REPLACEABLE YOU THE BUSINESS OF CREATING SPARE PARTS FOR THE HUMAN BODY IS GETTING EVER MORE REFINED. SCIENTISTS ARE NOW ENGINEERING LIVING HUMAN TISSUE IN THE LAB: THE TECHNIQUE MAY ONE DAY SAVE YOUR LIVER, YOUR KIDNEY, AND EVEN YOUR SKIN.
By DAVID STIPP REPORTER ASSOCIATE ALICIA HILLS MOORE

(FORTUNE Magazine) – There had been limit-shattering paradigmatic breakthroughs in life extension during the 2060s and 2070s. As for the 2050s, the stunts they'd been calling "medicine" back then (which had seemed tremendously impressive at the time) scarcely qualified as life extension at all, by modern standards ... If you were smart or lucky, you chose an upgrade path with excellent long-term potential. Your odds were good. You would be around for quite a while. (Bruce Sterling, Holy Fire; Bantam, 1996)

In sterile rooms, moon-suited technicians routinely fabricate disks of translucent skin. Destined for the elderly, the six-layer dermal upgrades roll off the assembly line like little wedding cakes. But unlike yesteryear's prosthetics (lifeless hunks of metal or plastic), they are living bionic subunits, cloned from the vibrant cells of human infants. They literally grow on people. The lucky recipients soon forget they are no longer entirely themselves. (The scene at Organogenesis, Canton, Massachusetts, 1996)

Science fiction novelists like Bruce Sterling give their fantasies an air of reality by deftly alluding to recent research. But a hot new field called tissue engineering is turning this device on its head by seeming to echo sci-fi. At Organogenesis and other firms, researchers really are creating replacement body parts from living cells, conjuring up the bionic genre launched by Frankenstein.

In contrast to such dark yarns, however, tissue engineering promises happy endings--or at least delayed ones. The aging process rarely takes the same toll on all our parts, and often a critical organ like the heart gives out long before others do. The best hope in such cases is to replace the decayed part with an organ transplant or mechanical prosthetic, such as dialysis for kidney failure. That can add years of life. But prosthetics are more like crutches than substitute parts. And only the lucky get transplants: About 18,000 human organs are transplanted annually in the U.S., while an estimated 100,000 Americans die waiting for a spare heart, liver, kidney, or other organ.

Tissue engineering may well revolutionize medicine over the next ten to 15 years, reshaping the $40-billion-a-year medical implant industry just as biotech is transforming the drug business. The main idea is simple: Sculpt biodegradable polymers in the shape of body parts, then seed them with cells that multiply and knit together. The polymers eventually disappear, leaving living tissues that can function very much like original equipment.

Cyborgs-R-Us is still a way off. But a bevy of biotech companies--mostly startups whose still-wobbly revenues come from research contracts with partners such as Sandoz--are surprisingly close to commercializing some of the body's simpler parts. Within months the Food and Drug Administration is expected to approve tissue engineering's first major offering: Organogenesis's living skin substitute. It looks so much like the real thing under the microscope that science teachers have requested pictures of it to illustrate the skin's architecture. Advanced Tissue Sciences of La Jolla, California, is developing a similar skin product.

Living surrogates for cartilage, bone, heart valves, and blood vessels should be in clinical trials by the end of the decade. Replacements for more complex organs are further off. But tissue tinkerers rule nothing out: Recently a team at Boston's Children's Hospital fabricated, on a small scale, an approximation of the tissue of the liver, one of the body's most complicated parts.

Spare parts also may come from genetically engineered pigs-- during the past few years scientists have implanted genes in swine that hinder rejection of their transplanted organs by the human immune system. The approach is less advanced than suggested by recent hype surrounding a race to bring the pigs to market (see box). But its promise is huge--according to a recent Salomon Brothers forecast, some 450,000 pig organs will be transplanted annually by 2010.

So when will the all-new you be possible? Don't count on making the NBA at age 70. But if you're a baby-boomer, reasonable facsimiles for major organs should be ready in time to give you some good years that otherwise mightn't be. Joseph Vacanti, leader of the Children's Hospital project, keeps a futuristic drawing of a bioengineered arm on his desk. "I get phone calls from people who say this is crazy," he says. "But everything except the nerves are just extensions of what we're already doing."

To be sure, the body bionic is decades away, and the road there will doubtless be littered with the bleached skulls of money managers--investors should keep in mind that biotechnology's biggest fizzles began with the hubris of professors who convinced Wall Street they could boss around Mother Nature like a graduate student.

Still, replacement-parts researchers sound reassuringly modest when describing their work--despite their audacious goal, they tend to view themselves as Ms. Nature's humble assistants. That's largely because they have no choice. The biological systems they work with are so dauntingly complex that pretending to micromanage them would seem silly.

There's another reason for the relative absence of Zeus complexes in the spares crowd: They have found that they don't have to understand exactly how all the biological wheels within wheels work in order to succeed--if they create the right milieux for their cellular building blocks, the metabolic mimicry they seek will often happen automatically.

Boston's artificial-liver researchers, for example, place liver and blood-vessel cells in computer-molded scaffolds resembling Wheat Chex. Like nostalgic expatriates, the cells erect within the polymer tenements a likeness of their former home in the body, including tiny blood vessels. Says Vacanti: "Cells are so smart that we don't have to create all the complexity of tissues from scratch. We just have to give them the right cues so they'll re-create the complexity themselves."

Developing living substitutes is one of two big challenges for spare-parts researchers. The other is overcoming the body's not-invented-here syndrome. Implanted foreign cells usually draw heavy fire from the immune system--that's why transplanted organs get rejected unless the patient is dosed with immune-suppressing drugs. Artificial materials spliced into the body trigger a no less problematic response called the foreign-body reaction.

Scientists are beginning to find ways around the body's xenophobia. One ploy is to keep the immune system from detecting molecules that provoke it by packaging implanted cells in chemically inert polymers. It sounds easy. But researchers are only now getting it to work, after decades of struggle. Says David Clapper, chief cell biologist at BSI, a private company in Eden Prairie, Minnesota, that is developing replacement arteries: "It turned out that the body recognizes everything. Nothing is inert."

Moreover, the holes in the porous packages have to be exquisitely engineered--small enough to block antibodies, large enough to allow passage of smaller molecules bearing signals like "start making insulin." Another killer issue: Many kinds of cells go metabolically insane when torn from their familiar surroundings, because signals that keep them balanced are transmitted through the molecules that tether them in tissues.

Companies such as CytoTherapeutics of Providence and Neocrin, a private outfit in Irvine, California, appear to have solved the packaging problem for small clusters of cells. The two are among the companies working to replicate critical functions of decaying organs with implanted cells that release hormones in patterns geared to the body's cycles. CytoTherapeutics is testing implanted cells that offset brain-chemical deficiencies caused by Lou Gehrig's disease and other neuron killers. Neocrin is developing pancreatic proxies for diabetics, using a particularly clever recipe. It immerses bunches of insulin- making cells in a liquid polymer, then dances a laser over the clusters to form permeable plastic skins around them. Another private company, Metabolex of Hayward, California, is working on a similar product. Doctors hope to inject the encapsulated cells in outpatient procedures.

Just as tissue engineers have made advances by abetting Mother Nature, many researchers working on the immune-rejection problem are trying to harness natural processes. BSI, for example, dots its porous artery substitutes with proteins that promote tiny blood vessels to grow into them after implantation, like vines on a trellis. Protein Polymer Technologies and closely held Desmos, both in San Diego, are developing bioengineered glues based on body proteins that serve as the cement between cells. Such adhesives promise better anchoring of dental implants and other replacement parts.

Some tissue farmers are adding fertilizers to their trellises: bioengineered proteins called growth factors. The strategy appears especially promising as a way to generate missing bone. Within a few years doctors may patch bad breaks with porous materials laced with bone-growth factors. Companies developing such products include Creative BioMolecules, of Hopkinton, Massachusetts; DePuy, of Warsaw, Indiana; and Genetics Institute in Cambridge, Massachusetts. Genzyme, also in Cambridge, already offers a kind of living cement for repairing divots in knee cartilage--it extracts a patient's cartilage cells, multiplies them in the lab, then re-implants them.

Weaving spare parts within patient's bodies can go only so far--even if scientists knew how to regenerate failing organs, there generally wouldn't be enough time. Instead, researchers dream of mass-producing organs like bacteria in petri dishes. After a ten-year struggle, the dreamers at Organogenesis almost have to pinch themselves: Studies show the little doilies of imitation skin fabricated at the Canton, Massachusetts, company work. In clinical tests involving patients with venous ulcers--which afflict a million elderly Americans--"Apligraf" disks healed the ugly leg lesions 40% more often than the main alternative, wound compression. And Apligraf did its work in about one-third the time.

Organogenesis, often slammed by skeptics, has defied medical dogma. Says chief scientific officer Nancy Parenteau: "Two years ago I was practically booed off the stage at a scientific meeting for saying Apligraf isn't rejected by the immune system." But its clinical successes support a theory that bodes well for tissue engineering: Selected "non-self" cells, purified of surrounding molecules that trigger immune reactions, aren't rejected when placed in the body. Skeptics still don't buy that. But in June 1995 the FDA put the company's marketing application on its fast track for revolutionary treatments. Approval isn't certain, but it appears likely. Sandoz hopes so: Last January the drug giant licensed rights to Apligraf in a deal valued at up to $37.5 million, plus manufacturing and royalty payments to Organogenesis once Apligraf hits the market.

The company's wizards begin by salting mats of a fibrous protein called collagen with cells extracted from donated infant's foreskins. Lavished with TLC, the cells extend protoplasmic arms and pull the collagen strands into a tight mesh that serves as a seedbed for the skin's multilayered epidermis. Its formation is the hardest part, and Parenteau struggled for years to get its toddlerlike cells, called keratinocytes, to behave. She says, for instance, that "they don't know what an edge is, so they tend to crawl around and fall off" the proto-skin disks. Details of her methods are trade secrets. But like many tissue engineers, she says the key is letting cells do their own thing: "You give them a permissive environment so they can recapitulate who they really are."

Some cells, however, manifest their inner selves best in a structured environment--especially ones from highly organized places like the liver, a factory with some 500 products and services from digesting fat to sweeping toxins from the blood. Over the past decade Boston's Dr. Vacanti and Massachusetts Institute of Technology chemical engineer Robert Langer have pushed the envelope on tissue fabrication by jointly developing biodegradable polymers to help structure cell growth. You may know of their work: The experimental human ears grown on the backs of mice, which hit the media last year with stunning pictures, sprang from it.

Commercial offshoots of their research, including cartilage and urinary-tract replacement parts, are taking shape at Advanced Tissue Sciences and at Reprogenesis, a private company in Boston. Another of their creations is heart valves made of living cells--when implanted in lambs, the valves apparently grow right along with the animals.

Walking past the impressive array of prototype spare parts growing in Vacanti's lab--from glistening cartilage to marrow-filled bones to coronary arteries--one feels the future has suddenly arrived. But a sobering picture hangs on one wall: A portrait of one of Vacanti's former patients, a little girl who died awaiting a liver transplant. Each year some 30,000 Americans die of liver failure--such deaths are particularly heart-rending, he says, for patients often "gradually fade away from their families as you watch." Vacanti, a crack transplant surgeon as well as pioneering researcher, says the picture spurs members of his team trying to solve one of its most daunting problems: getting liver cells to grow en masse outside the body.

Why they won't is largely mysterious, for the cells are among the body's most prolific in their natural habitat. Says Vacanti: "I can take 85% of a patient's liver out, and within a couple of months it will totally regenerate." But when researchers have planted these "hepatocytes" in polymer scaffolds, "they turn up their toes and die."

Scientists think they wilt partly because they're cut off from unidentified, blood-borne growth factors. And with so many things to do, the cells have frenzied metabolisms that rapidly stall when separated from the liver's dense thicket of tiny blood vessels. Thus, making livers requires a quantum leap: Researchers must grow hepatocytes with blood vessels in a three- dimensional matrix--the equivalent of playing tournament-level chess and bridge at the same time.

They made little progress until a young MIT researcher named Linda Griffith met a gang of ceramics experts in 1993 at a campus pub called the Muddy Charles. A hyperkinetic woman whose office is crammed with books, bicycle, and orchids, Griffith had developed a plan to tackle the liver problem: "Every tissue can heal over some small scale, perfectly organizing itself to repair wounds. My question is, 'What's that scale for liver?' If we knew, we might make polymer scaffolds with pores of the right size and configuration to get hepatocytes and blood vessels to self-organize."

But Griffith, a Vacanti collaborator, was stymied. There was no way to carve polymers into the tiny honeycombs she needed --until she heard the suds-quaffing ceramicists enthusing about a cool new toy in their MIT lab. Somewhat like an ink-jet printer, its "print head" repeatedly sweeps across a powdered surface, spitting droplets of sticky stuff to build up ceramic layer by layer. Under computer control, it can rapidly turn out objects of fantastic inner intricacy. A bulb went on in Griffith's head. After the device was rejiggered to sculpt plastics, she began making polymer Wheat Chex that, in Vacanti's lab, are generating exactly the kind of liver-tissue self-organization she envisioned.

Similar scaffolds may work for a wide variety of tissues. Therics, a private company in Princeton, New Jersey, has licensed the MIT technology for use in making bone and other applications. "We finally have in place all the enabling technologies" to make tissues, glows Griffith.

The bionic revolution being hatched in labs like Griffith's will doubtless pose a host of knotty issues, not the least of which will be how to pay for it. But if her work is any indication, the cost of new body parts will be kept in line by a decidedly old-fashioned principle: economies of scale.

REPORTER ASSOCIATE Alicia Hills Moore