We’ll Never Know

Ignorance begat fear and fear begat religion. And it’s been downhill ever since; until the day in 1953 when the dark secrets of human nature became explicable more in terms of Crick and Watson’s Golden Helix than of Frazer’s Golden Bough. Or so they would have us believe, those high priests of the Human Genome Project, the bounty hunters of the Brave New World of genetic manipulation and the ‘selfish gene’. The dispiriting apogee to this curve of ‘hope’ took the form for me of a sad request from an aspiring Indian PhD student to seek the name(s) of god(s) in the sequences of DNA.

So, how did we descend to this vacuous replacing of one level of ignorance by another, and the proclaiming of each in turn as the final solution to the problem of life? The answer is not straightforward but resides more in widely-held false notions of genetic determinism, and ‘universal laws’ that supposedly govern the biological processes of development, behaviour and evolution, than in any overt political agenda. Teasing out the essence of what it means to grow – irrationally, unpredictably and uncertainly – into an approximation of an evolved living organism requires a deeper awareness of modern biology than can be gained from standard descriptions of the New Genetics: a goal not made easier when these are written largely by scientists more accustomed to imploding on their microspecialisations than to lifting their eyes to worlds that may, as J.B.S. Haldane famously said, be queerer than we can ever imagine. Nor was much enlightenment to be drawn from a recent TV documentary on genetic engineering (typical of its genre), inevitably beginning with the Nazi eugenics movement and ending with drunken cameras swinging from one iron door to another in an underground corridor of a Cologne laboratory, to burst finally onto a tray of pathetic gene-manipulated petunia seedlings – all to the accompaniment of eerie Stockhausen-like music. What other branch of learning or culture would allow for its structures and practices to be so crudely misrepresented in print and on screen, ironically as much by arrogant professionals striving to set the research agenda as by ignorant voyeurs?

Against such an opera buffa background of claim and counter-claim, Robert Pollack’s Signs of Life is as inspiring for its original insights as it is unexpected: a real molecular geneticist, with more than his 15 minutes of fame as a respected researcher into viruses and cancer, has composed a convincing and agreeably lyrical text on the hopes and limitations of the new biology. The book has its scientific antecedents, most specifically Richard Lewontin’s The Doctrine of DNA and Stephen Jay Gould’s Wonderful Life; yet it stands alone in trying to reach to the very essence of biology, with its ‘knowable pasts and unknowable futures’, in the best tradition of Italy’s two scientific literati, Italo Calvino and Primo Levi. Indeed, the links with Calvino are closer and more meaningful than Pollack probably realises, as I will argue later.

First, let me get one complaint off my chest. The text suffers from a surfeit of fast-switching metaphors – no doubt with the best pedagogic intentions – which are seemingly based on the premise that the natural images of science cannot speak directly to the Great Unwashed of non-scientists. Did you know, for example, that ‘if the cell were as big as the Old City of Jerusalem, each chemical “letter” in the DNA would be as big as a letter in any familiar book’? Or that if DNA were ‘enlarged 100 times more, then its “letters” would be as big as pizza pans and the human genome would encircle your waist’? And if you didn’t know, or you failed to get a mental measure of relative sizes from such unnatural imagery, then relax and enjoy the metaphorical tour of the structure of DNA, which goes from pizza pans to marbles to golf balls to vines wrapped around trees to Venetian blinds to phonograph records to milled-edge coins to pitch pipes: all within four pages in a chapter called ‘Invisible Cities’ (shades of Calvino?) But why not tell it as it is: a double helix, first described simply and elegantly in the 900-word ‘prose poem’ (Pollack) of Crick and Watson’s 1953 publication in Nature? Is there any lumpish viewer left who has not seen a double helix? It has become the logo of the late 20th century. It is the fons vitae, the source of all knowledge, the panacea to all our problems: we are our DNA. Almost but not quite; and if a shift in paradigm is needed to seduce professionals and amateurs away from the primal comfort of the blameless gene, then Pollack’s book is a significant step forward.

The subtitle – ‘The Language and Meanings of DNA’ – is misleading, for the book is essentially about the unknowability of DNA in the current state of biology. The popular image is of a monotonously long linear molecule composed of four chemical units (A, C, T, G) in which there can be approximately three thousand million such units for each human genome. Somewhere in all of this useless DNA lie the genes (approximately fifty thousand of them), accounting for less than 5 per cent of the total. If we could only locate those fifty thousand genes and work out the precise order of As, Cs, Gs and Ts within each, then (it is claimed) ‘Man’ could be reduced to a book exhibiting the fundamental instructions that govern normal and abnormal development and behaviour. The costs of doing this run into billions of dollars and the task currently occupies thousands of molecular zombies: an expense in time, money and personnel that would only be justified if it were to uncover all genetically determined human disorders. But locating and sequencing genes has as much relevance to the proper understanding of development as looking at the pictures but failing to read the words has to the comprehension of a book.

The real ‘text’ of biology is not the linear sequence of DNA(falsely assumed to be the ‘blue-print’ of life) but the three-dimensional, interactive processes of the molecular origami beyond the DNA that governs development. There is no one-to-one relationship between different parts of our bodies and behaviour (our phenotypes) and different genes. Even if we ignore the contribution of the environment to phenotypic differences (so setting aside the eternalred herring of ‘nature’ v. ‘nurture’) we are still left with a fundamental difference between a linear sequence and the emergent phenotype, which consists of a multitude of interactions between 3-D macromolecules such as the proteins (the products of the genes). The essentially unknowable gene-to-phenotype relationship (based on inspection of the genome alone) is thought by Pollack to be as circuitous as that between the Greek (and cursive Egyptian) words on the Rosetta Stone and the symbols of Egyptian hieroglyphs. The latter are rebuses in which many of the signs are symbolic, representing and summarising an idea or object previously expressed alphabetically. Similarly, organs in our bodies (an eye, a limb, a brain) are ‘ideas’ that result from finite, flexible and often redundant molecular interactions between structures that can ‘talk’ and ‘signal’ to each other in bizarre ways not directly readable from the DNA. If, on top of this, we consider social shifts in who talks to whom as different sets of structures which have come together at different moments of time and in different places during individual development, then we have a major problem of dissection on our hands. (No matter how tirelessly Australian chemists can break down a wine into 540 essences, they will never re-create the natural time-dependent processes of a French grape – unfortunately.)

Pollack prefers to see the genome more as a lexicon with arbitrarily ordered sentences (genes), equivalent to alphabetical entries in an encyclopedia, than as a book. But this is too optimistic, given his descriptions of many versatile genes that can give rise to different proteins from one and the same DNA sequence (known in the trade as ‘differential splicing’), and given that many proteins can adopt similar shapes and functions, although coded by dissimilar genes.

The marvel of biology is that it is a mess – which is all that can be expected of something produced by evolution, as organisms are buffeted by the forces of natural selection and drift, and subject to the blind vagaries of mutation and of the ubiquitous mechanisms of promiscuous DNA. We are as the cookie crumbled. It’s true that coded instructions go to individual genes about when and where to begin coding for a protein – otherwise each fertilised human egg would not follow the developmental lines decreed by the lineage of evolutionary events on our branch of the Tree of Life: ‘a gene speaks only when it’s spoken to’ and ‘the more complex the pattern, the more important the silences.’ However, as Pollack recognises, there are no discrete, finite sets of instructions in the genome that say this is how to make an eye or not make an eye; there is no textual recipe in linear form waiting to be decoded by over-eager molecular bakers.

The ‘meaning’ of the genome takes shape during a time-dependent process of developmental unfolding, without recourse to a master-plan. Hence, genes can only have meaning in a historical context: they cannot be rationalised. They are what Crick has called ‘frozen accidents’ of evolution. Or, as Pollack writes, ‘no matter how fine the resolution of locating genes in the map of the genome, they are only maps of a territory we want to explore, not the territory itself.’ In biology, the functional synergism of molecular interactions means that 1+1=7. For some geneticists, wishing for the enviable precision of the laws of physics, this is depressing; for others, awed by the illogical mess yet eventual triumph of individual development, it is exhilarating. Pollack summarises it well:

The intrinsic incomprehensibility of our own genome cannot be fitted inside the paradigm, derived from physics, that has kept the search for a complete set of time-independent biological mechanisms at the centre of molecular biology. For classical physicists, the dust settled when it became clear that tangible objects behaved predictably, although made of unpredictable atoms. For biologists, the challenge will be to come to terms with the discovery that although individual genes may behave predictably, they do not together form a predictable – let alone completely knowable – genome. Experimentation on human genes, no matter how imaginative, will never give a single, complete meaning to the human genome.

Such statements have important biological implications. DNA can only be understood as if it were literature, in which individual words come with their attendant ambiguities and inconsistencies. A gene and its mutant versions (alleles) can only be ‘known’ in the context of the organism. And there is no such thing as the organism or the genome. The individual organism is a momentary affair occupying a millisecond of evolutionary time, and representing a unique combination of parental genes and a unique set of environmental conditions that have never previously occurred and will never re-occur. At any given moment, a momentary individual co-exists within a momentary population of similarly momentary individuals – very different from beakers full of water molecules that are, to all intents and purposes, the same, at all times and in all places. In this context of shifting genetic alliances, it is pertinent to ask what is meant by a ‘normal’ or ‘abnormal’ allele. This is more than an academic question: it gets to the heart of many misplaced fears over the manipulation of genes from one species to another or the attempts to identify arbitrary human groupings with diagnostic genetic markers.

‘There’s no such thing as a Jewish disease,’ wrote the Chief Rabbi of the UK in a letter to the Times many years ago in response to an article on the high incidence of Tay-Sachs disease among Ashkenazi Jews. He was right, but for the wrong reasons. His concerns originated from Hitler’s dictum that ‘politics is applied biology,’ that national and racial identities can be defined by one or a few genes open to eugenic manipulation. Today we are similarly embarrassed by the crudity of the genetic arguments that link genes to IQ and IQ to race or class, a fundamentalist approach to biology that has its roots in the Twenties in John Davenport’s testimony to Congress that alcoholism, poverty and avarice are genetically determined traits of Irish, Italian and Jewish populations, respectively. It is easy to criticise such views as ‘standing on a mountain of ash’ (as Pollack writes), but the erroneous claims made for the Human Genome Project, the media distortions of biotechnology and the pseudo-intellectualism of Richard Dawkins’s ‘selfish gene’, do not allay such politically malignant attitudes.

We can no more judge a person’s ‘normality’ from particular genetic variants than we can from particular parts of the phenotype. Captain Fitzroy might well have rejected Darwin as naturalist on board the Beagle on the grounds that the shape of his nose gave his personality away; fortunately he didn’t. Darwin went on to show that the well-known inherited features between parents and offspring are just the tips of an iceberg of a 3.5 billion-year history of genetic change. What the Chief Rabbi might have said is that the particular course of history which placed more of the Tay-Sachs allele in Ashkenazi Jews, relative to other populations, cannot be used as a genetic marker for racial identity. Nor can high-frequency alleles of any other gene in any other group be so used. There are few (if any) alleles that ‘type’ a human population: genetic diversity is the norm, with as much difference existing between individuals within a population as between populations. Understanding the basis of genetic diversity promotes the politics of tolerance; ignorance leads to fear of genetics in general and to the genetic gibberish of racial typing in particular.

Getting at the true scope of genetic diversity requires a diachronic, comparative approach: the molecular dissection of deep time and of the ancient similarities between genes. Not-withstanding our anthropocentrism, the study of one species’ genome will not answer even the most elementary questions of how and why we are as we are, developmentally and behaviourally. Ironically, the little we do know of human genetics has not emerged from the Genome Project. Important disease-related genes have been targeted and located using new tricks of genetic probing irrespective of the genome as a whole; exciting discoveries of genes involved with major events in our construction arose from probes taken from banana fruit-flies. The course of development cannot be understood outside the context of evolution. Nor is it a simplistic toss-up between the perennial which came-first, the gene or the protein? They have co-evolved ab initio: development and evolution ‘bring out structures of astonishing complexity from the interactions between genes and proteins; they are structured hierarchically; they are time-dependent and historically-rooted; and we are finding out the hard way, neither is totally knowable or predictable.’

The last word should go to Priscilla in Calvino’s description of meiosis: the haphazard separation of parental chromosomes that precedes the formation of sperm and eggs. Calvino’s nose for biology, for the evanescence and unknowability of the individual, is unsurpassed.

But for the moment let’s limit ourselves to answering the question of [whether] I, in quotes, and Priscilla, in quotes, are our genetic heritage, in quotes, or our form, in quotes.

In my parents’ instructions are contained the instructions of my parents’ parents handed down in turn from parent to parent in an endless chain of obedience. The story I wanted to narrate therefore is not only impossible to narrate but first of all impossible to live, because it’s all there already, contained in a past that can’t be narrated since, in turn, it’s included in its own past, in the many individual pasts – so many that we can’t really be sure they aren‘t the past of the species and of what existed before the species, a general past to which all individual pasts refer but which no matter how far you go back doesn’t exist except in the form of individual cases, such as Priscilla and I might be, between which however, nothing happens, individual or general.

And it’s pointless for us to run, Priscilla. We were only the preparation, the envelope, for the encounter of pasts which happens through us but which is already part of another story, the story of the afterward: the encounters always take place before and after us, and in them the elements of the new, forbidden to us, are active: chance, risk, improbability.