BIOTECH BODIES
Business Week: July 27, 1998

Decades of research into tissue engineering are about to pay off as dozens
of startups perfect living organs grown in the lab, not the body

Sean G. McCormack of Norwood, Mass., seems like your average 16-year-old
boy, if a little more reckless, given his passion for mountain biking. In
fact, though, he is an advance scout for a brave new world: He has the
first chest grown in a lab rather than in the womb.
Sean was born without cartilage or bone under the skin on his left side,
a rare congenital condition known as Poland's Syndrome. The cartilage down
the center of his sternum pointed out, and his heart was virtually
unprotected--you could see it beating under the skin. Doctors talked of
implanting an artificial plate once he reached 21 and stopped growing. But
by the time he was 12, Sean was a star pitcher for his Little League team
and no longer wanted to put up with a condition that put him at risk every
time he played ball. His doctor referred the family to a team of scientists
and surgeons at Children's Hospital in Boston who are leading the way in
growing human body parts in the lab.
Dr. Joseph Upton and Dr. Dennis P. Lund, working with tissue-engineering
pioneer Dr. Joseph P. Vacanti and his brother, Dr. Charles A. Vacanti,
scraped away Sean's protruding cartilage and used the cells to seed a
biodegradable scaffold made of artificial polymer, molded to the shape of
his torso. Dr. Yilin Cao added growth factors to the cells and ``cooked''
the concoction in a bioreactor for several weeks until a chest grew. ``The
procedure was so experimental that none of the polymer companies would give
us [custom-designed] material for fear of a lawsuit,'' says Joseph Vacanti.
The doctors had to adapt off-the-shelf polyglycolic acid, normally used to
stitch up wounds, adding to the risk of the operation.
Sean admits that ``at first I was like, `What if they mess up?' But
after a while, I put it in my head that they've done this a million
times.'' Of course, they had never even done it on an animal. Nevertheless,
after receiving special dispensation from the Food & Drug Administration,
doctors implanted the engineered cartilage in Sean. Within a year, the boy
had a normal-looking chest that was able to grow along with him. Now, four
years later, the six-foot-tall teenager says: ``It's pretty cool. It looks
like something I was born with.''
This is more than a nice human-interest story. It is a glimpse into the
future of medicine, one in which doctors will routinely order up newly
grown, living body parts whenever existing ones fail. Or they will prod the
body into regenerating itself. After some 20 years of painstaking
investigation into the processes by which cells grow, the nascent field of
tissue engineering is ready for prime time, and dozens of startup companies
are preparing commercial products. Regenerated or lab-grown bone,
cartilage, blood vessels, and skin--as well as embryonic fetal nerve
tissue--are all being tested in humans. Livers, pancreases, breasts,
hearts, ears, and fingers are taking shape in the lab.
Scientists are even trying to develop tissues that would act as
drug-delivery vessels. Salivary glands could secrete antifungal proteins to
fight infections in the throat, skin could release growth hormones, and
organs could be genetically engineered to correct a patient's own genetic
deficiencies. ``I think [tissue engineering] holds the possibility for
revolutionizing clinical medicine,'' says Kiki B. Hellman, coordinator of
the FDA's biotechnology center for devices and radiological health.
The age of the biotech body is dawning. Tissue engineering offers the
promise that failing organs and aging cells need no longer be
tolerated--they can be rejuvenated or replaced with healthy cells and
tissues grown anew. The prospect signals ``a profound revolution in
medicine,'' says William A. Haseltine, a leading genetic scientist and
chief executive of Human Genome Sciences Inc. in Rockville, Md. ``The
current chemical era of medicine may, in retrospect, appear to be a clumsy
effort to patch rather than permanently repair our broken bodies,'' says
Haseltine. ``Cellular replacement may keep us young and healthy forever.''
Haseltine's genetic fountain of youth is a long way off. After all,
lab-grown organs, the first step towards his vision, are still subject to
the ravages of age. But tissue engineering can certainly keep failing
organs from shutting down life prematurely. The principle has already been
proven with the first off-the-shelf tissue approved by the FDA in May: a
living skin, Apligraf, for the treatment of leg ulcers, a common ailment in
the elderly. Apligraf maker Organogenesis Inc. of Canton, Mass., turns a
few cells of infant foreskin into acres of living skin that can be handled,
cut to fit, and grafted on to anyone without fear of rejection or scarring.
Next up: cartilage to strengthen the urethra and repair the knee and a
method for replacing shinbones. Both processes are in late-stage clinical
trials and are likely to be considered for FDA approval in the next year or
two.
THUMBS UP. In the next 10 years, a veritable body shop of spare parts will
wend its way from labs to patients. ``It's time for us to move into
humans,'' says Charles Vacanti, and he's not wasting any time. At the
University of Massachusetts at Worcester, his team is growing thumb bones
right now in bioreactors for two machinists who cut off their own
appendages. Vacanti says one or both of the thumbs should be grafted back
on to the patients this summer, with growth factors added that will
encourage regeneration of the nerves and tendon. He figures that the thumbs
will be operational about 12 weeks after surgery.
In Boston, meanwhile, a team of doctors at Children's Hospital led by
Dr. Anthony J. Atala plans to implant a bladder grown from fetal cells into
a human in the next few months. Atala's lab caused a stir in the medical
community last summer when doctors there successfully used the same
procedure to implant new bladders into 10 baby lambs.
Creating even the most complex organs seems possible, though still 5 to
10 years out. Researchers from around the world met in Toronto in June to
set up a 10-year initiative to grow a human heart. ``It's an ambitious
project but not a farfetched one,'' says Michael V. Sefton, biomaterials
professor at the University of Toronto and head of the heart effort. ``The
likelihood of success is very feasible.''
Other complex tissues are already taking form. At Massachusetts
Institute of Technology, chemical engineer Linda Griffith-Cima is using
three-dimensional printers, first developed for computer-aided design, to
build up structures that are turned into mouse-size livers. And at the
University of Michigan in Ann Arbor, David J. Mooney, another chemical
engineer, is heading an effort to grow cosmetic breasts for women who have
had theirs removed. Researchers in Sweden and California have been able to
regenerate nerves in rats with severed or damaged spinal cords to the point
where they can walk again--albeit weakly.
With each success, more attention is paid. After years of barely
acknowledging tissue-engineering research, the National Institutes of
Health plans to award 30 grants in the field, some $6 million worth, this
summer. But the lack of government interest heretofore may have been a
blessing in disguise. Gail Naughton, president of Advanced Tissue Sciences
Inc. of La Jolla, Calif., says that because so little federal money was
available, tissue engineers had little choice in years past but to start a
company and go public in order to raise funds. ``I think that this field
has moved so quickly toward reality precisely because it spent very little
time in academic labs,'' she says.
Even as it gains recognition, tissue engineering remains hard to
categorize. The multidisciplinary field attracts surgeons, chemical
engineers, materials scientists, and genetic researchers. Products straddle
the boundaries between medical devices and gene therapy. The FDA even had
to set up a special task force three years ago to figure out how to
regulate the products.
The FDA is playing catch-up with a technology that has been 20 years in
the making. As early as 1979, Eugene Bell, professor emeritus of biology at
MIT and the founder of Organogenesis, figured out how to grow skin in his
lab. Since then, much of the field's progress stems from a 20-year
collaboration of two fast friends--Joseph Vacanti, a pediatric surgeon at
Children's Hospital, and Robert S. Langer, a chemical engineering professor
at MIT. Their lab ``seeded the entire country with people doing this
work,'' says Dr. Pamela Bassett, president of medical consultants BioTrend
in New York.
LIFE MISSION. The two, both 49, first met as researchers in the mid-1970s
and started working on a way to grow tissue in the early 1980s. In 1986,
they developed an elegantly simple concept that underlies most engineered
tissue. Start with a scaffold, bent to any shape, made of an artificial,
biodegradable polymer. Seed it with living cells, and bathe it in growth
factors. The cells multiply, filling up the scaffold and growing into a
three-dimensional tissue. Once implanted in the body, the cells are smart
enough to recreate their proper tissue functions. Blood vessels attach
themselves to the new tissue, the scaffold melts away, and the lab-grown
tissue is eventually indistinguishable from its surroundings.
Vacanti, who is remarkably self-effacing despite his pioneering role in
the field, says he is driven by his dedication to his patients. He
regularly saves the lives of the smallest children by replacing their
failing livers--and regularly sees others die for lack of donors. ``I
recognized fairly early that the biggest problem facing me as a surgeon was
the shortage of organs,'' he says. ``I've devoted my professional life to
solving that problem. Wouldn't it be nice if [tissue engineering] could
provide the solution?''
Nice is an understatement. A study done by Vacanti and Langer in 1993
found that more than $400 billion is spent each year in the U.S. on
patients suffering from organ failure or tissue loss, accounting for almost
half the national health-care bill. Some 8 million surgical procedures are
performed annually to treat these disorders, yet every year 4,000 people
die while waiting for an organ transplant. An additional 100,000 die
without even qualifying for the waiting list.
``OVER THE BRINK.'' Those kinds of numbers represent a huge commercial
opportunity as well as a humanitarian one. Dr. Peter C. Johnson, president
of the Pittsburgh Tissue Engineering Initiative research consortium,
estimates that the overall market for engineered and regenerated tissues
could reach $80 billion. As for individual products, Michael Ehrenreich,
biotech analyst with investment adviser Techvest of New York, says that the
most immediately promising are those that repair damaged knee cartilage,
now replaced with artificial materials. ``There are a quarter of a million
meniscus [knee-joint] operations performed every year, and no good options
for repair,'' says Ehrenreich. ``That's the killer app.''
Tissue engineering is dominated now by tiny startups (table, page 64),
but the big drug companies are beginning to take notice. Novartis
Pharmaceuticals Corp. has investments in four tissue-engineering companies,
including Organogenesis. ``With the [FDA] approval of Apligraf, this whole
area has really sparked the imagination of corporate executives,'' says
David Epstein, vice-president of Novartis' specialty-business sector.
``We've stepped over the brink into the future of medicine.'' Novartis is
not the only one with future vision. Britain's Smith & Nephew is investing
some $70 million in Advanced Tissue Sciences; Amgen has a deal worth up to
$465 million with Baltimore-based Guilford Pharmaceuticals to develop a
compound for regenerating nerves; Stryker is funding research into bone
regeneration at Creative BioMolecules of Hopkinton, Mass.; and Medtronic
has agreed to invest up to $26 million in lab-grown heart valves from
LifeCell in The Woodlands, Tex.
Although it may take a decade or more for some of these investments to
see any returns, scientists in the field are heartened by the rapid
progress of the past two to three years. ``The kinds of things that we are
doing now are the kinds of things that we used to think about sitting
around having beers 13 or 14 years ago,'' says Dr. Scott P. Bruder,
director of bone and soft-tissue regeneration research at Baltimore-based
Osiris Therapeutics Inc.
Perhaps most intriguing about tissue engineering, though, is how much
the scientists don't know. Much of the excitement in biotech these days
centers on figuring out complex cellular interactions and then intervening.
Tissue engineering, however, is driven by surgeons and engineers who are,
by nature, most interested in a successful endpoint--and less so in how
they got there. ``The great thing is, we don't need to know exactly why or
how cells organize into tissues,'' says Joseph Vacanti. ``We just need to
know that they do.''
This all sounds easier than it actually is. Scientists must still figure
out the best materials for the scaffolds that shape the organs, determine
exactly the right growth factors, and pick the right cells. For bone and
cartilage replacement, one possibility under investigation is a kind of
premature cell called a stem cell. First isolated from human bodies in
1992, this specialized cell can turn into everything from bone to tendon to
cartilage. Implanting these cells in the appropriate location can generate
the full range of cells normally found at that site. While only about one
in 100,000 to one in several million bone-marrow cells are stem cells,
Osiris Therapeutics, partly owned by Novartis, has been able to isolate
enough of them to regenerate bone in both small and large animals.
UNWELCOME STRANGERS. Scientists also must figure out ways around the immune
system's rejection of human tissue. That's not a problem for skin--it
presents relatively few resistance problems since the immune system will
accept some foreign dermal cells. Nor is rejection a problem when the
original cells are taken from the specific patient for which they are
meant. However, if off-the-shelf organs are to be transplanted, patients
must take the same immunosuppressant drugs now given to them when donor
organs are used.
Ideally, tissue engineers want to develop universal donor cells that
would not trigger an immune response, so that body parts can be
manufactured in large numbers. To that end, cells must either be
genetically stripped of their rejection-provoking proteins or encapsulated
in a porous membrane that the body will accept. The latter approach is
nearing clinical trials for the treatment of diabetics whose pancreases are
failing. BioHybrid Technologies Inc. in Shrewsbury, Mass., and Neocrin Co.
of Irvine, Calif., are harvesting insulin-producing cells, called islets,
from the pancreases of pigs and encasing them in a membrane that blocks the
immune response while allowing the cells to do their job. The capsules are
injected into the abdomen, where they go to work producing insulin.
Some companies are trying to avoid the whole immunity problem by
encouraging the patient's own tissue to regenerate. Genentech Inc., for
example, announced in March that 5 of 15 patients who were given a
genetically engineered protein called VEGF regrew blood vessels around the
heart. Integra LifeSciences Corp. of Plainsboro, N.J., believes that just
about any tissue can be regenerated by implanting a collagen matrix coated
with the appropriate growth factors at the site of the damage. It already
has such a matrix on the market for growing back a burn victim's skin and
is in clinical trials with a similar product for the nerve endings in arms
and legs. ``The body is continuously regenerating tissue,'' says Integra
Chief Operating Officer George W. McKinney III. ``We're just trying to
harness that process.''
Most scientists agree that regeneration is the ideal but doubt that it
is always possible, or practical. ``Sometimes you have complete organ
failure and can't wait for tissue to grow back,'' says Antonios G. Mikos, a
bioengineering professor at Rice University. ``In truth, I think we will
have both approaches. There is no one right way.''
Indeed, there are dozens of right ways in the works. Reprogenesis Inc.
of Cambridge, Mass., for example, is in late-stage clinical trials with its
method for using lab-grown cartilage to reinforce the urethra, a tube
leading to the bladder. Weakened urethras can lead to incontinence, which
afflicts an estimated 10 million people in the U.S., and reflux, a
potentially fatal condition affecting about 1% of all infants in which
urine backs up into the bladder. Reprogenesis removes a few cartilage cells
from behind a patient's ear, grows them in the lab, and then mixes them
into a gel matrix. The cells are reinserted endoscopically where the
urethra meets the bladder. There, they grow to bulk up the tubal walls.
A knee-repair product called Carticel, approved by the FDA last August,
uses somewhat the same principle. Made by Genzyme Tissue Repair, Carticel
grows cartilage cells removed from the patient in the lab and then
surgically reimplants them in the knee. No matrix is provided, however, so
the cells can only be used to repair small rents. To replace the entire
meniscus--that's the C-shaped pad in the knee between the thigh bone and
shin bone--ReGen Biologics Inc. of Redwood City, Calif., is in clinical
trials with a collagen scaffold in the shape of the meniscus. The pad is
implanted in the knee to encourage regeneration of the patient's cartilage.
Going a step further, Advanced Tissue Sciences is in preclinical trials
with a meniscus-shaped cartilage grown in the lab that's meant to work in
anyone. It hopes to start human tests by yearend.
NO MORE FILLINGS? After cartilage, look for bone products. Creative
BioMolecules Inc. in Hopkinton, Mass., bases its approach on a
bone-regenerating protein called OP-1. The company molds a porous scaffold
out of calcium, seeds it with OP-1 and a few of the patient's own bone
cells, and then reinserts the newly grown structure. Doctors reported in
March that in a clinical trial of 122 patients with tibia fractures, the
OP-1 graft performed as well as grafts using the patient's own bone.
The biggest market for tissue, though perhaps not the most dramatic, is
the mouth. Some 10 million dental surgeries are performed each year in the
U.S., on everything from teeth to periodontal ligaments, and most use
artificial replacements. One of the first tissue-engineered alternatives is
Atrisorb, made by Atrix Laboratories Inc. of Fort Collins, Colo. On the
market since 1996, it is a bioabsorbable material loaded with growth
factors and healing drugs that guides the regeneration of gum tissue.
But think of the implications if cavities could be filled with
engineered tissue. Harold C. Slavkin, director of the National Institute of
Dental Research at the NIH, says all the genes for making enamel have been
cloned and sequenced, and lab-grown human enamel could be a reality in 5 to
10 years. Some 90 million new fillings are placed each year, and some 200
million are replaced. If those could be filled with original tissue, says
Slavkin, ``we'd never have to do traditional fillings again.''
IN A HURRY. Of course, many of these lab-produced body parts may never make
it out of clinical trials. And doctors admit that they are entering
uncharted waters: Who knows what might happen to an engineered organ
decades after it has been implanted? Lab-grown tissues are put through far
more rigorous purification processes than donor organs to make sure that
they don't carry diseases, but it still is impossible to be completely sure
that a replacement organ won't cause as many problems as the original a few
years, or decades, down the line.
Still, there has been no evidence that these engineered tissues could
turn malignant, says Joseph Vacanti. Therefore, he asks, ``can we really
afford to wait for a complete understanding of how the process works?'' To
him, the answer must be no. Millions of lives are hanging in the balance.

By Catherine Arnst in New York, with John Carey in Washington

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