August 31, 2016


How to Get Another Thorax (Steven Rose, 9/08/16, London Review of Books)

Bringing genetics together with development was a tougher proposition. Genetics had since Mendel been a science of differences, seeking to explain why some peas are yellow and wrinkled, others green and round, or why one person has blue eyes, another brown. Development, though, was a science of similarities, asking for instance why humans, in their trajectory from fertilised egg to adult, are generally bilaterally symmetrical, each with two eyes, two arms terminating in five-fingered hands. An attempt to unify them was made by another of the Cambridge group, the polymath biologist C.H. (Hal) Waddington, who in the early 1940s coined the term epigenetics to refer to the study of the 'causal interactions between genes and their products which bring the phenotype into being'. (Phenotype is a Humpty-Dumptyish word, but can be roughly taken to mean any observable feature of a living organism, at any level from the molecular to the cellular to the entire organism and its behaviour. Richard Dawkins extended its definition by asserting that the dam a beaver builds is part of its phenotype.)

Epigenetics seeks to explain how, starting from an identical set of genes, the contingencies of development can lead to different outcomes. To illustrate this, Waddington imagined what he called an 'epigenetic landscape' of rolling hills and valleys. Place a ball at the top of the hill and give it a little push. Which valley it rolls down depends on chance fluctuations; some valleys may converge on the same endpoint, others on different ones. Waddington called this process 'canalisation', though the material basis for the metaphor was, at the time, unknowable. He imagined the hills and valleys as held in place by strings stretching from nodes (genes) located below the surface landscape.

He also went further, proposing that if a strongly canalised phenotypic change was repeated generation after generation, some random mutation would eventually catch up with it and it would be assimilated into the genome. He demonstrated that this was possible by exposing developing fruit fly embryos to ether, which induces them to develop a second thorax. After some twenty generations (it takes a fruit fly about seven days to develop from a fertilised egg to an adult ready to mate, so experiments using them are fast and easy), the flies developed the second thorax without exposure to the ether - the epigenetically induced bithorax had become fixed in the fly's genome. To many of his contemporaries, it appeared as if Waddington was arguing for a version of the ultimate evolutionary heresy, Lamarckism - the inheritance of acquired characteristics. It was easy for them to dismiss Waddington's results as the artificial product of extreme laboratory conditions, irrelevant to the real world.

The TBC sought funding from the Rockefeller Foundation to set up a theoretical biology institute in Cambridge, but Rockefeller turned the proposal down in favour of a major investment in biochemistry, which presaged the later triumphs of molecular genetics. By now, many of the group's members had been drafted into war work. Needham was posted to China, where he began the work on the history of Chinese science for which he is now best known. Waddington worked on operations research for the air force. In 1947 he left for Edinburgh, where he remained for the rest of his career, but despite his continued advocacy of the theory, epigenetics faded from view.

With the discovery of the structure of DNA by Francis Crick and James Watson in the 1950s, there was a renewed conviction among biologists - especially the physicists and engineers turned biologists like Crick - that what was needed was a ruthless reductionism. It was immediately recognised that DNA's helical structure provided the chemical form of a program - a code made up of the molecule's four subunits or 'bases', adenine, cytosine, guanine and thymine, represented by the letters A, C, G and T - that could direct an organism's development, and also a copying mechanism by means of which information could be transferred from generation to generation. Life, it seemed, was computable. The triumph of reductionism seemed so secure that by the 1990s ambitious molecular biologists were able to persuade their funders, public and private, to embark on the massive project of sequencing the entire three billion As, Cs, Gs and Ts that spell out the human genome. The information the sequence provided would, they claimed, transform our understanding of medicine, and in so doing give a powerful boost to a languishing economy.

As the project got underway, the sequencers conducted a poll. How many genes - that is, mini-sequences of A, C, G and T coding for specific proteins - would they discover embedded in the human genome? The betting suggested around a hundred thousand, roughly the same as the number of different proteins in the human body. When it came to it, the chastened researchers reported that the actual number of genes was just over twenty thousand, about the same number as in a millimetre-long nematode worm. Twenty thousand genes to direct the development of the human embryo from fertilised egg to newborn baby, to code for the hundred thousand proteins, to determine the fates of the 37 trillion cells in the human body.

The numbers made a nonsense of the idea that there is a 'gene for' any particular human characteristic, from eye colour to IQ to sexual orientation, and has confounded the hope that sequencing the genome would generate a cornucopia of precision-tailored treatments for complex diseases. The problem lies in the common misconception of genes as 'master molecules' directing the operation of the cells in which they reside. In fact DNA is a rather inert molecule, as it has to be if it is to serve as a code. It is the cells that do the work. Cellular enzymes read, edit, cut and paste, transcribe and translate segments of DNA - the literary metaphor, universally employed by molecular biologists, isn't accidental; they think of DNA as the language in which the Book of Life is written - in a scheduled flow during the development of the foetus, according to whether the cells are destined to become liver or brain, blood or bone. No gene works in isolation but as part of a collaboration. Many genes may be required to produce a single phenotype - more than fifty main gene variants have been shown to affect the chances that someone will contract coronary heart disease, for example - and a particular gene may influence many different phenotypic traits, depending on which organ's cells it is active in. It is during this period of rapid growth that living organisms are at their most plastic, responding to environmental challenges by modifying anatomical, biochemical, physiological or behavioural phenotypic traits. This is epigenetic canalisation.

Posted by at August 31, 2016 5:16 PM