Brain-washing drugs with a new twist

Press, 6 May 1983, Page 13

Brain-washing drugs with a new twist

The diagram, right, shows four of the 30-40 brain hormones, or neuropeptides, so far discovered. Each blob representa an amino acid which acts like a letter of the alphabet, “spelling out” instructions to the brain. The exact combination and length of each sequence is believed to influence memory, mood, perception of pain, etc. • Vasopressin. By “snipping off” one amino acid from the end of the sequence making up this hormone, scientists can produce a drug which improves memory without the side-effects associated with the whole hormone.

• Oxytocin. The sequence is identical to vasopressin — except for two amino acids. But this difference is crucial: it seems to make the difference between remembering and forgetting. • ACTH 4-10. By leaving out one amino acid, a Dutch firm has produced a drug, ACTH 4-9, which, in animal experiments, has 1000 times the effect of the natural hormone. It has been found to induce feelings of well-being in depressed old people. • Met-encephalin. This hormone seems to produce effects similar to those of opium. Its discovery, by Hughes and Kosterlitz in Aberdeen, started the neuropeptide revolution.

Reversing the ageing process

® Scientists have isolated vital hormones in our brains which, they believe, hold the key to much of our behaviour. By altering and synthesising such substances, they are trying to produce a new generation of drugs that will influence our memories, our ability to learn, and how we feel. Report by MARJORIE WALLACE, of the London “Sunday Times.”

For four years Theo Goossens was a man without memory. He could not remember his name, his home, the faces of his wife, his family, or his friends. He could not read, talk coherently, or sign his name. He lived in a world without a past, experiencing only a vanishing present. Goossens, who ran a laundry at Heerlen, in southern Holland, lost his memory after an operation to “bum out” a nerve running from his brain to his face, which had been causing him severe pain. It was a desperate measure after years of unsuccessful treatment, including the removal of all his upper teeth, operations on his nose, and such heavy drug treatment that part of his stomach had to be removed. By 1976, the pain had become so intolerable that he went to the renowned Dutch surgeon Professor Henk Verbiest and begged him to operate on his brain. When Goossens woke up from the operation the pain had gone, but so had his memory. “I didn’t know who I was. I thought my wife was my sister. I recognised no-one except an old comrade from the Resistance.” Memories of the Second World War, long repressed, flooded his mind but everything else in his past had been erased. He tried desperately to make sense of a world which had become a timeless jumble of experience. It is difficult for Goossens, now 65, to recall those lost years, but by piecing together his own recollections with what others have told him, he can give a rare insight into a mind without memory. “I had forgotten how to do the simplest things, even how to walk,” he says. “I had to go downstairs slowly like a child. I knew I had to

eat and sleep and live somewhere, but it didn’t matter where. I was like a dog in my own home. I was vaguely aware that there were people around me who were affectionate to me but I didn’t know who they were or what they were doing there. I had the experience one moment and had forgotten it the next.

“I felt nothing. When you have no memory, you have no feelings. I didn’t miss the love of a woman. In clearer moments I had the feeling people didn’t take me seriously and it made me very sad. But luckily it didn’t last because I couldn’t remember what I’d been feeling the moment before.”

Jeanette, his 37-year-old wife, intervenes: “I’m sure he had emotions. Sometimes the tears would pour down his cheek from the one eye which hadn’t been damaged in the operation. Once we were at a friend’s wedding and he looked at me and cried. I am sure there was something there.” The operation had been on the left hemisphere of his brain, the side where language is organised, and afterwards Goossens lost the use of words. “I barked rather than talked,” he says. Gradually, with Jeanette’s help, he relearned the meaning of words but was unable to use them coherently. Despite his strange state, he wanted to be independent and insisted he should go alone for his monthly hospital check-ups at Utrecht. The two-hour journey was a hazardous experience. Like Paddington Bear he would set off for the station wearing a label with his name and address.

“I had written down important words like ‘taxi’ and ‘station’ on separate pieces of paper in my pocket, but more often than not I forgot I had them there,” he says. “I would get into a taxi and the driver would ask where I wanted to go. Of course, I had forgotten. And I had forgotten I had a piece of paper with ‘hospital’ written on it. They thought I was crazy.” Theo Goossens might still be spending his life in a twilight world but for a remarkable experiment at Utrecht University’s Project for Memory and Memory Disorders. The research at Utrecht, led by Professor David De Wied, is part of a worldwide reappraisal of now the brain works. Scientists now believe that rather than being

organised like a telephone exchange or computer, the brain is instructed by complex chemical codes.

The key breakthrough, five years ago, was the discovery of the first brain hormones, or neuropeptides. These are made up of a number of amino acids, strung together in various sequences. They are believed to control important areas of brain function, according to their precise combination. Their discovery and analysis has led to a frenzy of research by several big drug companies, excited by the possibilities of marketing medicines that might restore lost memories, speed up learning, improve concentration, and induce behaviour changes — even, perhaps, making old people feel happy, like the users of the “soma” pill in Aldous Huxley’s “Brave New World.”

Dr John Hughes, co-discoverer of neuropeptides, has just become director of a Cambridge laboratory opened last month by the pharmaceutical firm, Parke-Davis. “In five years we have discovered 30-40 neuropeptides, in the next five years we would expect to discover at least 100 more,” he says. “It is a totally new look at the way the brain functions.” Another firm, Merck Sharp and Dohm, is opening a laboratory at Harlow, Essex. “There is great scientific excitement about the discovery of these new substances,” says Dr Leslie Iverson, another leading British researcher. “They are unlike anything discovered before in brain chemistry. Tiny amounts of them can switch on or off whole areas of brain function. They will alter an animal’s behaviour. You can make it hungry or thirsty, remember or forget, or change its mood at will.”

Researchers discovered that the hormone vasopressin, which controls certain metabolic functions in the body, could also have powerful effects on the memory. But any dose sufficient, to produce these effects carried unpleasant sideeffects such as water-retention and raised blood pressure. In Utrecht, Dr De Wied found that by isolating a particular string of amino acids from the chain which makes up the hormone — and by “snipping off’ one amino acid from the end of the sequence — he could eliminate side-effects. Rats given a drug containing this

particular sequence of the hormone — known as DGAVP — had far more ability to learn and remember than those who were not treated. In November, 1979, Theo Goossens became one of the first

volunteers for the experimental use of DGAVP on the human brain.

“The experiment consisted of four treatments,” says Dr Jelles Jolies, the brain research scientist who treated him. “It was a doubleblind test in which active treatments and placebos were given. We didn’t know which treatments contained the active peptides. When we carried out neuropsychological tests, we discovered there was much faster improvements during the period of active treatment than when the placebo was given.” Within a few weeks of the first treatment, Goossens felt his memory coming back. He began to speak more coherently, understand things he read or heard, and remember at least one or two digits of a telephone number. But as his memory returned, so did his pain. “My wife was against my taking part in the experiment,” he says. “She was glad I had got rid of the pain and she wasn’t so interested in my getting my memory back. But if it’s a choice between the pain, no matter how terrible, and being nobody, doing nothing, I’d rather have the pain.” He still has difficulty in finding complex words and says he speaks slower than he did before the operation, but he no longer has to carry his name and address in case

he gets lost and he has taken a job with a pressure group which works for former Resistance members.

Goossens was one of eight “guinea pigs” whose memories improved dramatically. A further eight among the 40 volunteers showed some improvement. The remainder experienced no significant change. Dr Jolies believes that only some cases of memory loss can respond to treatment. If the brain is too damaged or there are other medical complications, there is nothing for the peptides to work on.

“For the future” he says, “we are looking for patients who are just a little slower than normal and are becoming forgetful with age. Maybe they are finding it hard to follow television or a conversation as easily as they did. I am sure this treatment will be able to reverse this normal ageing process of the brain.”

The Utrecht experiments have given added impetus to the race to produce “brain pills.” So far research has focused on five kinds of neuropeptides. © Non-addictive painkillers based on the discovery of encephalin, the brain “opiate,” by Dr Hughes and his colleague Dr Hans Kosterlitz.

® The anti-psychotic pill based on the neuropeptide endorphin,

being researched by the Dutch pharmaceutical firm, Organon. “We are at stage two of the trials,” says Dr Roger Pinder, research director. “So far it seems most effective with acute schizophrenia. We have had some dramatic results. We could have a major anti-psychotic drug by the late 1980 s.”

® The “memory drug” containing the synthetic hormone DGAVP, developed by Dr De Wied. His results have not been repeated in this country and there has been strong criticism of his claims. However, Herberyt Weingartner at the national Institute of Mental Health in the United States has tried vasopressin on healthy students with significant improvements in their memories.

@ The “forget drug” based on the hormone oxytocin (the chemical released during childbirth), which can help to induce amnesia. It has been tested in Canada on women volunteers who tended to forget information given at the same time as the peptide. It has also been used to treat some patients who have had traumatic experiences. • The “contentment pill,” which has been shown to induce in depressed or very old people a feeling of well-being. This hormone sequence (ACTH 4-9) has also been found to increase concentration and motivation in healthy young people. It was also developed by Dr De Wied.

Organon has made some clinical trials which have produced “improvements of mood ... in social contact and better co-operation with other residents and nursing staff of the geriatric institution.” “We expect the drug to be on the market by 1986 or 1987,” says Dr Pinder. The next move for Dr De Wied’s group is to work with people who are gradually losing their memories and to experiment with children whose intellectual development has been disturbed or delayed. Dr De Wied is excited by other

possibilities too. “We will be able in future to affect all the process of the brain,” he says. “If you have people with sexual or behaviourial disturbances, you will treat them with neuropeptides as a stimulator or an inhibitor. And if, as seems likely, the ageing process of the brain is due to deficiency of neuropeptides, we could boost them and perhaps reverse the ageing process.”

However, Drs De Wied and Jolies are cautious about the use of these peptides for normal people. “I hear they’re already sniffing vasopressins before examinations in America, but I don’t think doing this will make anyone invent the Bomb,” says Dr De Wied. “If people found out that they could improve their abilities this way, there would certainly be a demand for them.

“The neuropeptides are the oil in the machine, they make everything go smoothly, but like everything else they can be abused. It is of course possible, if you want to brainwash someone, that these substances could be used to reinforce indoctrination aand extinguish ‘bad habits’ — such as having ideas about society.” The new generations of drugs is not without its critics and Dr De Wied and his team have been accused of exaggerated claims. Professor John Jenkins at St George’s Hospital, Tooting, London, has used the memory peptides on a few volunteers, but without sue-' cess.

He does not dispute that hormones such as vasopressin are active all over the human brain. “The stuff is there, therefore it must be doing something important,” says Jenkins. “The trouble is, we don’t know exactly what.”