In a spurious hybrid of science and bigotry, Mott announced that his ‘Law of Anticipation is one method by which nature seeks to end or mend a degenerate stock.’(7)

In 1909, myotonic dystrophy was defined as a specific adult onset disease found to affect muscles throughout the body, causing stiffness and wasting.  It was found to be dominant so that anyone carrying a faulty copy of the gene would express symptoms and have a 50% likelihood of passing the disease to their offspring. In 1918, Swiss ophthalmologist, B. Fleischer, noted that, in many of the children affected with muscle wasting, their parents suffered cataracts between the ages of around fifty to seventy while their grandparents had cataracts in old age. This led to the conclusion that the gene does not cause the muscle disease in the first generations but appears gradually, via cataracts, which pointed to anticipation.

In the aftermath of the Second World War, at the Galton Laboratory in London, Julia Bell undertook a detailed quantitative analysis of clinical data and patterns of heredity in myotonic dystrophy sufferers. Bell was able to apply statistical tests to her findings and concluded that the age at which the disease became apparent was markedly younger in offspring than in their parents, suggesting that the condition was amplified through the generations, which again seemed to concur with Mott’s concept of antedating or anticipation.(8)

A year later, working from the same laboratory, Lionel Penrose – brother of Roland, who introduced the work of the Cubists and Surrealists to a British audience – interpreted Bell’s results rather differently. A Quaker and humanitarian, Penrose had been a conscientious objector during the War, driving an ambulance for the Red Cross. He was vehemently against the concept of eugenics, eventually changing the name of the Department of Eugenics, of which he was Chair, to that of Human Genetics. Medically qualified, Penrose worked very closely with his mentally ill patients and could not reconcile himself to views expressed by Mott such as: ‘it has always struck me that Jews were, on account of their neurotic temperament, more liable to insanity than Christians.’(9) Instead, Penrose concluded that earlier studies were inherently biased in the way families were studied, for example that grandparents and parents necessarily presented symptoms later in their lives while their children showed them earlier because, if the opposite was true, it would be unlikely that three generations would be alive at the same time.

Between 1945 and 1962, familial studies continued and anticipation continued to be observed while its reverse was not demonstrated. Clinicians with close contact to myotonic dystrophy sufferers insisted that the disease did, indeed, become progressively worse through the generations and children born with the congenital form of the disease were the most severely affected at a very young age. After 1962, anticipation is rarely mentioned in the literature associated with genetic diseases and Penrose’s view came to be misinterpreted by the scientific community as a refutation of anticipation.
           
In 1975, Frederick Sanger developed a method of sequencing DNA, whereby the helical molecule could be unzipped and the position of each of the four component bases – adenine (A), cytosine (C), guanine (G) and thymine (T) – precisely defined. From this four-letter alphabet, spelling a seemingly nonsensical word, the complementary strand of the double molecule of DNA could be deduced (because A is always found opposite T and C opposite G). In the same way, the messenger RNA (mRNA) strand that will be transcribed in the nucleus of each cell is determined by the DNA code, with uracil (U) substituting thymine. This mRNA is then transported out of the nucleus and into the cytoplasm of the cell where it is ‘translated’. Every block of three letters within the code corresponds to one of twenty amino acids in the body which are assembled in a chain along the RNA molecule to form a long polypeptide which, subject to internal attractions and repulsions, twists into a three-dimensional protein molecule. Every gene in the human body works in this way, whereby DNA code is transcribed to RNA and translated into protein. Many of the functions of the human body rely on proteins, perhaps as enzymes in other processes, and mistakes at any stage in this process can have disastrous consequences. This ability to study biology at a molecular level led to exponential progress being made in the field of human genetics.

In the 1980s in Maastricht, Christian Höweler, who had read Penrose’s article ten or fifteen times, instinctively felt that something was wrong about the biases cited as possible ways of explaining away anticipation. By studying families affected by myotonic dystrophy, Höweler was able to examine each of the biases put forward by Penrose and to refute them. He found that ages of onset diminished through the generations in 98% of sixty-one parent-child pairs in fourteen families and reopened the case for anticipation.(10)

Also in the 1980s, DNA studies enabled the identification and mapping of mutant genes. Huntington’s disease was the first disease to be genetically mapped using DNA markers alone, in 1984 by Nancy Wexler and colleagues. The condition appeared to show patterns of worsening through the generations, or anticipation, when transmitted by males of the family, but this was debated until later genes were cloned. The actual mutation (an expansion of a cytosine, adenine, guanine repeat in the coding region of the gene which led to the production of an altered protein) was not discovered until 1993 by the Huntington’s Disease Collaborative Research Group which included Wexler and Peter Harper, amongst others. In the early 1990s, the team working on spinal bulbar muscular atrophy (SBMA), headed by Kurt Fischbeck in Bethesda, USA, found a sequence in the gene they were studying that extended well beyond the normal range and, while it was not immediately obvious that unusual genetics provided an explanation for anticipation, it did become implicated in causing the disease.

In the 1960s, fragile X had been shown, by H.A. Lubs,(11) to demonstrate specific behaviour during cell division, at the point at which chromosomes condense and may be stained and studied. At the exact position of the fragile X gene on X chromosomes, the DNA was found not to condense properly but to remain elongated, leading to ‘fragile sites’ that gave the disease its name. These results had proven difficult to reproduce over the years. In 1977, however, Grant Sutherland, working in Australia, observed a higher proportion of fragile sites in his tests than other teams. He deduced that the reason for this was that he was using a version of cell culturing medium that had been superseded by other media in different parts of the world and that the medium his team was using was low in folic acid, which was found to cause the fragile sites.

Simultaneous to studies in Huntington’s disease, SBMA and DM, Stephanie Sherman and Pat Jacobs, working together in Hawaii, were looking at the incidence of fragile X, a recessive condition causing mental retardation in affected individuals. Linked to the X-chromosome – two copies of which are carried by women and one copy by men (together with a Y chromosome, connoting maleness) – fragile X may be carried by females, who do not show symptoms because their other X-chromosome supplements the functionality lost by the mutant copy of the gene, but is always expressed by males, who lack an alternative X-chromosome. By studying the pedigrees of affected families, it was found that ‘normal transmitting males’ existed, whereby no symptoms were demonstrated by grandfathers but, by the time the disease reached their grandsons, symptoms had begun to be expressed. The greater number of generations the mutation passed through, the higher the chances seemed of expressing fragile X.

In the 1990s, multiple groups – including those headed by Sutherland, Jean Louis Mandel, Stephen Warren, and Tom Caskey – isolated an extended region of DNA, a repeat of cytosine-guanine-guanine (CGG) in fragile X which showed great changes in length between members of different generations in affected families. Although the repeat expansion was found in the untranslated region of the gene, it was found to affect the production of mRNA and prevent the relevant protein from being translated. It was established that fragile X demonstrated a ‘threshold effect,’ whereby a specific number of CGG repeats (in the region of 200) need to be present before protein synthesis is blocked and symptoms are expressed.

Before the prevalence of the Internet, scientists relied on conferences for information-sharing and it was at just such an event, at Coldspring Harbour in May 1991, that Keith Johnson (who would go on to clone the DM1 gene, amongst others including Harper and Caskey), heard Jean Louis Mandel speaking about this mutant region of extended DNA in fragile X. Johnson realised that this could also explain anticipation in DM1 and was able to predict what the mutation would look like at the molecular level, as it grew from one generation to the next, on the nineteenth of the twenty-two chromosomes in the human body (autosomes) not linked to sex determination. In what he has described as an ‘indescribable moment of eureka!’,(12) h is investigations were swiftly rewarded with the discovery of an extended cytosine-thymine-guanine (CTG) repeat at the tail end of the gene coding for myotonic dystrophy protein kinase (DMPK). This CTG repeat occurs anywhere between five and thirty-five times in healthy individuals, but, in DM1 sufferers, it was found to exist between fifty and a thousand times, with the number of repeats in muscle cells being higher than anywhere else in the body. A higher number of CTG repeats was found to enhance the degree of severity of the symptoms that people with DM1 experienced and, as irrefutable evidence of the existence of anticipation in DM1, the length of the CTG repeat was found to increase as it passed through the generations, directly enhancing the severity of the disease and lowering the age of onset of symptoms which came to be regarded as the classic pattern for anticipation.
At the time of writing, much work still needs to be done before a cure for any of these genetic diseases is found, but the suppression of repeat expansions between generations does suggest a possible way of eliminating the effects of anticipation.

American folk singer, Woody Guthrie,
describing the mother from whom he inherited Huntington’s disease.(13)

Imagine for a moment that you are pregnant with your first child, monitoring every slight change in your body with a hypochondriac’s vigour. Though countless millions have given birth before, this experience is unique to you and, while you defer to the knowledge of your older sister, ahead of you with her second baby, her tendency towards the blasé is unfathomable.
            When your sister goes into labour dangerously prematurely, you share her panic and comfort her during your first vision of childbirth, thinking of things to come and surreptitiously stroking your belly.
         When the baby emerges, little heavier than a couple of bags of sugar, all thoughts turn to her survival. Angry and wrinkled from her entry into the world, the tubes that invade her monitor progress while medics swarm, performing tests you presume to be routine.
            You are there when the rest of the family descends on the Special Care Baby Unit, watching your father totter over to the incubator and listening to the platitudes of your mother as the little one’s chest conforms to the artificial tides of the ventilator. You are there to share the incomprehension as the doctors share their results. You feel the guilty reassurance of the baby still cocooned safely inside you.
            Together, you are told that your sister’s baby has something that one in 8,000 babies in the UK inherit, a form of muscular dystrophy. Until now, the household name of this disease has held the abstract resonance of someone else’s charity campaign. But, now, you both begin to take notice as the symptoms are described. You hear about hands gripping objects tightly and finding it hard to let them go and faces sagging and losing all expression.  And you hear about bad hearts and lungs, bad balance and co-ordination. The finger of genetic suspicion scans your immediate family for clues and points to your father. No-one is comforted by the textbook inheritance pattern your family shows, from a mildly affected grandfather to a more affected mother and severely affected children or by the fact that many families are diagnosed when a baby is born with the condition. You are all thinking of the changes in your father over the last few years, which everyone had put down to self-pity and self-medication. You begin to fear for other members of your family. You are suddenly terrified for the life of your unborn child.
            On your own initiative, and at the doctors’ insistence, you begin to consider the risk to yourself and your baby. In the barrage of information, you understand that the chances are 50:50 whether you have inherited this condition from your father. One thing’s for sure – if you have inherited the disease, there is no chance that it will sit quietly into old age. Just like your sister, you can expect to start getting ill in your thirties. And, if your baby is affected, it would be ill from infancy.
            As luck would have it, the healthy copy of the gene is the one your father has given to you, which means there is no chance of passing it on. In your relief, you can only imagine what your sister is going through.

Over time, three generations of your family test positive for the disease. You watch as they compare symptoms, trying to make light of them, and notice the stress take its toll on your mother as she sees her husband, children and grandchildren deteriorating before her eyes.
            You inhabit a world of family suffering. You watch the alien movements of doctors and scientists within it. You feel abstracted, watching everything at one remove. You feel impotent in the face of a disease that has wound itself into every fibre of your loved ones, a disease that cannot be scratched or salved.

Imagine yourself in the position of the only healthy member of the second generation of a family, having given birth to the only healthy grandchild of the third. Wouldn’t you want to increase awareness of this disease, to make sure as many people as possible knew about it, to increase their chances of diagnosis and diminish the stigma for your relatives? The chances are that you would also want to do all you could to find out thing possible about this condition, what is known about it so far and what still needs to be discovered before a cure is found.
            To this end, you might begin to involve yourself other sufferers. You might meet families with different levels of sickness in them and watch your family compare themselves favourably to the more extreme cases, fearing the worst. You might put yourself in the position of their carers, not wanting to contemplate the demise of your own family and your responsibility towards them. You could hardly avoid considering a future that has not yet happened, one that you can hardly imagine ever will.