IUPS President’s Lecture (Sponsored by Wiley)

17:30 - 18:30, Sunday 21 July Hall 1 (The ICC)

Physiology moves back onto centre stage: a new synthesis with evolutionary biology

Denis NobleUniversity of Oxford, United Kingdom

1809 Jean-Baptiste Lamarck published Zoologie Philosophique. Established transformation of species;

assumed inheritance of acquired characteristics

1859 Charles Darwin published The Origin of Species. Proposed theory of natural selection, but had

no theory of heredity. Also assumed inheritance of acquired characteristics

1900 approx. Neo-Darwinism: incorporation of Mendelian discrete inheritance. Weismann barrier: exclusion of inheritance of acquired characteristics

1940 approx. The Modern Synthesis: Julian Huxley, R A Fisher, J B S Haldane, Sewell Wright

Evolution: a brief history

Gene-centred view of natural selection (slow accumulation of ‘random’ mutations, followed by selection)

Impossibility of inheritance of acquired characteristics (mis-called ‘Larmarckism’)

Distinction between replicator (genes) and vehicle (phenotype)

Buttressed by [mis-interpretations of] The Central Dogma of Molecular Biology (Crick)

Evolution: the Modern Synthesisoften called Neo-Darwinism

Popularised by The Selfish Gene (1976)

All these rules have been broken !

Are mutations random?

Shapiro, 2011: Evolution. A view from the 21st Century

“It is difficult (if not impossible) to find a genome change operator that is truly random in its action within the DNA of the cell where it works. All careful studies of mutagenesis find statistically significant non-random patterns of change.” (page 82)

Random?

The question is not just whether changes are random, but whether they are functionally relevant.

“I will use the definition that the changes are assumed to be random with respect to physiological function and could not therefore be influenced by such function or by functional changes in response to the environment. This is the assumption that excludes the phenotype from in any way influencing or guiding genetic change.” (Noble 2013)

That assumption is now insecure since some genome changes are related to physiological function.

Example of targeted genome insertion

P element homing in fruit flies. These are DNA transposons that insert into the genome in a functionally significant way, depending on the added DNA. There is up to 50% greater insertion into regions of the genome that are related functionally.

Possible explanation: donor element and target site may be brought close together in the nucleus, i.e. organisation of the genome is important. This kind of information is also therefore ‘genetic’.

Hama, Ali, and Kornberg 1990 Genes Dev 4: 1079–1093

“The 2001 Nature report of the draft human genome contained two important figures illustrating what genome sequencing had taught us about protein evolution. Using transcription factors and chromatin binding proteins as examples, the figures showed that these classes of protein did not evolve one amino acid at a time. Instead, the two classes of protein “shuffled” and “accreted” copies of functional protein segments called domains…...”

Shapiro, 2011, page 95

Are mutations random?Are gradual accumulations of mutations

the cause of speciation?

Initial sequencing and analysis of the human genomeInternational Human Genome Sequencing Consortium Nature 2001, 409, 860-921

Domain accretion in chromatin proteins

Domain accretion in yeast (Y), worm (W), fly (F), vertebrates, (V) Human (H) shown by stars,

* *** * * * *

* * *

First conclusion

Proteins did not all evolve via gradual accumulation of mutations

Some other forms of genome reorganisation must have occurred

What was wrong with neo-darwinism?

The errors are both

philosophical (conceptual and linguistic)

and

scientific (empirical, experimental)

in reply to Midgley (1979):“that was no metaphor. I believe it is the literal truth,

provided certain key words are defined in the particular ways favoured by biologists” (Dawkins, 1981).

Selfish gene:Metaphor or empirical science?

But a metaphor does not cease to be a metaphor simply because one defines a word to mean something other than its normal meaning. Indeed, it is the function of metaphor to do precisely this. (Noble, J Physiol, 2011)

Noble D. (2011). Neo-Darwinism, the Modern Synthesis, and Selfish Genes:

are they of use in physiology? Journal of Physiology 589, 1007-1015.

Conclusion

The selfish gene idea is not falsifiable

Further details in

Noble D. (2011). Neo-Darwinism, the Modern Synthesis, and Selfish Genes:

are they of use in physiology? Journal of Physiology 589, 1007-1015.

“selfishness cannot be defined as an intrinsic property of nucleotidesequences independently of gene frequency. It is a strange hypothesis that uses its own definition of its postulated entity as its only prediction”.

“It is important to note that selection has never led to formation of a new species. Selection operates as a purifying but not creative force.”

(Shapiro, 2011, page 144)

Are mutations random?Are gradual accumulations of mutations

the cause of speciation?

Thousands of years of domestic selection produced new varieties not new species

By contrast, hybridisation in plants does achieve speciation

Second conclusion

‘Selfishness’ is not a testable hypothesis

Question

Has the concept of a gene changed?

Biological Networks

signalling pathways, filters,

conditioners

incubators that enable and

restrict reactions

DNA

PhenotypeE

nvi

ron

men

t

‘determinants of phenotype’ ≡

original concept of ‘gene’

molecular biology notion:

gene = DNA sequence

Kohl P, Crampin E, Quinn TA & Noble D. (2010). Systems Biology: an approach. Clinical Pharmacology and Therapeutics 88, 25-33.

X

X

Biological Networks

signalling pathways, filters,

conditioners

incubators that enable and

restrict reactions

DNA

PhenotypeE

nvi

ron

men

t

‘determinants of phenotype’ ≡

original concept of ‘gene’

molecular biology notion:

gene = DNA sequence

Most knock-outs and mutationsare buffered by the networks

X

Most knock-outs and mutationsare buffered by the networks

Some examples

Model of sinus node – ibNa & if

Example of ‘gene knock-out’

Em

If

IbNa

20% 40% 60% 80% 100%

Noble, D., J. C. Denyer, H.F. Brown. & D DiFrancesco (1992). Proc Royal Society B 250: 199-207.

Hyperpolarization Activates if

Genetic buffering:How extensive is it?

Hillenmeyer ME, Fung E, Wildenhain J, Pierce SE, Hoon S, Lee W, Proctor M, St Onge RP, Tyers M, Koller D, Altman RB, Davis RW, Nislow C & Giaever G. (2008). The chemical genomic portrait of yeast: uncovering a phenotype for all genes. Science 320, 362-365.

80% of knockouts are sile

nt!

Why should a physiologist be concerned about evolutionary theory?

The modern synthesis is a gene-centred theory of evolution

Yet organisms are very good at ‘immunising’ themselves from their genomes

Noble D, Differential and integral views of genetics in computational systemsBiology, 2011, Interface Focus 1, 7-15

Conclusion:Knockouts do not reveal regulators

Davies, J. 2009 Regulation, necessity, and the misinterpretationof knockouts. Bioessays 31, 826–830.

Origin of the problem:

Downward causation

The reductionist causal chain

organism organtissue

cellular sub-cellularpathwaysprotein

gene

I know one approach that will fail, which is to start with genes, make proteins from them

and to try to build things bottom-upSydney Brenner, 2001

They [genes] created us, body and mindRichard Dawkins, 1976

NOBLE, D (2002) Nature Reviews Molecular Cell Biology 3, 460-463.

Unravelling complexityNeed to work in an integrative way at all levels:

organism organtissue

cellular sub-cellularpathwaysprotein

gene

There are feed-downs as well as upward between all these levels

Systems leveltriggers ofcell signalling Systems level

controls ofgene expression

Protein machineryreads and corrects genes

Epigenetic marking by all levels

Origin of the problem:Downward causation

Royal Society journal Interface Focus

Focused issue, 2012(Editors: Ellis, Noble, O’Connor)

Some principles of Systems Biology

So, the ‘central dogma’ of biology is insufficient or even incorrect!(Shapiro, J. A. 2009 Revisiting the Central Dogma in the 21st Century. Annals of the New York Academy of Sciences 1178, 6-28Shapiro, J.A. 2011 Evolution. A view from the 21st Century, FT Press Science)

There is ‘downward causation’ from all levelsThis influences gene expression, and gene marking (epigenetic inheritance)

“Lamarckism is not so obviously false as is sometimes made out”(John Maynard Smith, Evolutionary Genetics, OUP, 1998)

Second principle

Transmission of information is NOT one-way

Some principles of Systems Biology

We all inherit a complete egg cell

DNA marking – methylation, histone marking and other processes(maternal factors can transmit through generations)

Epigenetic marking can also be transmitted through sperm line (via RNAs)

We should invert the usual question: What prevents inheritance of acquired characteristics?

Jablonka & Lamb (1995) Epigenetic inheritance and Evolution (OUP)

Third principleDNA is NOT the sole transmitter of inheritance

Examples of Inheritance of epigenetic information

Rechavi, O, Minevish, G, Hobert, O. 2011 Transgenerational Inheritance of an Acquired Small RNA-Based Antiviral Response in C. elegans. Cell, 147, 1248-1256.

Weaver, I. C. G.,. 2009 Life at the interface between a dynamic environment and a fixed genomeMammalian Brain Development (Ed Janigro) 17-40.

Anway, M. D., Leathers, C. & Skinner, M. K. 2006Endocrine disruptor vinclozolin induced epigenetic transgenerational adult-onset disease. Endocrinology 147, 5515-5523.

Sun, Y. H., Chen, S. P., Wang, Y. P., Hu, W. & Zhu, Z. Y. 2005 Cytoplasmic Impact on Cross-Genus Cloned Fish Derived from Transgenic Common Carp (Cyprinus carpio) Nuclei and Goldfish (Carassius auratus) Enucleated Eggs. Biology of Reproduction 72, 510-515.

Pembrey ME, Bygren LO, Kaati G, Edvinsson S, Northstone K, Sjostrom M, GoldingJ & ALSPAC_study_team. (2006). Sex-specific, male-line transgenerationalresponses in humans. European Journal of Human Genetics 14, 159-166.

The Guardian, 14 February 2007

Weaver et al The Journal of Neuroscience, February 14, 2007 • 27(7):1756 –1768

ARE

Inheritance of epigenetic information

Anway, M. D., Leathers, C. & Skinner, M. K. 2006Endocrine disruptor vinclozolin induced epigenetic transgenerational adult-onset disease. Endocrinology 147, 5515-5523.

An endocrine disruptor) can induce transgenerational(four generations were followed) disease states or abnormalities, and this suggests a potential epigenetic etiology and molecular basis of adult onset disease.

Sharma, A. & Singh, Priyanka. 2006Detection of transgenerational spermatogenic inheritance of adult male acquired CNS gene expression characteristics using a Drosophila systems model. PLoS one 4, e5763.

Chronic PTZ treatment of adult males changes CNS transcriptome. This is inherited. First demonstration of spermatogenic inheritance of an adult-induced characteristic.

Third conclusion

Environmentally-induced changes can be inherited

Question

What happens in cross-species clones?

Sun, Y. H., Chen, S. P., Wang, Y. P., Hu, W. & Zhu, Z. Y. (2005)

Inheritance of epigenetic (cytoplasmic) information

Carp 33 Carp nucleus in Goldfish egg ? 28

Sun, Y. H., Chen, S. P., Wang, Y. P., Hu, W. & Zhu, Z. Y.(2005) Cytoplasmic Impact on Cross-Genus Cloned Fish Derived from Transgenic Common Carp (Cyprinus carpio) Nuclei and Goldfish (Carassius auratus) Enucleated Eggs. Biology of Reproduction 72, 510-515.

Goldfish 26

Inheritance of epigenetic (cytoplasmic) information

X-ray photographs showed that the vertebral number of six cloned fish was of the enucleated egg providing goldfish type, ranging from 26 to 28. In contrast, thevertebral number of nuclear-donor common carp was 33–36. These data suggest that the goldfish egg cytoplasm plays an important role in regulating the somite development and vertebral number in the nuclear transplants.

Goldfish 26

Carp 33 Carp nucleus in Goldfish egg 28

Sun, Y. H., Chen, S. P., Wang, Y. P., Hu, W. & Zhu, Z. Y.(2005) Cytoplasmic Impact on Cross-Genus Cloned Fish Derived from Transgenic Common Carp (Cyprinus carpio) Nuclei and Goldfish (Carassius auratus) Enucleated Eggs. Biology of Reproduction 72, 510-515.

McClintock, Barbara. 1984 The significance of responses

of the genome to challenge. Science 226, 792-801.

And Nobel Prize Lecture, 1983

In the future attention undoubtedly will be centered on the genome, andwith greater appreciation of its significance as a highly sensitive organ of thecell, monitoring genomic activities and correcting common errors, sensing theunusual and unexpected events, and responding to them, often by restructuringthe genome. We know about the components of genomes that could be madeavailable for such restructuring. We know nothing, however, about how the cellsenses danger and instigates responses to it.

A genome consists largely of semistable genetic elements that may be rearranged or even moved around in the genome thus modifying the information content of DNA.(Beurton et al 2008)

Fourth conclusion

Cytoplasmic changes can be inherited

Question

Possible mechanisms?

Rechavi, O, Minevish, G, Hobert, O. 2011 Transgenerational Inheritance of an Acquired Small RNA-Based Antiviral Response in C. elegans. Cell, 147, 1248-1256.

• Viral replication triggers an RNAi-dependent viral silencing response

• The acquired silencing response is transgenerationally transmitted

• Transgenerational transmittance is non-Mendelian

• involves small antiviral RNAs

• Inheritance is robust

• for over 100 generations

Stop press: from Joe Nadeau’s lab

Nelson, V. R., Heaney, J. D., Tesar, P. J., Davidson, N. O., & Nadeau, J. H. (2012). Transgenerational epigenetic effects of Apobec1 deficiency on testicular germ cell tumor susceptibility and embryonic viability. Proceedings of the National Academy of Sciences, 109, E2766–E2773

“the belief that the soma and germline do not communicate is patently incorrect.” PNAS Commentary article

these [epigenetic] effects persist for many generations and are as strong as conventional genetic inheritance

The heritable epigenetic changes persisted for multiple generations and were fully reversed after consecutive crosses through the alternative germ-lineage

Sixth conclusion

Environmentally-induced changes can be inheritedThe inheritance is robust,

can carry through many generations and the molecular mechanisms are known in some cases

Question

If gradual mutations is not the answer, what is responsible for re-organisation of genomes?

THE NETWORK OF LIFE “Contrary to traditional theories, it is now well

documented that all prokaryotes and many eukaryotes acquire novel genomic segments and biochemical functions from other, often unrelated cells rather than exclusively by vertical inheritance from progenitors”

Shapiro: Evolution. A view from the 21st Century p 91

Beurton PJ, Falk R & Rheinberger H-J, ed. (2008). The Concept of the Gene in Development and Evolution:

Historical and Epistemological Perspectives. Cambridge University Press, Cambridge.

“it seems that a cell’s enzymes are capable of actively manipulating DNA to do this or that. A genome consists largely of semistable genetic elements that may be rearranged or even moved around in the genome thus modifying the information content of DNA.”

Genes “begin to look like hardly definable temporary products of a cell’s physiology”

Final conclusion

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

then physiology – the analysis of function – IS highly relevant to evolution.

“It is hard to think of a more fundamental change for physiology and for the

conceptual foundations of biology in general”(Noble Exp Physiol 2013)

Gene-centred view of natural selection Selection is multi-level

Impossibility of inheritance of acquired characteristics Acquired characters can be inherited

Distinction between replicator (genes) and vehicle (phenotype)The genome is an ‘organ of the cell’ not its dictator. Control is

distributed.

The Central Dogma of Molecular BiologyGenomes are not isolated from organism & environment

Evolution & physiology: towards a new Synthesis

Evolution & physiology: towards a new Synthesis

Evolution & physiology: towards a new SynthesisQuestions page

http://musicoflife.co.uk/pdfs/Answers.pdf

Pigliucci, M., & Müller, GB. (2010). Evolution - The extended synthesis. Cambridge, Mass: MIT Press.

Further readingDoes the Modern Synthesis need

extending or replacing?

Gissis, SB., & Jablonka, E. (Eds.). (2011). Transformations of Lamarckism. From Subtle Fluids to Molecular Biology. Cambridge, Mass: MIT Press

Shapiro, J. (2011) Evolution: a view from the 21st Century FT Press

Beurton, PJ, Falk, R. & Rheinberger, H-J. (2008) The concept of the gene in development and evolution: historical and epistemological perspectives. CUP.

Noble, D. (2006) The Music of Life, OUP.