THE SWEETEST REMEDY

Injections for diabetics could soon be a thing of the past thanks to the patient studies of one team of researchers. Hilary Bower reports on the groundbreaking results of a 24-year project

My friend Nicholas is in his mid-thirties. Three times a day, every day, he retires to a bathroom to search for a soft piece of flesh to push a needle into. He's been doing it since he was a young boy and there are parts of his body - the tops of his thighs, patches on his buttocks and stomach - that are now so leathery as to be almost impenetrable.

I have vivid memories from university days of Nicholas disappearing - at the beginning, middle or end of a date - ranting, running, climbing over railings, trying car-door handles as if to thieve, turning into an aggressive Mr Hyde character. And of rescuing him hours later from casualty wards, where he'd been taken after being found slumped on the street - assumed drunk or high. Hooked up to a drip, he'd have bruises and bloodied knuckles. From falling? From fighting? He couldn't remember. He'd be exhausted and tearful.

All this feels a long way from the peace of Philip Cohen's deck overlooking the River Tay, the wide mudflats gleaming gold and silver in the setting sun, the air threaded with the cry of curlews, the dusky garden smells. Far, too, from the burgeoning laboratory complex in downtown Dundee where Professor Cohen is director of the Medical Research Council's Protein Phosphorylation Unit. For all the feeling of distance, however, the scenarios are intimately connected.

Nicholas is an insulin-dependent diabetic, and in his teens and twenties a particularly unsettled one. He refused to eat when he knew he had to, refused to inject insulin until it was essential, and spent days, weeks and months swinging wildly from "hyper" to "hypo" - blood sugar too high, then too low. Now in control, he's one of 370,000 people in the UK and 35 million worldwide who have no alternative but to inject insulin daily.

Five months ago Professor Cohen and his team of molecular biologists discovered something that could put an end to this daily search for needle space. After 24 years, they have found the final missing link in a biochemical chain that has puzzled, frustrated and teased scientists around the world since the discovery of insulin in 1922.

Diabetes mellitus (literally "sweet urine") is caused when the body either lacks or fails to react to insulin, the hormone which regulates our use of the sugar energy we get from food. Insulin is crucial to health because the brain cannot store glucose and needs a more or less constant supply to run properly. It is released from the pancreas when blood sugar is high and its principle function is to transport excess glucose into storage in the cells of the body where it can be called on when blood sugar gets low.

In insulin-dependent diabetics, the pancreas does not produce insulin, so when blood sugar is low, the body starts digesting itself to make glucose and compensate. In non-insulin-dependent diabetics, the body for some reason does not respond to the insulin floating around in the bloodstream and the same thing happens.

As any chocoholic knows, "sugar shock" or hyperglycaemia does funny things to your well- being. First your heart ups its beat, then come the shakes and, finally, the drooping tiredness. In diabetes, the same thing happens: too much glucose in the bloodstream and the brain gets "flooded", making its owner weary, lethargic and incredibly thirsty as the body craves for dilution of the syrupy blood. If the levels continue to rise, the brain simply gives in and the unfortunate person drifts confused and dehydrated towards coma.

On the other hand, too little blood sugar (hypoglycaemia) - or too much insulin - and the brain is starved and the body gets weak at the knees, irritable, aggressive, disorientated even. In the worst-case scenario, unconsciousness follows.

Food, exercise, work and stress all meddle with blood-sugar levels, and the aim of diabetic therapy - either insulin injections, drugs which reduce sugar levels in the blood, or dietary control - is to keep sugar and insulin in some sort of balance. This tricky feat has its effect on many body systems and tells on later health. Diabetics have double the risk of a heart attack or stroke, kidney disease and hypertension. A quarter have eye problems which can lead to blindness, there is increased susceptibility to infection and many suffer from vascular problems which lead to leg and foot ulcers - 50 per cent of non-emergency leg amputations in the UK result from infected leg ulcers.

In 1993, a major trial in the US found that diabetics who kept their blood sugar on an extremely tight rein dramatically reduced their risk of later illness. But this meant following the terribly intrusive regime of not only using insulin up to four times a day, but also monitoring blood-glucose levels using finger-prick blood tests or urine tests a similar number of times each day. But also, such sensitive control actually puts the testers on a knife-edge and it is easy to slip into a hypo or hyperglycaemic state with all its distressing instability.

With one in every 60 people in the UK and a staggering 135 million people worldwide - four times the number in 1987 - who have problems controlling their blood sugar, it's no surprise that finding a "cure" for diabetes comes pretty high on the list of research priorities. But while some scientists search for genetic explanations and place their hopes in gene therapy, and others look to techniques of implanting insulin-producing cells into the pancreas, Philip Cohen has doggedly been tracking down exactly what is going on when insulin meets cell using basic - some might say old-fashioned - biochemistry. In doing so and unravelling the incredibly complex events that lead to the most common of chronic diseases, he has won the 1997 Louis-Jeantet Prize for Medicine, an award second only in prestige to the Nobel Prize.

The keys to his breakthrough are two complex but absolutely fundamental biological processes known as "signal transduction" and "phosphorylation". Discovered in the Fifties by Edmond Fischer and Edwin Krebs, who won a Nobel Prize for their achievements, these processes have fascinated Cohen since his neophyte days in Fischer's laboratory at the University of Washington in Seattle.

Signal transduction is the process by which a "signal" in the blood - like a hormone, a neurotransmitter, or a molecule produced by an infectious agent - makes itself known to a cell and prompts a response in the body. Such signals might, for example, tell your immune system to get moving because a virus has just infected you, or prompt the stomach acid needed to digest lunch, or mobilise the energy needed to scratch your nose.

These molecules, which carry the tiniest fragment of a signal, don't actually enter the cell themselves to get their message across, but instead click into a receptor on the outside of the cell. Their message is picked up across the cell wall by a chemical known as a "second messenger" which in turn trip-switches any number of other proteins in the cell until, seconds or minutes later, the body responds with an action a million times greater in size than the signal in the bloodstream.

The motor for this game of chemical dominoes is phosphorylation, a chemical process that causes phosphate to be either attached to or removed from a protein. It is this attachment and detachment that triggers action. It can alter a protein's properties in a number of ways - such as making it move from one part of a cell to another, become more or less active, or stop doing what it was doing altogether.

Imagine this: you're walking home late at night when suddenly you're startled by a figure in a doorway. In a split second your heart leaps, your pulse races, your eyes swivel, you tense and almost break into a run. The figure says "Sorry", crosses your path and hails a taxi. You relax and walk on.

What just happened was that molecules of adrenalin - the "fight or flight" hormone - surged out of your adrenal gland and hit the cell receptors that control mobilisation of energy. Within seconds, the adrenal signal gets multiplied 1,000 times by a second messenger which forces two kinases to attach phosphate to two proteins. These, in turn, fire the enzyme which makes muscle cells release the major glucose reserves they need to run like hell. Seconds later, the threat got his cab, and your signal transduction cascade of adrenalin went into reverse, separating the chemical chain and relaxing the alert.

This type of chemical chain reaction - based on adding and taking away phosphate - regulates almost all biological process - from digestion to memory, immune-system reaction to growing nails.

"In the early days, phosphorylation was thought to be a control mechanism confined to glucose metabolism. The penny hadn't dropped that this was the key to almost every regulatory mechanism there is," says Cohen.

And the principles also illuminate illness.

"In many illnesses something is going wrong with the signalling mechanism. Things get turned on, or off, at the wrong time, in the wrong place, in response to the wrong signal or even in response to no signal at all." So all you have to do to "cure" diabetes, for example, is work out which part of the chain is going wrong. Simple.

Not surprisingly, it isn't. For a start there are two different types of chemicals at work in phosphorylation: kinases which attach phosphate and phosphatases which detach it. At each stage you have to work out what is taking place and which kinase or phosphatase is doing it to which protein. Given that there are about 2,000 kinases and phosphatases in the human genome and roughly 50,000 proteins in a cell, this can take some fiddling around. And once you've done that, it's very likely there are several more links in the chain to be worked on.

Cohen's coup is that, after 24 years of painstaking attention to minute biological detail, he and his colleagues have finally mapped the whole of the signalling pathway triggered by insulin - a huge, multi-stranded labyrinth of a chain.

To find the elusive factor, Cohen worked backwards from one of the key physiological effects of insulin - its ability to stimulate muscle tissues to store energy from food in a form known as glycogen - the opposite action to adrenalin.

"We knew from work done in the Sixties by Joe Larner in Minnesota that the end product of the cascade was an enzyme that made glycogen," says Professor Cohen. "And that this enzyme was triggered by a loss of phosphate, so the inference was that back along the track insulin either stopped a kinase from working or activated a phosphatase which took the phosphate off."

"At a stage like this it's very easy to go in the wrong direction," he adds. "For many years we thought a phosphatase was the key and because of this, and for a whole lot of complex technical reasons, we missed the effect of insulin on a kinase called glycogen synthase kinase 3 or GSK3."

Turning off GSK3, it turned out, was a key step needed to get muscle cells to store energy. But that was only the beginning of the story.

"Now we had to find a kinase that could be turned on by insulin's signal and which could then switch off GSK3." This took almost 20 years. In early 1995 Cohen and his team finally discovered that an enzyme called protein kinase B (PKB) did the trick.

But still there was an infuriating gap between insulin and PKB. Though other researchers had leapt into the breach and identified a chemical messenger called PIP3 as a possible candidate for second messenger, no one had been able to find the kinase that switched on PKB and made the final link between signal PIP3 and PKB. The frustration was palpable. There are 50,000 proteins in a cell. To identify and purify the right one, you have to get rid of the other 49,999. This was not a game for the impatient.

But on 5 January, Dario Alessi, a young protege of Cohen's, had an inkling he'd broken the impasse. By 18 February he had not only managed to purify his candidate protein PDK1, but had proved it responded only when PIP3 was there. PDK1 was the final link. On 19 March 1997, Cohen and Alessi published their findings both in the new up-and-coming European science journal Cell Biology and on the Internet - 75 years after the discovery of insulin.

Like a relay race with insulin as the starter's gun, each "runner" protein passes energy and momentum to the next, and finally persuades a muscle cell to transform the blood sugar collecting in the body from food into the stored energy vital to life.

"PDK1 is only one millionth of the total protein in a muscle cell, yet it was the missing link in the whole insulin-signalling pathway," says Cohen. "And although we have been working on what happens when insulin stimulates the production of glycogen in the muscles, we believe branches coming out from this cascade will also explain how insulin converts glucose to energy in the heart, how it stimulates the uptake of glucose into cells, how it promotes the synthesis of protein as well as glycogen, and the other metabolic actions of insulin.

"Now we know the whole cycle, it should be possible for a pharmaceutical company to develop a drug which can mimic PIP3 and turn on the PDK1 enzyme. This would trigger most of the actions of the insulin cascade and alleviate both insulin dependent and non-insulin dependent diabetes. Because if you can activate PDK1 without insulin, those who can't make insulin don't need to inject it and, in non-insulin-dependent diabetes, turning PDK1 on would bypass the block."

Such a drug could be on the market in a decade. So excited by Cohen's work are four large pharmaceutical companies that they are on the verge of signing over pounds 6m to fund a new Signal Transduction Unit that will make Dundee the most advanced and sophisticated centre of this aspect of science in the world, with work going on not only for diabetes but also for cancer, rheumatoid arthritis and psoriasis.

A signal cascade called the MAP kinase pathway is thought to be a key player in cancer. Normally prompting cell growth in response to growth factor hormones in the blood, the pathway appears to be thrown into chaos by the presence of abnormal proteins created by anything from inherited gene malfunctions to environmental spanners such as ultra-violet light, tobacco smoke and viruses which turn on the cascade indiscriminately.

"If you can find ways to suppress the cascade, then you can stop the abnormal proliferation," says Cohen, adding that there are already trial compounds which in the test-tube can completely reverse the development of cancer cells.

"That drug works by stopping one of the kinases in the MAP kinase pathway activating another. For it to be useful therapy in humans, it will have to be made 1,000 times more potent but the fact that we now know it can do it, and how, means it is possible, and we just have to find a better compound."

Compounds that inhibit kinases in similar pathways are being tested to treat inflammatory conditions such as rheumatoid arthritis and psoriasis.

"The exciting thing here is that we have found the components of an important pathway that has to be damped down to alleviate inflammation and drug companies are now trying to develop drugs that turn off all the kinases in a pathway to see which one produces the least side-effects when it is knocked out," says Cohen.

Such a drug for diabetes would be a sweet remedy for millions. And sweet success for Cohen and his back-to-basics biology. !

SIGNALS NOT TO BE FORGOTTEN

THE EFFECTS of signal transduction and phosphorylation are not limited to physical conditions. Scientists believe they could explain why some of us remember better than others, and even explain those mysterious moments of sheer blank that sometimes hit us in times of pressure and stress.

The outline of the hypothesis comes from studies with mice and fruit- flies. Mice bred without the ability to make a protein named CREB, it appears, cannot remember anything, while others bred without a chemical called caM kinase can't learn anything. Forgetful fruit-flies, on the other hand, frequently appear to be missing a second messenger called cyclic AMP. (And just in case you are wondering exactly how one knows whether a fruit-fly has forgotten something - it's simply Pavlovian. Fruit- flies love rotting fruit but if they get a mild electric shock when they land on it, like most of us, they'll remember and steer clear. Mutant fruit-flies with short or no memory just keep on landing and being shocked.)

It's clear, say researchers, from these findings that these three chemicals are key players in the signalling pathways of memory. But they are also active in many other pathways including those which trigger all sorts of stress responses in the body, and it is possible that the crossover may explain, in biological terms at least, everything from momentary lapses and examination "empty-brain" to Retrieved Memory Syndrome.

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