In tangible terms, "co-operation" means giving a blood sample for DNA analysis, racking your memory for the names and whereabouts of long-lost cousins and long-dead aunts, and trying to remember at what age Uncle Orpheus went a bit doolally. Less concretely, it means opening the door to the possibility that something that seems to "run in the family" may be running right now in your genes, or in your children's.
Carol Jennings has had direct experience of being at the centre of this kind of research. Indeed, along with her family, she was the catalyst for a breakthrough which has led to a whole new understanding of the shattering brain condition, Alzheimer's disease.
The Jennings' story started in 1982 when Carol's father - one of 10 siblings - was diagnosed with Alzheimer's at the age of 58; it doesn't usually kick in until well past 65. "We knew nothing about this disease - nobody did then. Senile dementia, yes, but my father was in his 50s. It was a huge shock," Carol recalls.
The shocks kept coming: in 1983, her 54-year-old aunt was found to have the condition, and in 1984 another uncle, aged just 55. While the family reeled, Carol started thinking. "Three out of 10 - it seemed an awful lot. Then I remembered that my grandfather had `gone a bit funny' when he was about 59. People said he became almost childlike and that it was because he'd been gassed in the war. But I started to think, `Hang on a minute, childlike, going a bit funny, not knowing what's going on. That sounds like Alzheimer's to me.' Then I thought, `What if it's genetic?' And then I started thinking, 'This could happen to me.'"
In 1987, amid all the uncertainty and fear created by the appearance of this devastating disease, Carol decided she had to do something. That something was to fire off letters to half a dozen doctors she'd been told were researching Alzheimer's. "No one had ever suggested it could be hereditary, it was just seen as a terrible coincidence. But on my little A5-size Basildon Bond paper, I drew the family tree. There were my grandma and grandad, both of whom I suspected had Alzheimer's, and in the next line I put their 10 children and marked the three who had been diagnosed. In the letter I said we'd love to take part in any research. I wasn't necessarily thinking that they would find a missing link, but that if they could give us any information, any idea about how to treat it, it would be worth it. Our family tree is now shown to students, doctors and nurses as a huge slide on a wall."
Although all the scientists responded, only one group took up Carol's challenge. Led by Martin Rossor and John Hardy, the team (based then at St Mary's Hospital Paddington and now at the National Hospital for Neurology and Neurosurgery in Bloomsbury) leapt at the chance to investigate a genetic link in Alzheimer's. It was then that Carol asked her relatives whether they were willing to give the blood samples the researchers needed.
"Going around them made me realise just how much fear there was about the disease. There was a feeling that if we ignored it, it might just go away. But most of all, they were scared - scared that someone would come and say that they were next. Of course that couldn't happen then, but it can now - if they want to know."
In the end, 44 family members - including several who were traced by a medical genealogist - agreed to give blood. In 1991, after the death of the affected aunt and an autopsy that confirmed that her early dementia was indeed a form of Alzheimer's, the entire family came together to hear that as a direct result of their participation, the research team had identified the first known cause of Alzheimer's disease - a rare mutation of chromosome 21.
"Although I'd suspected that it was genetic all along, when the men in the white coats confirmed it I felt as though I'd been kicked in the stomach by a very large horse. I'd guessed it before, but now I knew it was true - and that I was at high risk," says Carol.
Only 30-odd families worldwide have been discovered to have this particular genetic fault, which causes carriers to succumb to the disease in their 50s. But as Professor Martin Rossor (now a highly regarded international expert in Alzheimer's disease and other dementias) says: "Don't underestimate the huge impact the data from these families has on our understanding of all the forms of a disease - genetic or otherwise. The genome project can churn out massive amounts of information on the make-up of genes, but it can't tell us what diseases the errors in those genes may cause - for that you need affected families."
It may sound unkind, but families with genetic disease provide a natural experimental "control". They reveal the exact outcome of a particular mistake in the genetic make-up and, by implication, highlight what should happen when things are as they should be.
"Even when we've sequenced the entire human genome," Professor Rossor continues, "we'll still need to know where the genetic faults are and to understand what goes wrong. Finding these links just by looking at people with sporadic [ie non-genetic] disease would be considerably more difficult, if not impossible."
Although genetic Alzheimer's is very different from sporadic Alzheimer's, says Rossor, after death the brains of people with either version look the same. "The final pathway of the disease is common to both. There might be different triggering factors early on, but all those pathways converge. It's like streams merging into a river: one stream would be these affected families, another might be elderly people with sporadic disease caused by an environmental trigger. So understanding one stream tells you about the river. That's why family research is so powerful - the knowledge gained is quite out of proportion to how common the mutations are.
"Carol's family allowed the first mutation for Alzheimer's to be identified and there's no doubt that this had a profound effect," Rossor continues. "It happened at a time when an abnormal protein - the amyloid protein - had just been identified in the brains of people with Alzheimer's disease. But there was a big argument as to whether amyloid was central to the disease or whether it was just a side-product. Finding a genetic mutation that pro-duced amyloid in an affected family established the protein as a critical central component."
This knowledge of amyloid is driving much of the research into Alzheimer's today and a direct line can be drawn between the family-based work and the development of new drugs, which will appear in the next two to five years. But the work doesn't stop when a gene is found, says Rossor:
"While they are fit and well, the Jennings family, along with others, are very selflessly participating in the big longitudinal study we are running to try to identify the very earliest signs of Alzheimer's disease. Once a year they undergo various memory tests and brain scans to try to monitor any early signs of disease or changes in brain structure. But it's not easy work, because these people are at risk themselves. It takes a lot of courage to be involved and therefore reminded of that risk on an annual basis."
So far, four of Carol's father's nine siblings have developed Alzheimer's and the next generation, Carol's own, has 10 years to go before they move into the danger zone - she's 44 now. By then, Carol hopes, there could well be treatments that, if they can't prevent the condition developing, will at least alleviate it. And she, for one, will certainly volunteer herself as a guinea-pig if necessary.
But researchers are rarely lucky enough to find a large family, with enough affected members for conclusive investigations, handed to them on a plate as Carol's was. In other circumstances, explorations must move further still from the sterile laboratories of biochemical inquiry, and plunge into the messiness of human relations.
Juliet Gayton is a medical genealogist who goes into action when researchers need to accumulate enough people affected with a disease to sort out the genetic connections. She has spent the past 30 years honing her genealogical detective skills, and says: "I'm very committed to this because it's such a worthwhile application of what I do - much more satisfying than helping people discover whether they've got aristocratic ancestry! If I can help in the fight to crack some of these awful diseases, that will really be something.
"The more people you can trace in a family, the more you can reduce the areas of the genome for searching purposes. It's rather like doing a jigsaw," she explains. "If you have a jigsaw that's half green and half blue sky, you can sort out the two lots but you've still got an awful lot of pieces to choose from. It's like that with brothers and sisters - you can sort out some of the genome, but they still overlap hugely. But if you can find more distant relatives, the bits that overlap are much smaller. What I need is as much knowledge of a family's ancestors and of their sideways relatives as possible, so that I can find those distant members of the family."
Juliet is currently working with a team from the National Hospital for Neurology and Neurosurgery, investigating a family with an inherited form of Parkinson's disease. Parkinson's is not usually passed on genetically and it's very rare to find a family with more than one affected member. But this family, says researcher Dr Naheed Khan, has a unique genetic mutation which she believes may help her penetrate the disease's elusive mechanism.
"At the moment, no one understands why cell death occurs in Parkinson's - whether it's a genetic predisposition or a predisposition to an environmental toxin. But if we did find a gene, it would enable us to see what the gene product is and how it relates to cell death. If we can identify the mechanisms of cell death, that will have repercussions for all types of Parkinson's disease and may prompt the development of something that can prevent cell death. And finding the gene is the first step.
"We've been working with this family for two years and we're finding more and more of members all the time. We had a major breakthrough last month when we found a whole new branch, which gave us much more statistical weight. But what we really need is more affected members. If we could find just two more, I think we could pinpoint the disease gene in this particular family - and that would be a tremendous breakthrough," says Dr Khan, who is keen to hear from any family in the UK which has two or more relatives, living or dead, affected by Parkinson's disease.
The Parkinson's research started with two families with the same surname, both of which appeared to have the same sort of inherited Parkinson's disease, explains Juliet Gayton. But there weren't enough affected people in either family in this generation to reveal the site of the genetic mutation. "What we hoped was that they would have a distant common ancestor. So we went right back and found one in 16th-century Lincolnshire. From there I worked forward, tracing the descendants of other children from that time who by now are such distant relatives that no one knew they were part of the same family. I gave the names to the team and they made an approach through local GPs."
It may sound straightforward, but it isn't, especially as Juliet is not only trying to uncover hidden family members but to detect, several generations later, the causes of their demise. Death certificates, for example, only started to record the cause of death from 1837, and even then in many cases reported only what the doctor saw - a heart attack, say - and not the condition that prompted it.
"Dementia is fairly easy to deduce because sufferers often died in institutions," says Juliet, "but conditions such as Parkinson's are more difficult to detect. If it's not clear what somebody's under- lying state of health was, then you have to draw on things like memory - people tend to remember that Great-Aunt Maria did have a bad shake - or newspaper reports which say things like so-and-so died after a long illness with the shaking palsy."
And tracing a biological family can also be thwarted by all sorts of things, she adds: illegitimacy, hidden liaisons, common surnames, forgotten first marriages ... "For example, in the last century it was very common for a member of a family who couldn't have children of their own to be passed one or two by a relative. So biologically these children's parents are not their own, but you can't pick that up very easily. Then there are ancestors who went out to the colonies - Irish genealogy is a real mess because a lot of the salient records were burnt in the 1920s (in the Civil War after Partition). To do this work, you have to be the kind of person who likes solving puzzles."
It can be delicate work too, Juliet adds, because some families don't want to be linked to conditions like dementia: their fears are often mixed up with things like the ability to get insurance and mortgages and their own health. "If a family does co-operate, younger members are often left wondering `am I next?' Scientifically, they may want to participate, but they're afraid of how our findings may relate to their own future."
No one who takes part in family research is ever told their own personal status unless they request it. But even the broad confirmation of a condition "in the family" raises difficult questions of how much each person wants to know, and what repercussions that knowledge will have on them, and on other family members.
Carol Jennings says that her family's reaction varied widely. "One cousin said he wasn't going to tell his wife - he was afraid that she might divorce him. Another was scared to tell anyone in case he couldn't get insurance. A few simply chose to ignore the whole thing: one of my cousins had a child with a woman he has now left, but he hasn't told her anything about the Alzheimer's. I think she and her baby have a right to know - what if something came up that could cure our family? That child could die needlessly at the age of 50."
Emily, Carol's 17-year-old daughter, describes her own dilemma: "I don't know yet if I want to know whether I'm carrying the gene. Sometimes I think I do, but if I took the test, maybe I'd wish I hadn't and then I couldn't un-know it."
Carol, who now works in counselling and raising awareness of early-onset dementia, wonders how she will feel if, as a result of getting the family involved with genetic research, her own children are denied mortgages or find their job prospects damaged. But she concludes vehemently: "If people don't know about conditions like this, they'll never do anything about them. We have to talk about it, get involved and get it sorted."
Her husband Stewart adds: "No news in medical research is ultimately bad news, because even if you don't get the benefit of research yourself, you do at least have the chance to lay down some hope for your children and their children. It's absolutely essential to have families like ours involved, because so much of medical research is about discovering patterns."
For Carol's family, "getting it sorted" is likely to mean some kind of gene therapy. And for the rest of us, understanding, early diagnosis and the development of new drugs as the mechanisms of disease are illuminated by family research are now on the horizon. But one thing is for sure, genome project or no genome project: the future would be less healthy for all of us without the courageous involvement of these special families.
! If there are two or more people in your family with Parkinson's (living or dead) and you are willing to help Dr Khan with her research into the disease, please contact her at the National Hospital for Neurology and Neurosurgery in London on 0171 837 3611, x 3936, or fax her on 0171 278 5614Reuse content