CJD: can your genes save you?
The political row over beef seems to be over, but will we ever know if BSE can be passed to humans? New evidence suggests that even if it can, some of us may be immune - but our chances are 50-50.
Monday 01 July 1996
But don't look at the coin just for the moment. Find out first why it's important. It has been three months since Stephen Dorrell, the health secretary, told the Commons that the best explanation at present for 10 recent cases of Creutzfeldt-Jakob Disease was "exposure to BSE before 1989". A great deal of political wrangling over beef bans and culling strategies has followed - in the course of which, the scientific debate has been all but drowned out.
Only one new case of the new variant of CJD (described more simply in the scientific literature as "vCJD") has been confirmed since then, and another identified from samples in France. So can we relax? Not according to Rob Will, director of the CJD Surveillance Unit in Edinburgh. "It's very difficult to interpret," he said. "We had 12 cases in 24 months - one more since April suggests the same rate as before. It's far too early to predict or have any reassurances about what is going to happen." It will probably be six months before a clear picture emerges, and perhaps five years (because of the disease's long incubation period) before it is clear whether the risk has passed.
But according to a growing body of scientific opinion, our personal susceptibility to CJD lies in our genes, and particularly in the pair of genes that every person (and most of the higher mammals) has which manufacture the PrP protein. This protein is produced widely in the body but, according to recent experiments in which it was "knocked out" in mice, its principal function is to keep nerve cells in the brain functioning.
According to the theory, in BSE, CJD and related forms of the disease in other animals, misshapen versions of the PrP protein - known as "prions" - somehow recruit the normal form into changing shape, creating more prions. Though it takes years, the result is the deposition of insoluble plaques of the misshapen protein in brain cells, leading initially to loss of cell function and finally to the decay and "spongy" appearance of the brain.
Everyone has two copies of the PrP gene in each cell. By chance (more probably, a quirk of evolution), there are two different versions of this gene randomly spread throughout the Caucasian population. The difference occurs at the 129th "codon" of the gene. Each codon is a set of instructions within the gene, and specifies a particular amino acid to be added to the protein being made. In one version of the PrP gene, codon 129 specifies the production of methionine; in the other, it specifies valine. These are known as the "meth" and "val" versions of the PrP gene.
The key to the prion diseases (as BSE and CJD are sometimes known) is shape. Depending on the sequence of amino acids, the protein folds into a particular shape. Substitute one amino acid for another at some point - say, methionine for valine - and you create a differently shaped product.
If you are Caucasian, then because the two versions are randomly spread through the population, there is an equal chance that you have identical copies of the gene. Both copies might be "meth", or both "val". In the standard phrase, you are homozygous for c129. Alternatively, there is a 50 per cent chance that you have one of each PrP gene - that is, you are heterozygous.
And here is the crux - all 12 cases so far identified of vCJD are homozygous for c129 of the PrP gene. Furthermore, previous research suggests strongly that people who are heterozygous have a very low risk of developing prion diseases.
This fact was highlighted recently by John Collinge, head of the Prion Disease Group at Imperial College of Science, Technology and Medicine, and one of the leading scientists in this field. "We express [produce the PrP protein from] both genes," he said. "It seems that if they are different, then the misshapen version of the protein has more trouble in causing the change in shape of the normal ones. It just doesn't seem to happen. But if the PrP genes are the same, then the change can occur much more easily."
Adriano Aguzzi, of the Institute of Neuropathology at the University Hospital in Zurich, says the two different original versions of the PrP protein "reduce the efficiency of the conversion [to the misshapen prion form] by reciprocal competition". It may be that one form of the PrP protein does change shape into prions, but that it cannot affect the other form, which retains its function. But here, the science turns into pure hypothesis, since the prion theory still has some gaps - specifically, in how the infectious prion affects the normal PrP protein.
None of this relies on vCJD being derived from BSE, though the experimental data is beginning to accumulate to suggest that it is. James Ironside of the CJD Surveillance Unit said that recent work, in which macaque monkeys were injected with BSE and showed brain plaques after three years which strongly resembled vCJD, "strengthens the hypothesis". However, earlier experiments with marmoset monkeys given BSE did not produce vCJD plaques. The problem is that if BSE does not cause vCJD, there is no way to prove it. Science can't prove a negative.
But even so, Collinge and Aguzzi seem to suggest that half of us really have nothing to fear, even if BSE is transmissible to humans - which the scientific evidence suggests with growing insistence. But equally, half of us have a great deal to fear, since CJD is fatal and untreatable, and nobody knows what the lower limit is for exposure to the disease agent. So, would you like to look at your coin now?
In the real world, of course, looking at the coin to find out whether you are really at risk requires genetic testing - an option which is both slow and expensive. Unsurprisingly, the British Government is taking a more pragmatic (and cheaper) approach than widespread genetic testing of everybody's PrP genes - a measure which would hardly reduce public concern and would probably cost as much again as the planned cattle cull.
A private company has been hired by the Ministry of Agriculture, Fisheries and Food (MAFF) to find out just what happened between 1980 and 1989 to all the bits of cows - the head, brain, spinal cord, spleen and lymph glands - that since 1989 have been declared "Specified Bovine Offals" (SBOs), and banned from human and animal consumption. The medics on SEAC, the specialist committee of scientific advisors to the Government on BSE and CJD, requested the study some months ago, though budgetary limits meant it has only just begun. "The medics on SEAC want to have information about the most likely route of infection, if there was one," explained a MAFF spokeswoman last week. "So the research is looking not just at how SBOs were used in food and pharmaceuticals, but also in paints, tyres and oils."
The worrying thing about the BSE prion, as Dr Aguzzi puts it, is that "it is highly promiscuous in its choice of hosts. Unlike its counterpart in sheep, mice and hamsters, it appears to infect animals of other species easily, especially when transmitted orally." Furthermore, he points out, the French research on the macaques used only about 50 to 100 milligrams of BSE-infected material for each monkey. "These amounts are well within the range of brain tissue present in commercial food products for human consumption until a few years ago," he comments.
Cause for concern? Certainly. But quite possibly half of us don't have anything to worry about. Would you like to flip your coin again?
Creutzfeldt-Jakob disease in the UK
The most important figures in this table are in the bottom right- hand corner: the nine deaths so far from the "new variant" of Creutzfeldt- Jakob Disease (CJD) in the UK. While every death from CJD (and its other forms) is a personal tragedy, those nine deaths have further importance. Besides those nine deaths, two people with the disease are still alive.
Diagnosis is usually only made after a death has been referred to the CJD Unit from hospitals or GPs. As the left-hand column shows, referrals have been holding steady. "Sporadic" CJD is the common form, usually found in people aged over 60. "Iatrogenic" is caused by the disease being introduced to the victim - mostly through treatment with human growth hormone. "Familial" cases occur in families which have a mutation of the PrP gene (see main text). "GSS" - Gerstmann-Straussler-Scheinker syndrome - is an extremely rare inherited disease also associated with PrP mutation.
The CJD Unit is convinced vCJD is a new phenomenon. One non-UK case has been discovered - retrospectively - in Lyons, bringing the total number of definite vCJD cases recorded to 12. The possibility that more might be out there is occupying many medics' time.
Year Referrals Deaths of definite & probable causes
Sporadic Iatrogenic Familial GSS NVCJD Total
1985 - 26 1 1 0 - 28
1986 - 26 0 0 0 - 26
1987 - 23 0 0 1 - 24
1988 - 21 1 1 0 - 23
1989 - 28 2 1 0 - 31
1990 52* 26 5 0 0 - 31
1991 75 32 1 3 0 - 36
1992 96 44 2 4 1 - 51
1993 78 37 4 2 2 - 45
1994 115 53 1 2 3 - 59
1995 79 33 4 1 2 3 43
1996 46 12 0 0 1 6 19
The CJD Surveillance Unit was set up by the Department of Health and the Scottish Home and Health Department in May 1990. Source: Department of Health
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