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Biology

A finely-tuned orchestra without a conductor

An integrated approach to the functioning of the organism places in check the sovereignty of genes

carlos fioravantiA biologist who is also a musician: “We’re inclined to ignore complexity”carlos fioravanti

From Oxford

Heart specialist, Denis Noble, usually suggests to the young people that turn up at his lectures and talks at Oxford University: “To change the expression level of your genes go to the theater and let yourselves be overwhelmed by  passion. Some days later the expression level of your genes will be different. Furthermore, you’ll be happier!”

At 70, kind and helpful, Noble is one of the main authorities in the world to question the limits of genetic determinism – the predominant view in biology, according to which the appearance, development and destiny of any organism depends essentially on DNA molecule sequences, known as genes.

“We’ve become incapable of seeing living systems in any other way”, says Noble, who lectures and researches cardiovascular physiology at Oxford. Both in conferences as well as in his most recent book, The music of life – biology beyond the genome (Oxford University Press), published last year in England and this year in France, he issues an invitation: give up this obsession with genes and look at the highest organization levels of living organisms in  search of a broader understanding of nature.

“The music of life” offers a counterpoint to the view that the instructions for the development of each living being lies in its genes, as presented by Jacques Monod and François Jacob, Nobel Prize in Medicine winners in 1965. This idea took off with a book published in 1976, called “The Selfish Gene”, in which English biologist, Richard Dawkins, describes the gene as an autonomous entity and the body as a prisoner to its orders and whims. ” ‘The selfish gene’ is a metaphor that tries to convince its readers of the truth, not a scientific truth”, comments Noble.

Like Dawkins, he makes use of metaphors that also cannot be scientifically demonstrated in order to explain the key concepts of systems biology, a study area that favors integration instead of separation, a view of the whole rather than a view of the parts. Created by scientists like South African, Sydney Brenner, Nobel Prize  winner in Medicine and Physiology winner in 2002, and by Noble himself, systems biology comes from classical biology and physiology, with generous doses of mathematics and computer science.

It is this mathematical foundation that allows for an approximation between the various plains on which organisms function. This was what Noble did, for example, in an article published in 2002 in BioEssays when he integrated mathematical models of cells with models of tissue and of the heart itself.

Noble recognizes: in the past he was a fanatical reductionist – and had good results. He studied the functioning of the ways in which calcium enters and leaves the heart muscle cells and created the first mathematical model for the functioning of the human heart, published in 1960 in Nature. But he later concluded that some phenomena of the heart could not be understood merely by means of genes, proteins or cells, because they resulted from the interaction of many cells on a broader level. He began, therefore, to look around in his search for more eloquent results.

Over the last few years Noble has been working on the virtual heart, a computer model that combines his knowledge of the functioning of genes, cells and cardiac muscles. By means of the virtual heart it becomes a little easier to understand better, for example, the effect of genetic mutations, arrhythmia and the heart attack. “Successful integration at the systemic level must be built on well-done reductionism, but reduction in itself is not enough”, he comments. In one of the metaphors in his book he warns: “If we all put our noses too close to the painting no one’s going to see the bigger picture”.

His colleague, Eric Werner, another professor from Oxford and a specialist in systems biology, works with computer simulations within a dynamic multi-cellular context for studying the growth of tumors and the action of medication on the organism. According to Werner, integrated analyses of the organism may warn of the undesirable interaction of drugs with organs or tissues other than those that it is intended to treat.

In addition to the scientific challenges Noble and Werner enjoy discussions with specialists from other areas. Some time ago Werner assembled together in Oxford physicians, mathematicians, economists, physiologists and computer specialists, who described the problems they would like to solve and investigated the possibilities for working together. “Because it’s broad and has few previously defined limits,  systems biology is attractive for anyone who’s ever thought about life and has some technical specialization”, commented Werner in March 2007 in Nature.

In “Music of life”, the most poetic of recent books on systems biology, Noble sees the genome, the set of genes in an organism, as an enormous organ with 30,000 pipes. Each pipe corresponds to a gene and the shapes, as they are activated, provide the organ with immense possibilities for varying the intensity, tone and effects of the musical notes. Just as in a piece of music where the organist calls into play many pipes at the same time, many genes – perhaps as many as 10,000, the equivalent of a third of the genome – are expressed at the same time in organs like the brain, heart and liver.

But who is the musician, the composer and the conductor? “There’s not just one organist”, says Noble. “The organist consists of the regulatory networks of interaction at all levels, from the highest to the most basic, including networks that integrate genes to genes themselves. There are no privileged components telling the other what to do. There is, however, a form of democracy, with all elements at all levels having the chance of being part of the regulatory network. The coordinating hand is not so much a conductor. Or perhaps we should think of it as a virtual conductor – the system behaves “as if” it was itself the conductor. The genes behave as if they think they are being played by this maestro. The orchestra of life functions without a conductor.”

For Noble, genes represent just a database by means of which organisms can be reconstructed. “The book of life is life itself, which cannot be reduced to just one of its databases, the genome.” Noble remembers that DNA – undeniably important for transmitting information about organisms to succeeding generations – is relatively passive when compared to proteins, which are the truly active molecules in the unfolding of life.

DNA, passive? Yes; in the first place because it does not leave the nucleus of the cell. In the second place because it is not the DNA itself that matters, but the way cellular machinery reads it. From time to time the cell copies the sequence it needs to produce proteins, which in turn are going to form the cells, tissue, organs and the whole organism – that is the expression of the gene. “DNA does nothing outside the context of the cell that contains these sets of proteins, in the same way that a CD does nothing without a CD player.”

For Noble, to say that DNA is the absolute lord of life is like saying that it is the CD that brings the pleasure of listening to music by Schubert and is capable of moving someone to tears: “The effect of the music obviously depends on Schubert, but also on the musicians who played with technique and inspiration and the emotional context in which the music is appreciated, the company and the significance of this episode in the life of each one”. According to the scientist, if we wanted to identify an author of the action it would be the biological mechanisms that read the DNA.

Noble tries to overthrow the idea that the development chain of a living being moves in a single direction: genes leading to the production of proteins, which are going to constitute the cells and tissues like skin, bones and muscles; in turn, tissues are going to form organs and all together, along with the immune and hormonal systems, they form a complete being. The information path (the causality) may be two way, since the environment, both cellular as well as external, determines in what measure the genes are going to express themselves. One of the principles of systems biology is precisely this: the instructions that lead to the formation of the organism result from relationships from top to bottom and from bottom to top and also sideways – in short, in all directions.

Life results from this intricate network of connections and feedback between genes, proteins, organs, the body and the environment. Each level of organization consists of an integrated network with its own logic (and the relationships of cause and effect that regulate one do not regulate the other). “It’s not possible to understand this logic by simply investigating the properties of the components of the systems”, he says. “Nor is there a privileged level in systems biology that dictates to the rest.” In practical terms, problems resolved on an organizational plane are not, a priori, resolved on other planes.

This is why this professor from Oxford has been looking skeptically at reports about genes being seen as responsible for the most varied types of cancer or for the origin of criminal behavior. It may be risky to attribute a gene as being responsible for a disease, because gene fragments may also be combined in many ways and have more than one function. Furthermore, many genes cooperate to form proteins, which also act together when they carry out biological functions at higher levels of organization (from regulating heart beat to the secretion of insulin by the pancreas).

Except that proteins integrate in a much more complex way than genes. “We’re inclined to ignore any complexity which is uncomfortable”, says Noble. But this integration path represented by systems biology may show how to take advantage of the knowledge accumulated over the last few decades. The fact that the benefits to health have taken a long time to appear, according to Noble, has to do with how small scales relate to larger scales. “We know a lot about molecular mechanisms. Now the challenge is to extend this knowledge to broader scales.”

Besides liking music, Noble is an amateur linguist and sometimes gives talks in French, Occitan and Limousin, two French dialects, in addition to Italian, Japanese, Korean and Maori. In a conference at Balliol College where he lectures (and where Dawkins studied zoology), Noble combined his two loves when he played the guitar and sung a song in Gascon, another French dialect, providing everybody with the words so that they could follow the song and sing along with him.

A few weeks later at Exeter College, the talk was even more refined. Talk or recital? At times, Swiss Christoph Denoth, resident musician at Balliol College, played the guitar softly while Noble was speaking, waiting for questions from the audience. Denoth and Noble ended the presentation by playing Bach together.

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