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2024 ✪ Members first on August 5, 2024 Theories of Everything with Curt Jaimungal
Denis Noble is a renowned biologist and pioneer in systems biology, known for his groundbreaking work on the heart and his influential contributions to the understanding of biological systems.
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LINKS:
- Denis Noble's Q&A: • "The Facts Are Clear: Neo-Darwinism i...
- The Music of Life (Book) - https://amzn.to/4drSFSP
- The Selfish Gene (Book): https://amzn.to/3zYLyTx
- Understanding Living Systems (Book): https://amzn.to/3AgLhvt
- Denis’ Article: https://www.nature.com/articles/d4158...
- The Third Way of Evolution (Website): https://www.thethirdwayofevolution.com/
TRANSCRIPT
Denis Noble is a maverick biologist, a fellow
of the Royal Society, and a professor at the
University of Oxford, who spent his career
challenging the fundamental assumptions of
modern genetics. From pioneering computer models
in biology in the 1960s to his current crusade
against gene-centric biology, Noble has never
shied away from overturning scientific orthodoxy.
I'm Curt Jaimungal, and in this lecture for
my series on Rethinking the Foundations,
Noble makes the case that our understanding of
life and evolution is due for a radical overhaul.
One that could revolutionize medicine and
reshape our view of what it means to be human.
Professor Denis Noble, you're one of the
pioneers of systems biology at Oxford University,
and also along with your collaborator
Shapiro, you've spawned a concept called the Third Way of Evolution, which we'll discuss
in the subsequent Q&A. For those of you who are
watching, this is a presentation by Professor
Denis Noble for the series here called
"Rethinking the Foundations of Biology – What
Lies Beyond Darwin?" Denis Noble will be giving
the inaugural talk, and I'm almost uniformly
going to shut my mouth for the next 30 minutes.
And in the second video, which is linked in the
description, we'll delve into the material from this one in the format of a
podcast. Take it away, Professor.
Thank you very much, Curt. It's a
pleasure to come onto your series and
"Rethinking the Foundations of Biology." I love
that title because it's precisely what is implied
by the title I've used for this, Genes are Not
the Blueprint for Life. You can hardly reinvent
Overview of Lecture
the foundations of biology with a more dramatic
title than to show that it doesn't just come
from the genome. But that is, in practice, what I
really think is the case. Now, I chose that title
partly because in February of this year, I
was asked by the top science journal, Nature,
to write an article on precisely this
title, Genes are Not the Blueprint for Life.
And I've also put on this screen not only the
Nature page, but also a little book called
Understanding Living Systems,
which is an attempt in very simple language, lay language, not requiring
much technical knowledge at all, the essence of
what I'm going to say today in this presentation.
So, to give the structure of the talk, I'm going
to argue that since genes are not the blueprint
of life, measuring them and their association
scores with common diseases cannot work.
And I will first explain why that is the case, and
then by concluding by showing that statistically,
it does not in fact succeed, even in predicting
common diseases. Then the second part of the talk
will be, since that approach fails, what is the
alternative that may work? And I think the answer
is to switch to investigating the functional
networks in living organisms that control
the genome and controversially enable it to be
edited. That is supposed by the modern theory
of biology, the modern synthesis, to not be
possible. I'm going to show that it is both
possible and does happen. And I will then
close with two what I think
are very encouraging examples to show that medical scientists, particularly
physiologists, can achieve that. But I want to
start with just a brief explanation of what the
genome is. I'm assuming that the listeners to
What is the Genome?
this program may not be completely familiar
with the technical details of what a genome is.
It's a very long, thin thread of molecules in
all of our cells, and those molecules are called
nucleotides because they reside in the nucleus of
our cells. You don't need to know the technical
names for them. We just call them A, T, G,
and C. There are four types. And in us humans,
the genome, that's the total number of these
nucleotides, it contains three billion of them.
That's a figure that will matter in just a moment
or two. And all of our cells, except red blood
cells incidentally, contain a complete set of the
DNA. Now, the important point to make right from
the very beginning is that as molecules, chemicals
in other words, they can only do what chemicals
automatically do. And what we know is they like
to connect together, to bind together in pairs.
A likes to be with T, G likes to be with C. And
in doing this, they have absolutely no choice.
They cannot therefore be described, as
many modern evolutionary biologists do,
as selfish, selfish genes, either metaphorically
or literally. Only organisms, you and me,
with freedom to choose, can be described sensibly
as either selfish or cooperative. And we all know
that when a baby is born, it is not born selfish,
it simply has needs. It has a need for food,
it has a need for care to enable it to live,
grow, and flourish. And it only slowly learns
that it can choose. Returning now to the
genome, focusing on the sequence of the genome
is a little bit like taking
the pixels for the message.
This is a bit of text from the ending of my
little book, Understanding Living Systems.
We wish them all well. I'll come to that at the end of the presentation.
The main point of this part of the presentation is
that when we look at a message, if we expand
the size of the message sufficiently,
all we can see are the individual pixels.
The message is no longer clear to us.
Is the Genome the Book of Life?
So I want to ask the question, how did the
genome become described as the book of life,
creating us body and mind, as Richard Dawkins
would say in his book The Selfish Gene?
Because if that were so, the conditional logic
of life would have to be found in the genome.
But it's not there.
You see, I'm a computer programmer, amongst other things, because the way I do systems
biology is to model cells, tissues, and organs.
And I know, as a computer programmer, that if
you look for where all of those conditional
expressions are, if this, then that, else
something else, if you look for all of those
control routines that computer programmers
are very familiar with, you won't find them
in the genome.
Now there are switches in genomes.
Every sequence of DNA that is a gene has
another little bit of DNA, which is its switch.
But those switches are controlled by other
physiological processes, not by the genome itself.
So I ask the question, where
are life's control routines?
Well, they're in our cells.
Because our cells, this is a figure
showing a complicated diagram of a cell.
You don't need to understand the details of the diagram.
What you can see, though,
is that it's absolutely packed with structure.
And that structure is formed from what we call
fatty membranes, lipid membranes, with
protein channels in them.
And those routines that control the genome depend
on those protein channels in the lipid membranes.
And those are our conditional
on-off decision processes.
And they're sensitive to electrical and
chemical processes that we experience in life.
Without those membrane processes, there could
not be choice between various behavioral options.
And yet choice is an essential element in any
theory as the ability to be either selfish
or cooperative.
Moreover, all of our nerve cells
have these controllable on-off switches.
So do all the other cells.
But now I come to something that may surprise you.
There are no genes coding for those membranes.
We inherit all of those membrane
structures from the egg cell of our mother.
Every single one of us
depends on that inheritance. There are no genes controlling
and forming membranes.
Sir, before you move on, do you mind briefly
expanding on how membranes come only from
the mother and not the genome?
The important thing about the membranes in
our cells is that there are no genes coding
for membranes.
And yet all of those membrane structures
are inherited in the egg cell of our mother.
You see, when a sperm with its DNA enters
an egg cell, it not only enters the egg cell
to fuse its DNA with the DNA from your mother,
but it also enters a complete cell from the
mother, that is the egg cell.
And that contains, just as all other cells in
our bodies do, all the membranous structures
that get inherited
automatically with the egg cell.
So when, for example, a couple of years ago,
Richard Dawkins told me, Denis, we can keep
your DNA for 10,000 years, and in 10,000 years
we'll be able to recreate you.
I said, no you won't, Richard. And he said, well why not?
I said, where will you find the egg cell
from my mother as it was in 1936 when I was born?
You see, there's no way we can avoid the fact we
inherit the membranous structures, and
those membranous structures are where
all the control of the genome lies.
Now I want to come to some simple proofs
20th Century Gene-Centric Biology is Wrong
that 20th century gene-centric biology, the
idea that genes are the blueprint for life,
that they alone can develop into being us,
is necessarily wrong.
And there are four major dogmas.
First is the central dogma of molecular biology.
I'll explain that in just a moment.
The second is a dogma called the Weissman barrier.
Again, I'll explain that in a moment.
The third dogma is that DNA can replicate itself,
just like a crystal.
And the fourth dogma is that that DNA is separate from its
vehicle, that is, the cell that carries it.
Now I'll just go through these very simply.
The central dogma of molecular biology is
in fact a very simple chemical fact, that
from DNA we make another kind of nucleotide
called RNA, and that enables our bodies to
make proteins.
Proteins are the real driver of
activity in living organisms.
Now that's a simple chemical fact.
DNA forms RNA that forms proteins.
But that simple chemical fact does not prevent
the organism editing and changing its...
genes. What the standard biologists will
tell you is, well, it does prevent that
because you can't go backwards. You can't
go from proteins to make DNA. The point
here is that you don't need to. The body
knows how to control its genes without
that being the case. So first point, the
central dogma of molecular biology does
not prevent organisms changing their
DNA when they need to. The second dogma,
the second foundation stone of modern
evolutionary biology, is the Weissman
barrier. This is the idea introduced
over a hundred and forty years ago by a
geneticist called August Weissman. It's
the idea that the egg cells and sperm
cells in the reproductive organs are
totally isolated from the rest of the
body. So there's no way in which what
my body learns during its life can be
transmitted to the egg and sperm to form
the future generation. Well, I have to
tell you that we now know that little
molecules, they're called control RNAs,
but don't worry about the technical
term. Little molecules that control the
DNA have been shown to communicate
body characteristics, like whether your
metabolism is this way round or that way
round, to the germ cells via tiny little
packets of molecular information. There
is no Weissman barrier. It's not able to
prevent transmission of information
from the body to the egg cell.
And are you referring to
epigenetics here or something else?
Good point. It is to some extent
epigenetic, yes. So the third major
assumption of standard evolutionary
biology is that not only is DNA the
source of everything that's needed to create
us, it also accurately self-replicates.
It doesn't need anything to control that.
Well, it's simply not true. It is true,
coming back now to the four types of
nucleotide, A will attract a T and G
will attract a C. That is true, and
that helps the replication of DNA,
but the error rate of that is such that there
would be hundreds of thousands of errors in the
DNA as one of our cells divides to form
two new cells. And what happens is amazing.
The cells themselves contain the proteins
necessary to cut and paste the DNA and to
correct all of those errors. So the replication
of DNA depends upon that ability of the living
cell, and only a living cell can do that. And the
final fundamental dogma is that the replicator,
that is DNA, is separate from its vehicle,
which is the cell or, if you like, our bodies.
And the fact is that since self-replication
of DNA is impossible in our genomes,
the replicator cannot be seen as separate from
its vehicle. So the correct interpretation of
the molecular biological evidence shows that
all of these four fundamental assumptions of
modern biology are incorrect. So just to summarize
where I've got to in this part of the talk,
Neo-Darwinism is Incorrect
living organisms can change their DNA. And
incidentally, you and I were experiencing
exactly that during the pandemic. How else did
our immune systems be able to change the DNA
coding for what are called immunoglobulins, that's
a long technical term, the part of our immune
system that grabs the virus and neutralizes it.
How is it possible for the immune system to do
that? It's because the immune system, like other
systems in our body, is capable of changing the
DNA. It actually creates millions of new possible
shapes for that protein that captures the virus.
So we know that organisms can change their
DNA, and the central dogma clearly does not
prevent that. And as I said, this is precisely
what was happening during the pandemic.
Second major point in the summary here is
that DNA itself is not a self-replicator.
It needs the living cell to do that. And the
third take-home message from this part of the talk
is that body characteristics can
be communicated to the germline,
that is the future eggs and sperm, via small particles that transmit from the body
to those cells. The Weissman barrier therefore
is not really a barrier. Now why is this
all important? It's important to you and me
Implications for Medical Science
because the great promise 30 years ago
when the Human Genome Project was launched
was that genome sequencing would deliver the
goods that matter, new medical treatments.
The idea was very simple. Find the gene variant
causing the disease, then replace or delete it.
Has that happened? No. It's an embarrassing
answer, with the exception of some rare
monogenetic diseases. Those are diseases where a
single gene can cause the disease. That is true
though only in about 5% of humans. The promise
before genome sequencing was that the big scourges
of mankind, cancer, diabetes, obesity, heart
disease, vascular disease, the various forms
of dementia, would all be solved within 10 years.
of full genome sequencing. Francis Collins,
who was the head of the National
Institutes of Health in the United States, and therefore the head of the Genome Project over
there, claimed in 1999, nearly 25 years ago now,
that within 10 years, and I'm quoting
him, human genome sequencing would lead
to previously unimaginable insights,
and from there to the common good,
including a new understanding of
genetic contributions to human disease
and the development of rational
strategies for minimizing or preventing disease phenotypes altogether.
Well, I have to tell you that the latest
study from a major university
here in the United Kingdom, University College London, published in
the British Medical Journal just last year,
shows that the genome does not succeed in
predicting cardiovascular disease, cancer,
and many other forms of disease.
Sorry to disappoint, Dr. Collins,
but the great promise of the Human Genome
Project has simply not been fulfilled,
and it's not been fulfilled for the reasons
I've already explained in this talk, the foundations of biology are incorrect.
It can't be fulfilled. So, cures for those
diseases have not been found even 20 years
after the first full genome sequencing,
and it cannot happen in the future. And in
fact, the association scores, as they're called,
between the presence and absence
of most genes and the incidence of major diseases are generally very low.
The way geneticists now interpret that is to
say that all genes are involved in life processes.
Very few living processes depend on a single gene,
and those, as I explained
earlier, depend and will occur
only in a rather small percentage
of the population. Most of the time,
organisms manage very well,
even in the absence of key genes
and the proteins that enable them to be made.
I showed that as a systems biologist in the
case of heart rhythm more than 30 years ago.
We showed that if you block a pacemaker protein
or its gene that generates 80% of the rhythm,
shows only a modest small change in frequency.
This is called robustness, and I want
to tell you something very important. Most processes in our living
bodies are robust, and thank
goodness if one part of our system fails,
something else takes over. Most of the time,
the robustness copes with the problem.
And robustness just means a resilience to perturbation? So that is, you
have some grace under pressure?
Yes, it is exactly so. It is
resilience to perturbation. Absolutely.
So to summarize this part of
the talk, DNA sequencing does not reliably predict disease states.
That's been shown now quantitatively,
statistically, by a very important
study from University College London, published in a prestigious journal,
the British Medical Journal.
So why should we bother about what our DNA
is? Well, I'll tell you what it can tell you.
If you buy your DNA sequence from 23andMe
or other genome sequencing companies,
it might tell you who you're related to. You might
find an unknown relative elsewhere in the world,
but don't rely on it to tell you
what diseases you're likely to have.
That will just make you get upset
and anxious when you're told, well, you've got the gene for this kind of cancer.
Nobody can tell you that with confidence that
you will get cancer.
So except for those rare monogenetic diseases, the ones where
somebody has something like cystic fibrosis,
where if you've got the gene variant
that generates cystic fibrosis, you will necessarily get it.
Apart from those, the genome
does not predict what you will die from.
Can the genome state a probability,
though? Can it just say that it increases your
chances of getting a certain disease or decreases?
Yes, that's a very good question, Curt.
Yes, the answer to that question is that it gives
a very small degree of probability, first point.
What the University College London researchers
showed is that if you ask the question,
do we get as many positive predictions for
people as negative predictions for people,
which is what you do when you do a clinical
trial of a drug, for example,
what you expect is that most people will get cured by the drug.
And if so, then it gets to be approved.
If it fails that test and it makes as many
wrong predictions as correct predictions,
then it's obviously not then approved.
Well, what the University College London
team did was to use that same criterion.
Yes, there are some positive predictions.
You've got a slightly increased
percentage of possibility of getting,
say, cancer or heart disease.
But the trouble is that in many other individuals, it predicted just the reverse.
It would actually reduce the probability.
Interesting.
These are the criteria that you use when you test a new
chemical produced by a pharmaceutical company.
And by that criterion, the
Human Genome Project has failed.
Next Steps for Biology
So I ask the question, what do we do now?
Well, I think we have to stop focusing on genes.
What we need to do is to focus
on what actually makes us alive.
And incidentally, that's not genes.
Genes are bits of dead chemical.
What we need to study are the
living processes in our bodies.
I call those the functional
physiological networks. And the study of those is indeed called physiology.
I'm a physiologist, and I try to do this kind of
work. And I think what I'm showing in this diagram
is that we've left great parts of all of that out.
You see, focusing on DNA, RNA, and
protein, that's the central dogma focus,
leaves out the functional networks.
And it's those that are sensitive to the
environment, sensitive to how we feed ourselves,
sensitive to what the climate is doing to us,
sensitive to the social interactions that we have.
And it's these interactions that epigenetically,
as we say, over and above the genome,
influence the functional networks.
That is how we react to our environment
and to the environment of other
organisms. Those are our social interactions.
And therefore, that's what we need to study,
the functional networks. And can we do it?
I'm just going to close with two examples.
They're quite technical, but I won't
bother with the technical detail. I'll just give you the essence of the point.
So, let's first of all get an idea of
how big a cell really is and what the
problem is for communicating from the
environment to the nucleus of a cell.
Well, I've got on this slide a map
of the United Kingdom, with England
there, Ireland there, Scotland there.
And what I'm going to get across to you is
that if I enlarged a single nucleotide to
the size of my fist, perhaps the size of a golf
ball, as we're seeing in this slide, then the
living cell would be the size of a whole country.
If the nucleus were here in Oxford, there it is,
I've ringed it, then the surface of the
cell would be somewhere up in Scotland.
Now I want to tell you, cells can
communicate the two within seconds.
And they do that, so there's a communication
from the surface of the cell to the nucleus via
extraordinary, what are called tubulins, little
threads in the cell that go all the way from the
surface to the centre where the DNA is located.
And messages can go along those tubulin threads.
It's almost as though the living cell is like a
subway, or as we say here in the United Kingdom,
the underground, or the metro in France. It's
got a network of tunnels, literally tubes.
Yeah, I've been to London and
there would be delays, trust me. Now, I just want to mention two major
studies that show that we can identify
how activity at the surface of the cell,
sensing what the environment is doing,
can be communicated to the centre and to the DNA.
This is a study done by one of my former
collaborators, Dick Chen, worked with me 40 years
ago, and now working at New York University.
And he showed how tiny molecules, calcium as
it happens, entering the surface membrane can
create a messenger that attaches itself to
those molecular motors, as they're called.
And the motor goes along the tubulin thread all
the way down to the nucleus and then controls
the very gene that needs to be controlled.
It takes a few seconds to make that journey.
Now, for those who are interested in the detail
of that on the slide, I've included the reference
for those who want to go into the detail.
Not surprisingly, the detail is highly
technical, and you don't want me
to go through that in this talk. The second example is from my own university,
scientists working in my own department here
under a leading scientist called Anant Parekh.
They did it with two surface membrane processes
receiving calcium moving into the cell.
Two different sites creating two signaling
molecules that again travel on those tubulins
rapidly to generate changes in the nucleus
that change gene expression in the way required.
Again, the reference for that for those who want
to go into the technical detail is on the slide.
But I don't want to bother you with
the technical information.
It's difficult to understand. So, I want to finish this talk with a
challenge to the world's scientists.
A Challenge to the World's Scientists
You see, these two groundbreaking discoveries
shows that functional tubulin pathways from the
surface of a cell to the nucleus exist, and
they can mediate changes in gene expression.
I want to know how can the same kinds
of tubulins be used in the same kind
of way to change DNA when the immune system
changes our DNA, or when our nervous system
needs to generate new forms of behavior that
respond better to our social interactions.
I think I can guess that any scientist
who can provide the same kind of evidence
for the way in which that process
occurs ought to win a Nobel Prize.
There's my prediction.
That's what I want to do to finish what I'm presenting here.
I will just summarize that.
First, that medical scientists are already
succeeding in finding the control pathways.
We don't need to worry about whether the
central dogma prevents that from happening.
It clearly happens.
DNA can have... It's activity change, that's
changes in gene expression,
and it can also have changes in the DNA itself. Our immune system can do that. And I finish
by putting out once again the little review
in the top science journal, Nature, that I
published in February of this year entitled
Genes Are Not the Blueprint for Life. Not
surprisingly, it's had a huge amount of attention
because it clearly undermines the basic
assumption of modern evolutionary biology
and biology generally, that somehow
genes are the blueprint for life.
And I want to finish with a message for young
people because I think it will require creative
ingenuity to shift the culture away from
the misunderstandings of the 20th century.
It will be for you, the new generation,
to discover and create your own culture
fit for the challenges of the 21st century. That
will have to include understanding how DNA is
controlled. And you and your colleagues in the
younger generations will have plenty of looming
signposts to warn you what went wrong. It's a
generation that will have to take responsibility
for the way in which the earth ecosystems need
rescuing, even for our own species to survive.
And it will be a generation that faces the
challenge of aging societies, requiring medical
science to find solutions to the diseases of old
age that do not readily yield to gene-centric
solutions, since those diseases are what we call
multifactorial. Only an integrative approach
that understands those interactions, those
networks in living organisms, can possibly
hope to address those diseases. I finish with the
finish statement at the end of my little book,
Understanding Living Systems. It is arguably
a challenge the scale of which human society
has never faced before. And we wish
them all well. Thank you very much.
Thank you, Professor. Wonderful presentation.
My pleasure.
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