SCIENCE: GROWTH INDUSTRY

Laboratory grown livers and synthetic skin are no longer fantasies from science fiction. Norman Miller on progress highs (and possible ethical lows) in the world of bio-engineering

IN OUR throwaway society it's great when people find a use for something that usually ends up in a bin. So, let's hear it for the Californian scientists producing life-saving sheets of real flesh from the discarded foreskins of circumcised babies.

Until recently, if you needed large areas of skin to treat severe burns, for example, it usually had to come from a dead person or a dead pig. Now, bio-engineering laboratories are hard at work turning out not only skin but also veins, bone, liver, cartilage and breast tissue. Welcome to the body-part store - your replacement tissue is in the post ...

Though it all sounds very sci-fi, the earliest example of modern tissue engineering dates back to 1933 when an Italian scientist, Vincenzo Bisceglie, encased mouse cells in a membrane and inserted them into a guinea pig. Once inside they continued to function, protected by the membrane from the animal's immune system.

This groundbreaking experiment laid the foundation for one branch of tissue engineering where implanted tissue does its work from inside an immunoprotective membrane. It is now being studied with a particular eye on treating diabetes by implanting insulin-producing cells (called islets of Langerhans) to do the work of a defective pancreas. It is also being pitched into the fight against brain diseases such as Parkinson's, where dopamine- producing cells injected into the brain have significantly reversed the impact of this terrible disease.

A more recent branch of tissue engineering focuses on actually growing a variety of human tissue in the lab. Rather than trying to augment a faulty organ by injecting a few healthy cells under protective cover, these bio-engineers are out to grow a healthy new organ from scratch - replacement rather than augmentation. Remarkably, nature - so often the source of hurdles - seems positively helpful to the whole enterprise. Bio-engineers are finding that basic cells are remarkably adept at organising the regeneration of the tissue from which they were taken, and also developing into complex structures, so long as they are given the right nutrients and some orchestration in the shape of delicate scaffolds to help them do their building work.

Bio-skin illustrates this process perfectly. A Californian company, Advanced Tissue Sciences, has started growing a product called Dermagraft. Take starter cells known as fibroplasts from a nipper's foreskin, and attach them to a finely structured mesh made of a suitable biodegradable substance. The most commonly used materials are two synthetic polymers, polyglycolic acid and polylactic acid, which have ideal properties in terms of surface adhesion and porosity, lack of toxicity, malleability and the time-scale over which they degrade. Take the cells and their scaffold, culture in a mix of nutrients which stimulate the cells to secrete proteins and growth factors, leave for between 16 and 25 days and, hey presto, you get what boffins call a three-dimensional tissue matrix and what you or I would call skin - 5 by 71/2in sheets of it, ready to be frozen, sealed in sterile cases and shipped off to a hospital near you. Just open and apply.

Bio-skin is in high demand. In the USA alone, over 2 million cases of chronic, slow or non-healing skin ulcers are treated each year, with diabetics making up a large proportion due to their vulnerability to a condition called peripheral vascular disease. Until now, treatment has been hit and miss, with variable healing and a high recurrence rate dogging doctor's efforts. The inadequacy of current treatments results in thousands of amputations a year, with a healthcare bill of around pounds 13m in the UK. Dermagraft is altering this grim picture, with clinical trials showing it to be at least six times more likely to promote complete wound healing and prevent ulcer recurrence than other treatments.

Animal rights activists will also be happy to know that bio-engineered skin is now being used to test cosmetics and other substances for toxicity, while burn victims are benefiting from a modified version of Dermagraft, which is being used to treat second-degree burns (the commonest type of severe burn), in which the upper layer (epidermis) of skin and part of the lower layer (dermis) are damaged. Called Dermagraft-TC (the letters stand for "temporary covering"), it is a combination of a synthetic epidermal layer and a bio-engineered human dermal layer which is applied to burns to keep them clean and covered until some of the patient's own skin can be grafted on as a permanent fix (autografting). Here the bio-skin acts like a hi-tech natural bandage rather than growing and becoming an integral part of the patient's body.

If all this talk about growing body bits is making you feel a bit off- colour, maybe a new liver would pick you up. No problem. Bio-engineers are busy on that front, too, since the option of fighting liver disease through transplants alone is a dismal one - the number of people who die from liver failure is around 10 times the number of donors available. Once again, the starting point is basic cells (in this case, liver cells known as hepatocytes) inserted into a suitable scaffold.

Results so far look promising, with hepatocytes, given the right support, managing to form tissue structures resembling natural liver tissue and, more to the point, doing at least some of the work of detoxifying blood, though not yet as effectively as a normal working liver. A full laboratory- grown liver is some way off but a prototype bio-artificial liver is being developed at the University of Minnesota: 13,500 hollow fibres contain liver cells (around 200,000 in each fibre) packed inside a cartridge with inlet and outlet ports for the patient's blood.

Although 2.7 billion hepatocytes per liver sounds like a lot, bio-engineering's big numbers are matched by the big bucks involved. Robert Langer, a leading bio-engineer at MIT, puts the cost of treatment, support and lost productivity due to tissue loss and organ replacement in the USA alone at a staggering $400bn a year - the kind of money anyone would want to talk about.

Cartilage and tendon, on the other hand, aren't a topic of general conversation - not unless they belong to an injured sports star like Alan Shearer, in which case millions of people suddenly become fascinated with the stuff. For bio-engineers, though, it is always a good subject: over a million operations a year in the US involve cartilage surgery, and a multi-million dollar sports career can be ended by a bit damaged of tissue. "There is no lack of enthusiasm and interest from sports surgeons in our products," says Janet Wahl of Advanced Tissue Science.

Cells called chondrocytes are being used to create laboratory cartilage that's hard to tell from the stuff in your body and has already been used by Swedish doctors to repair knee injuries. Tendon trouble could also be a thing of the past thanks to cells called tenocytes from which tendons similar in structure and tensile strength to your body's own brand have been successfully grown. And bones may also become more repairable after the success of various bio-engineering teams in persuading bone-growth factor - called bone morphogenic protein - to turn into new bone, complete with marrow.

Another breakthrough has come in the shape of designer blood vessels for bypass surgery. Rather than trying to find some spare vein from elsewhere in the body, a team at Quebec's Laval University School of Medicine turned to bio-engineering to grow a blood vessel capable of withstanding pressures 20 times higher than they are ever likely to face inside your body. Human trials are set to begin before the millennium.

The tabloids, meanwhile, have shown a sudden interest in science at the mention of breasts. Bio- engineered breasts (grown on a suitable scaffold) could provide a wonderful natural alternative for the 8,500 women a year in Britain forced by breast cancer to have mastectomies. Although the product's American manufacturers, Reprogenesis, see the replacement breast tissue as primarily for cancer patients, they do not deny it could also find a use in cosmetic surgery for an off-the-peg bust.

But are there ethical questions to consider in the use of artificially grown tissue? If drugs don't boost performance enough, could the 21st- century sports pro turn to a bio-engineer to get some extra-strong muscle or tendon, or new "super" blood vessels to increase stamina? If that sounds like something so risky no-one would do it, remember how far some eastern European women athletes went in terms of steroid abuse, in the worst cases permanently damaging themselves to get that extra yard.

Of course, anxious types might start worrying about bio-reactors full of whole people floating in nutrient baths just waiting to be hauled out. This kind of nightmare vision isn't looming just yet - not unless you don't mind your bio-Adam or bio-Eve coming up a bit short in the brain and nerve department.

These two areas are still undeveloped on the bio-engineering map. Brain tissue growth remains largely unexplored, while nerve cells and polymers just don't seem to mix too well. "They don't adhere well to most plastics," says Langer.

But Langer is much more upbeat about something like growing an arm and hand, if you've got six weeks to spare. The shape isn't a problem in terms of building suitable polymer scaffolds, nor is making the relevant tissue (veins, muscle, bone, cartilage, tendon, ligament, skin). "This technology is already in place," says Langer. "The hurdle is regeneration of nerve tissue."

Even here, some ground is being gained, using what are called Schwann cells taken from sciatic nerves. Diffused in polymer membranes, these help sliced nerves regenerate in vivo (in the body) but not yet in laboratories. However hi-tech, they can't yet supply the benefits of a fully functioning central nervous system.

But bio-engineering is still a young discipline. Langer is confident in his predictions for things like artificial wombs, perhaps before the millennium. In these, severely premature babies could breathe oxygen-rich liquids called perfluorocarbons while their immature lungs grew strong enough to breathe air (most pre-24 week infants die from lung problems). Then they could be "born" again from their artificial home. Futuristic? This future is now, with such liquid breathing systems already on trial.

Helping the very young would be a fine way for bio-engineering to repay the debt of using infant cells. "After all," says Langer, "the developing child is the ultimate tissue engineer."