pace for shadowing. Only 80% of the words are among the 3,000 most common in English, so the vocabulary is demanding.

Key vocabulary in this video

The 15 most advanced words in the video, with pronunciation and meaning:

Word	Pronunciation	Meaning
genome noun	/ˈd͡ʒiː.noʊm/	The complete genetic information (either DNA or, in some viruses, RNA) of an organism.
phenotype noun	/ˈfiː.nəˌtaɪp/	The appearance of an organism based on a multifactorial combination of genetic traits and environmental factors, especially used in pedigrees.
organism noun	/ˈɔɹ.ɡəˌnɪz.əm/	A discrete and complete living thing, such as animal, plant, fungus or microorganism.
inherit verb	/ɪnˈhɛɹɪt/	To receive (property, a title, etc.), by legal succession or bequest, usually after the previous owner's death.
mutation noun	/mjuˈteɪʃən/	Any alteration or change.
rhythm noun	/ˈɹɪð.əm/	The variation of strong and weak elements (such as duration, accent) of sounds, notably in speech or music, over time; a beat or meter.
knockout noun	/ˈnɑk.oʊt/	The act of making one unconscious, or at least unable to come back on one's feet within a certain period of time; a TKO.
metaphor noun	/ˈmɛt.ə.fɚ/	The use of a word, phrase, concept, or set of concepts to refer to something other than its literal meaning, invoking an implicit similarity between the thing…
synthesis noun	/ˈsɪnθəsɪs/	The formation of something complex or coherent by combining simpler things.
replicator noun	/ˈɹɛplɪkeɪtɚ/	Something capable of self-replication, like a gene or meme.
inheritance noun	/ɪnˈhɛɹɪtəns/	The passing of title to an estate upon death.
characteristic noun	/ˌkæɹ(ə)ktəˈɹɪstɪk/	A distinguishing feature of a person or thing, a part of mental or physical behavior.
incidentally adverb	/ˌɪnsəˈdɛn(t)l̩i/	By happenstance; in a particular case which has little to no bearing on, and little to no causal relation to, any other case.
evolutionary adjective	/ˌiː.vəˈluː.ʃən.ɛɹ.i/	Of or relating to the biological theory of evolution.
sodium noun	/ˈsəʊ.di.əm/	The chemical element (symbol Na) with an atomic number of 11 and atomic weight of 22.990. It is a soft, waxy, silvery, reactive alkali metal that is never…

Phrasal verbs you will hear

Word	Pronunciation	Meaning
go through verb		To travel from one end of something to the other.
come on to verb		To start to.
die out verb		To become extinct.
go down verb		To descend; to move from a higher place to a lower one.
put together verb		To assemble, construct, build, or formulate.
work out verb	/ˌwɝk ˈaʊt/	To calculate.
do over verb	/ˈduˌoʊvɚ/	To cover with; to smear or spread on to.
follow up on verb		To take further actions regarding (something).

Sentences worth repeating

Short, complete lines from the video that you can reuse in everyday conversation:

If we want an answer to the question, therefore, what is life?
I'll show that in a moment in another slide.
I'll just jump the remaining slides.
They just simply summarize what I've already just said.
I know that's a bit artificial.

Grammar in this video

The structures the speaker uses most, with the exact words from the video:

Structure	In the video
Conditional sentences if + clause, will/would + verb — a condition and its result	if you want what I would regard
Present perfect have/has + past participle — a past action that still matters now	has emerged · has changed · I've already described
Passive voice be + past participle — the focus is on what happens, not who does it	were given · were made · was discovered
Relative clauses who / which + clause — extra information about a person or thing	mutations which will · heart, which is · those who want

Pronunciation to watch

The speaker uses 71 contractions and reduced forms, such as don't, I'll, didn't. Say them the short way, as you hear them.

The “th” sounds: rhythm /ˈɹɪð.əm/, synthesis /ˈsɪnθəsɪs/
The “sh” and “zh” sounds: mutation /mjuˈteɪʃən/, evolutionary /ˌiː.vəˈluː.ʃən.ɛɹ.i/, goldfish /ˈɡoʊldfɪʃ/, speciation /ˌspi.siˈeɪ.ʃən/, accumulation /əˌkjuːm.jəˈleɪ.ʃən/
Long words — get the stress right: organism /ˈɔɹ.ɡəˌnɪz.əm/, replicator /ˈɹɛplɪkeɪtɚ/, inheritance /ɪnˈhɛɹɪtəns/, characteristic /ˌkæɹ(ə)ktəˈɹɪstɪk/, incidentally /ˌɪnsəˈdɛn(t)l̩i/

How to practise with this video

Listen to the whole video once without speaking and note the words you do not know.
Shadow it sentence by sentence at normal speed, repeating each one until your rhythm matches the speaker.
Record yourself and compare with the original, paying attention to words like genome, phenotype, organism.

What is the Shadowing Technique?

Shadowing is a science-backed language learning technique originally developed for professional interpreter training and popularized by polyglot Dr. Alexander Arguelles. The method is simple but powerful: you listen to native English audio and immediately repeat it out loud — like a shadow following the speaker with just a 1–2 second delay. Unlike passive listening or grammar drills, shadowing forces your brain and mouth muscles to simultaneously process and reproduce real speech patterns. Research shows it significantly improves pronunciation accuracy, intonation, rhythm, connected speech, listening comprehension, and speaking fluency — making it one of the most effective methods for IELTS Speaking preparation and real-world English communication.

Shadowing technique: read the full step-by-step guide →

Shadowing Practice: "What is life"-lecture: Denis Noble - Learn English Speaking with Video

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