Science: A warm Wellcome to Tayside

Golf, cake and jam aren't all Dundee

has to offer. A new biomedical research

centre is attracting top scientists from

around the world. Hilary Bower talks

to four of its key players about their work

INKE NaTHKE sits with her smiling moon-faced baby on her knee and holds what appear to be parallel conversations. In one stream she describes to me intricate investigations of molecules involved in cell migration that could provide the clue to genetic cancer; in the other she's picking the brains of anyone who passes on mortgages, homes, childcare and schools.

Inke's not downshifting. Defying the "brain drain" and Britain's reputation for meagre science resources, she and her husband Jason Swedlow, have been seduced from their ivy-clad laboratories in Harvard to join the 250 scientific movers and shakers from Britain, Europe and the US who are to populate a new pounds 13m biomedical institute in Scotland on the banks of the River Tay.

Named the Wellcome Trust Building after its chief benefactor, when the airy five-storey science centre was officially opened recently with a biochemistry department staff of 450, it gave Dundee the largest concentration of life scientists in the UK after Cambridge and Oxford. More than 1,500 people are now involved in biomedical research in this city of golf, cake and jam. And if the building's director Professor Philip Cohen has anything to do with it, this is just the beginning. "People should know that some of the best science in Britain is going on in the `Tartan Triangle' - Dundee, Edinburgh and Glasgow - and not just the `Golden Triangle' of Oxford, Cambridge, and London," says Cohen. "People are falling over themselves to come to us."

A Sassenach and Royal Society professor, Cohen moved to Dundee 25 years ago and never left. Not only has he resisted the blandishments of any number of prestigious posts overseas, he even refuses to publish in American journals, arguing it simply makes it easier for those over the pond to pretend European science is a poor relation. "We must try to reverse the `brain drain' to the US. We need to get the best people back here because they are absolutely essential for training future generations," he says.

In Dundee, Cohen and his "search" team have certainly turned brain drain into brain gain. In the past seven years they have persuaded scientists from Germany, Holland, Ireland, Italy, Switzerland and the US to join them and have stolen key players from the "Golden Triangle".

What did they have to offer them, I ask. Huge salaries?

"Absolutely not," explodes Cohen. "We offer them absolutely nothing except a congenial atmosphere and a chance to develop their science. Our philosophy is to appoint people whose work we find most exciting and who we think will be congenial as colleagues - those are the two overriding criteria.

"Some people who we have invited here were turned down by other places which couldn't see what was interesting about their work. Now our people are being offered attractive positions elsewhere all the time. One of our investigators just turned down a chair in Cambridge," he adds. Quite a coup for a not terribly rich university, with little in the way of misty- spires influence.

Scotland has long had an international reputation for medical excellence, but it's a combination of good basic science and the perfect antidote to long hours in the lab - an easier living environment - that's attracting today's high-flyers, says Professor Birgit Lane, whose own groundbreaking work on epithelial cancers and skin disorders began in Dundee. "There are seagulls outside, water and hills and open spaces and the air is fresh and clean. In the evening I can get out of the lab and drive along a stretch of water to somewhere quiet. But there is also good science being done here. In the scientific world Dundee has really moved up in recent years."

Professor Jeff Williams, who's about to move his work on the primitive organism dichtyostelium, a valuable model for tissue development, from the Imperial Cancer Research Fund laboratories in Hertfordshire, sees both his science and his salary going further.

"It's the best of both worlds, you can buy more house for your money, live well on an academic salary, in a beautiful environment, and be involved in first class science. What more could you want?"

The Wellcome Trust Building is funded by a pounds 10m donation from the eponymous charity, and the gift, thought to be the largest single charitable donation ever given to a Scottish institution, has been swelled by Scottish Enterprise Tayside and Tayside regional council who have high hopes of a biotechnology influx to boost the local economy. And Cohen's legendary persistence has extracted money from a variety of charities and sources such as the Scotch whisky Gannochy Trust, romantic novelist Dame Catherine Cookson, and Sean Connery, who has marked his love of Tayside golf by dividing the pounds 160,000 he received for a one minute walk- on in Robin Hood, Prince of Thieves between four local charities, including the Wellcome Building.

The common scientific complaint of lack of research funds appears to be non-existent in Dundee. Most of the principal investigators have even brought their own salaries (in the form of fellowships), and collectively they have won grants totalling over pounds 18m.

This will fund research across the four new divisions - molecular parasitology and biological chemistry, molecular cell biology, gene regulation and expression and developmental biology - reflecting the hottest areas of biomedical science.

"Our aim is to use fundamental science to understand the causes of diseases such as diabetes, inflammation, hereditary skin conditions, immune system defects and parasitical diseases," says Cohen. And if all his recruits fulfil their potential, he predicts, we'll be hearing much much more about science north of the border.

MIKE FERGUSON: BOLT FROM THE BLUE

Though Professor Mike Ferguson's office looks out on to the cool Grampians, his mind is in the tropics on African sleeping sickness, Chagas disease and leishmaniasis. His team are as close as any in the world to producing treatments for these devastating diseases, all spread by a particularly nasty parasite family called trypanasomatids.

Between them, these parasites cause a huge burden of illness and death. Ten to 20 million people in South and Central America are thought to be infected with Chagas disease, of whom 15 per cent will die; while epidemics of African sleeping sickness and leishmaniasis often follow conflict or disaster, killing tens of thousands. Current treatments are at best ineffective, at worst toxic, expensive and difficult to administer.

It's against this background that Ferguson and his Dundee team, using the fundamental principles of cell biology and synthesis, have revealed chinks in the parasites' armour. It started with his discovery that although the parasites are very different, their surface molecules - which carry the infection - are anchored by a common biochemical "bolt" made up of enzymes.

"If we could make a drug that prevented the parasite from assembling this `bolt', all the organisms would essentially be naked. They'd lose their surface molecules and without their surface molecules they are non- infectious," explains Ferguson. "You only need to hit one enzyme to prevent the assembly of the bolt."

Earlier this year, the team succeeded in purifying and subtly modifying two of the first candidate enzymes for stripping their parasite naked. One relates to African sleeping sickness; the other is found both in trypanosome and in the malaria parasite.

"Now, for the first time, we have isolated a molecule that will both inhibit the parasite enzyme without touching the same enzyme in humans," says Ferguson. "It's the age old principle of the magic bullet."

There's still a long way to go: hundreds of different analogues of the compounds need to be generated and tested before the right one will be found. And there is also the task of trying to attract the attention of big pharmaceutical companies more attuned to drugs saleable in the rich West than those needed in the developing world. But Ferguson is enthusiastic - and when he needs to recharge, he heads for those hills and does battle with the midges instead.

CHERYLL TICKLE: OUT ON A LIMB

Why do our arms pop out just below our shoulders? How do our legs know to grow from the base of our trunks? How come there's a thumb on one edge of our hand and a pinkie on the other? Why indeed asks Professor Cheryll Tickle, a developmental biologist on the move to Dundee.

On her office wall hangs a picture of a smiling girl wearing cowboy boots. The girl is embracing a magnificently-plumed turkey - an appropriate metaphor for Tickle, whose days are spent manipulating the delicate collections of cells that make up early chick embryos in search of answers to fundamental biological questions like "how can a ball of cells end up as something that looks like a human being?"

"It's one of the most major biological problems you can tackle," she says.

Tickle's speciality is investigating how simple cells with no particular function specialise to become the muscle, skin and bone cells needed for live and kicking limbs.

"We've got very precise arrangements of muscles, particular shapes of bones, numbers of joints, even just in a finger. All that somehow arrives out of patterns of genes and signals. We know quite a lot about these, but how we go from them to something that looks like an arm is still a big gap."

One piece in the jigsaw is the discovery that limb cells start to grow out on the orders of chemical signals sent by a ridge of cells that encircles the limb bud. These signals, Tickle and colleagues in the US discovered, are fibroblast growth factors (FGF). "We've tested it by cutting off the ridge in early embryos and stapling little beads soaked in FGF on to the limb bud. If we use enough of these beads, we can rescue limb growth. The limb grows, not absolutely perfectly, but fairly normally right to the digits."

FGF, it appears, can activate limb development anywhere on a line running down the body from the top of the arm to the bottom of the leg, says Tickle.

But before the imagination runs riot on the possibility of growing new legs for the disabled, it's important to remember that this all happens in tiny embryos. "To correct disability, you would have to identify early on that something had gone wrong with the limb and then you would have to go into the early embryo to change it. We can't do that."

What is exciting, she says, is the combination of knowledge about these signalling chemicals and the increasing ability to identify genes responsible for inherited conditions. "We're beginning to get a match-up between the experimental embryology and human conditions. For example, one of the genes we have been working with is also responsible for a human condition called Holt Oram syndrome affecting the limbs and the heart." There are also parallels with tumours - one of the FGFs important in limbs was first identified in human stomach cancer, she adds.

And in case you are wondering: thumbs develop because their early cells sit farther away from a particular set of signalling cells than proto- pinkie cells that sit close.

BARBARA SPRUCE: THE MIND-BODY LINK

Fourteen years ago Dr Barbara Spruce became addicted to a chemical called proenkephalin, one of the body's "feel good" chemicals - the natural equivalent of morphine and heroin. Her fascination took her away from her hospital job and into Imperial College. August funding bodies laughed at Spruce's hypothesis that proenkephalin was any more than brain candy, but now her laboratory in Dundee is a leader in the field of programmed cell death and on the verge of creating an entirely new form of cancer drug.

Spruce found proenkephalin, which everyone thought was only active in the brain, is present in almost all body tissues and is one of the key regulators of cell death - a mechanism crucial for life. Disruptions (causing cells to die when they shouldn't, or not to when they should) are thought to be responsible for many diseases included cancer. "We know proenkephalin promotes cell death or cell survival depending on where it is located in the cell. We also have evidence that the opioid pathways give tumour cells an advantage allowing them to over-ride the cell death programme and survive when they shouldn't. By switching off the right opioid pathways, we believe we can make a tumour cell self-destruct, without killing non- tumour cells."

Spruce's combination therapy could be ready for trial in cancer patients in six months. She also turned up another "unthinkable" proposition - that the mind-body link proposed by alternative therapists may have some basis in biochemistry.

"It's hard for a scientist to admit, but the link between these chemicals - which control moods and behaviour - and cell death sets the scene for the possibility of feedback between our emotions and health in a fundamental way. We know that under conditions of stress, abnormal levels and forms of enkephalins and endorphins float around the blood stream. If these provide an inappropriate drive to cells to survive, it's possible stress could predispose to disease. An opposite example is exercise, where enkephalins and endorphins are released perhaps in more beneficial amounts or forms. These could set up a desirable equilibrium between cell life and death which protects against disease."

JULIAN BLOW: STOPPING THE GROWTH SIGNALS

Ever photocopied a large document and found you've got a page out of order, or duplicated? Imagine the margin for error if you and several friends had to photocopy the entire Encyclopedia Britannica. That, says Dr Julian Blow, is something like our cells have to do - precisely, accurately - over and over again for perfect growth.

Given the task of making multiple copies of the 3,000 million bases that make up the human genome, it's amazing that more mistakes don't slip through, especially since, in order to get the job done quickly, numerous molecular copying "machines" - known as DNA polymerases - start duplicating the DNA from many different places at once. Not surprisingly, nature has not left this feat to chance and after years of research, Blow discovered the mechanism to keep the copying machines working efficiently.

He has found that the length of our DNA is marked with chemical tags guiding the copying procedure - a process he has called "licensing". "They can only start copying DNA where there's a tag; they have to remove a tag if they copy past it - this prevents another machine starting on a section that's been copied," explains Blow.

"One implication is we've identified a new system involved in preparing a cell to divide. So if we wanted to stop the cell division, this could be a target. DNA replication is one of the first things cells do before dividing. If you stop the licensing - and get rid of the chemical tags - a cell will probably think its DNA has been copied and not continue, which would almost certainly be a better way to try to stop cell division."

Normal cells, he adds, differ from cancer cells by going through a resting phase where the licensing tags are switched off. They are only switched on again in response to a growth signal. In future, says Blow, it's possible, that a drug that shut down the licensing proteins could shunt tumour cells into a resting phase where they may be unable to respond to the abnormal growth signals coming to it.

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