Confusion and medical ethics

December 4, 1998

Is it really ethical to ask an Alzheimer's sufferer to take part in scientific research? asks Alison Goddard

Five years ago David Edmonds realised that his father, Ronald, was suffering from Alzheimer's disease. At the age of 83, Ronald was becoming increasingly forgetful and confused as the disease advanced. Three years later came a second tragedy. David's aunt, Elsie Edmonds, was also diagnosed with the disease.

Scientists have identified one faulty gene that increases the risk of developing Alzheimer's. David's aunt was always at a greater risk of developing the disease given that her brother had it. But the genetic basis for Alzheimer's is linked to more than one gene, and researchers at the University of Wales College of Medicine are recruiting pairs of siblings with the illness to take part in a study to identify those other genes.

The researchers rang David to ask him if his family would take part. "The call came out of the blue," David says. "I don't know how they knew that my father and my aunt had the disease."

Nevertheless he "almost immediately" gave consent. "My aunt was a little bit dubious at first," David says, "but I managed to persuade her that it was for the general good. As long as it is not intrusive, I would always want to help further the knowledge of disease."

Indeed, the research could help his own family: David's two children are now in their twenties. If scientific progress is swift enough, they could be saved from developing Alzheimer's.

Although David's decision seems straightforward, it throws up some profound issues, such as whether it is ethical to ask patients who are confused and suffering from memory loss to participate in scientific research. There are questions, too, about the purpose of the research, particularly in the light of the discipline's unsavoury history.

"Psychiatric genetics is a hot area of psychiatric research," says Peter McGuffin of the Institute of Psychiatry at the Maudsley Hospital in London. "But it carries a historical burden. Many ethical debates in psychiatric genetics are affected by the legacy of the subject's history."

Both eugenics and behavioural genetics originated from the work of one man, Francis Galton. A cousin of Charles Darwin, he became interested in the idea that genius could be inherited. Galton coined the term "eugenics", which he perceived as a branch of biology devoted to improving the human race. He also came up with the idea that a disease's cause could be identified by studying how the disease tended to cluster in certain families.

"The first systematic family studies of schizophrenia were carried out by Ernst Rudin," says McGuffin. "Although such work was in many respects seminal, Rudin's subsequent involvement with the Nazi Party and his possible contributions to the party's view on how eugenic principles might be implemented has led to heated debate."

The Nazi regime adopted a simplistic and ruthless set of eugenic policies that included the forceable sterilisation of the mentally ill and "euthanasia" of psychiatric patients, including people suffering from schizophrenia and manic depression. "Even though what the Nazi regime did was regarded by most geneticists as not just morally repugnant but scientifically incorrect, there is little doubt that psychiatric genetics suffered from a sort of guilt by association," McGuffin says.

Researchers across the country are sensitive to the ethical issues. Nick Craddock of the University of Birmingham is researching the genetic basis for manic depression. About 1 per cent of the population suffers from manic depression, swaying cyclically from elation to depression, he says. But if one of your parents, a brother or a sister is a manic depressive, then your chances of developing the disease are boosted to between 5 and 10 per cent. If you have a manic depressive twin, your chance of developing the illness rockets to 60 per cent.

"The main dilemma that we have to face is how to deal with genetic information and who has the right to know," Craddock says. "If, in the future, a person with an illness asked to be tested for a suspect gene, would other people in the family have the right to know the result?" Three months ago, the Nuffield Council on Bioethics examined the dilemma. It identified three types of families:

* relatives who might be aware of a family history of illness and be offered genetic testing and counselling

* relatives who might not want to participate in genetic tests, but the genetic testing of another family member might reveal information about them

* relatives who might not be aware of any family history of mental illness. Should they be informed and offered counselling?

The Nuffield Council on Bioethics decided that genetic information should be confidential, shared only with the individual who had asked for testing. But it also recognised that there could be exceptional circumstances and recommended that these be considered case by case.

The council also examined whether it is ethical for people who are confused and suffering from memory loss to participate in scientific research. Is it right for researchers to approach the relatives of Alzheimer's sufferers? What about patients who are only intermittently capable of giving consent, such as the manic depressives studied by Craddock's team at the University of Birmingham?

"In the case of mentally incompetent adults, since no one may consent on behalf of another adult, it would appear that in English law, non-therapeutic research is unlawful," concluded the Nuffield Council on Bioethics. This puts the study of Alzheimer's disease on shaky legal ground, although the council recommended that the law be reformed to allow these patients to participate in such studies.

The council also recommended that patients who are intermittently competent should only be asked whether they are willing to participate in research when they are fully competent. This is already done by the researchers at the University of Birmingham. "We only approach people when they are fully well," Craddock says.


Genetics and mental illness is a hot topic. Not only is the genetic basis for disease at the cutting edge of science, but the genetic basis for mental disease offers insights into the brain's workings.

"We have very little idea of the mechanisms of mental illness," says Julie Williams, a senior lecturer at the University of Wales College of Medicine. "One of the main contributions of the genetics of mental disorders is that it can pinpoint the biological systems that cause these disorders - that is what is so exciting."

Williams works on identifying the genes that are responsible for the late onset of Alzheimer's disease, which accounts for 80 per cent of Alzheimer's cases. "We hope that by identifying the genes that contribute to late-onset Alzheimer's - which is not only due to genes, there are other influences but we don't yet know what they are - we will be able to pinpoint the biological processes underlying the disorder and learn how it develops," she says. "With this knowledge, we hope to be able to produce treatments."

Scientists have already discovered that the risk of developing Alzheimer's is linked to a faulty gene. But the risk depends on much more than this single gene. "There may be about five genes that contribute at the same level and dozens of others that have a smaller effect," Williams says. To identify these genes, Williams has studied the DNA taken from blood samples from 300 United States families in which two siblings have Alzheimer's disease. "It showed 16 regions of chromosome that are worthy of following up," she says.

Williams is now recruiting 150 British families in which two siblings have Alzheimer's disease. She will look more closely at the 16 interesting regions on these people's DNA, along with more material from 100 US families. When the study is finished next November, it will be, to the best of her knowledge, the biggest genome screen worldwide.

The third stage of the research will involve 1,000 people who suffer from Alzheimer's along with 1,000 people who are the same age but do not have Alzheimer's.

This project will identify the specific genes associated with the illness.

"If there are indeed five genes, and if we get the funding and manage to recruit 2,000 people for our study, we should have a result within the next ten years," Williams says.


"The bee's knees" is how one leading researcher describes the work of 39-year-old Mick O'Donovan.

A trained psychiatrist, O'Donovan is now studying the genetic basis for schizophrenia at the University of Wales College of Medicine. "I have always been interested in the biological aspects of mental disorders," he says, "and the best way of studying that is through genetics."

O'Donovan is examining DNA from 200 pairs of schizophrenic brothers and sisters as part of a five-year research project. Schizophrenia is caused by many defective genes, and O'Donovan aims to identify which sections of chromosomes are most likely to contain genes associated with the disease.

"There are three billion units of information on human DNA," he says. "Any one could potentially cause disease. It is like looking for a needle in a haystack. The origins of mental illness, despite the best efforts of researchers, are largely unknown."

"Ultimately, if we can understand the biological basis of disease and where environmental factors fit in and how we can modify them, we can treat disease."

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