IUPS 2013: Sir Paul Nurse and Denis Noble

Sir Paul Nurse: Awarded the 2001 Nobel Prize in Physiology and Medicine for his post-doctoral research on the protein components that govern the cell cycle. Current president of the Royal Society and Director of the developing Francis Crick Institute (scheduled to open in 2015).

Key point: "We need to focus on the management of information to understand biological complexity".

As a researcher of molecular mechanisms governing cell function, Sir Paul Nurse may not be an obvious choice to open a Physiology Conference. He argues otherwise, however, stating "I'm always a physiologist - I want to understand how cells function, how they work, using whatever tools are available". He highlighted the importance of physiology using the Oxford English Dictionary definition "a branch of science that deals with the normal function of living organisms and their parts..." - in his view this encapsulated the central quest of biology. The second part of the definition bothered him however - "...in so far as it is not dealt with by more recent sciences". This gives the impression that physiology is merely there to "fill in the gaps" left by molecular biology, immunology, genetics, etc. Instead, Nurse argued, these other fields enhance our understanding but cannot substitute for physiology in meeting the key aims of biology. Having established the importance of physiology, he now asked: Where is this science going?

In the second part of the lecture, he emphasised how living organisms can only be understood as networks of interacting components, stating that higher order processes (such as homeostasis) can only be understood as the result of the gathering, storing and processing of information by a system. He cited DNA as an example of this- essentially a digital storage device. In addition, the Lac Operon (a genetic "switch" mechanism modulating metabolic control in E. coli) provides an exquisite instance of a negative feedback system, which responds to a flow of information. Future advances in physiology must be based on translating the chemistry of systems into modules that manage information. Nurse was keen to draw a distinction between metaphors relating biological systems to electronic machines or circuit boards, the key difference being that these are "hardwired" whereas biological systems are "wet wired"  - the components can be connected differently to change the information received. Information processing was so central to biology, he argued, that understanding how complex networks function in general - including models of airport hubs and ecological or sociological networks - can illuminate aspects of the physiology of cells & organisms. He rather daringly stated that our thinking must be more "feminine" - the point here being that men are supposedly more simpler systems, being "either off or on" whereas women have more complex constitutions. Rather than considering biological systems as simple, linear, input-output pathways, we must imagine an intricate network with superimposed levels of feedback control. Key questions to address in future include how the flow of information through such a system can generate fine spatio-temporal control, and how introducing dynamics can allow a greater degree of information to be transmitted. A formidable challenge is to place these complex systems within the evolutionary context. Nurse described the case of "John Harrison's clocks" who developed a series of machines to measure longitude in response to a commission from the English Admiralty. Each of these was intelligently designed and used to inform the development of the next with the clockmaker able to go back to the drawing board and start from scratch between each prototype. Biological systems, Nurse stated, do not have this luxury - they must carry the remnants of their evolutionary history. This constrains evolutionary development, rendering many physiological phenomena inefficient or redundant. As a result, "complexity may lead to counter-intuitive explanations" and we "cannot assume that the simplest explanation will be the adequate one" in each case. Nurse related this to physics, where "when dealing with the very big or very small, we are lead into the increasingly bizarre". Similarly, the evolutionary complexity of living systems may draw biology into "new worlds of strangeness", away from what we can understand counter-intuitively. This may require increasing assistance from mathematicians and physicists to understand a new level of abstractness. Nevertheless, Sir Paul Nurse's message was clear; physiology can only advance further if it embraces a view of living organisms as dynamic, intricate systems responding to a constant stream of information.

"Physiology moves back onto centre stage: a new synthesis with evolutionary biology"
Denis Noble CBE FRS. About: Eminent researcher in cardio-vascular physiology, current president of the IUPS.

Key point: New insights in physiology are exploding the traditional concepts of Neo-Darwinism evolutionary theory, and opening up a new world of hereditary mechanisms.
"If physiology has moved off centre stage, it is coming back with a vengeance".
"The genome is an organ of the cell, not a dictator. Control is distributed".

The focus of this lecture was in demonstrating how the classic views of evolutionary theory are being pulled apart by new physiological advances. According to Neo-Darwinism, evolution is primarily gene-centred and occurs through the gradual accumulation of random mutations. According to the Weismann barrier, the germline is completely isolated from the parent, hence there is no possibility of acquired traits being inherited. Noble first asked "Are genetic mutations actually random"? Current evidence indicates that genetic mutations follow distinctly non-random patterns throughout the genome. An example of this is P elements, DNA transposons in Drosophila fruitflies - demonstrated to hone in on functionally related areas as they jump between parts of the genome. Noble then explored whether evolution only occurs through gradual assemblies of single mutations. Analysis of the draft human genome sequence in 2001 indicated that the evolution of transcription factors and chromatin binding proteins could not have proceeded one amino acid at a time - rather whole areas and domains must have been shuffled to obtain the current conformation, indicating that mechanisms of reconfiguring the genome must exist. This was illustrated by the example of domestication, a process of introducing changes gradually through generations. However this form of selection "has never led to the formation of a new species. It is a purifying force, not a creative force". Compare this with hybridisation, which involves mixing up two distinct parental genomes. Noble also described how our very concept of a gene has changed and the classic linear progression of DNA --> phenotype has been abandoned in favour of a three way interaction between DNA, the environment and the phenotype via a biological network. This explains why knocking out genes rarely reveals their function as the network can compensate for their loss. This was demonstrated effectively by Hillenmeyer et al. who showed that approximately 80 % of knock out gene mutations in yeast are silent unless additional environmental constraints are imposed.

Noble then moved on to ask "Why should a physiologist be concerned with evolutionary biology?". Traditional evolutionary views are gene centred, yet physiological research is demonstrating that organisms can "immune themselves from the genome". Furthermore, information transmission is not a one-way process as organisms can impose downward control onto DNA through cell signalling, transcription factors and epigenetic modification. An example of this is provided by work on rats showing that regular grooming in early life makes the mature adult less fearfull - is grooming time limited in colonies stressed by predation or starvation? Another exciting illustration is the production of cross species fish by placing a carp nucleus into an enucleated cell from a goldfish. In the rare circumstances when this produces an embryo, the skeletal configuration is intermediate between the two, but much more similar to the goldfish. Hence, information cannot be transmitted solely by the DNA but must be influenced by maternal factors in the egg cytoplasm. Work on the nematode worm C.elegans meanwhile, has revealed that epigenetic changes can be incredibly robust. Here the inheritance of antiviral RNA molecules was demonstrated for up to 100 generations, even though the DNA template had been lost; inheritance had been achieved through RNA polymerase amplification in the cytoplasm. Our view of the DNA machinery should echo that of Barbara McClintock, who viewed DNA as a highly sensitive organ that can detect and respond to unexpected events. Noble cited how genome reorganisation may also occur through the lateral acquisition of new DNA material from unrelated cells, such as the ingestment of the prokaryote cells which became reduced to mitochondria and chloroplasts. The central concept of this stimulating lecture was clear: the genome is NOT isolated from the environment and furthermore, acquired characteristics can be inherited. Perhaps Lamarck wasn't so wrong after all.