Scientists Try To Grow Organs, Body Parts
By Tina Hesman
Of the Post-Dispatch
03/13/2004

If today is an average day, 17 people will die waiting for donor organs.

The situation is getting worse.

The transplant waiting list is already more than 80,000 names long. Another name is added every 13 minutes. Each year,
only about a third of the people on the list get the organs they need.

Now some innovative scientists are trying to increase the supply by growing organs and replacement body parts in the
lab.

The approach, known as tissue engineering, is only two decades old, but already scientists are learning to create skin,
bones and almost every other body tissue virtually from scratch.

Local researchers are engineering their own solutions to the organ shortage.

A physicist at the University of Missouri hopes to build 3-D replicas of organs using a machine that resembles a dot
matrix printer.

A Washington University group is trying to grow primitive pig parts into fully-functional organs. The approach already
has cured diabetes in some laboratory rats.

The most popular technique for engineering tissues involves building a scaffold in the shape of an organ. The scaffolds
are usually gels of synthetic polymers and proteins. Tissue engineers call such a gel a "matrix."

After engineers weave a matrix, they seed it with cells. The cells grow, divide and spread. The result is an organ that
looks and works like the one it was designed to replace.

That's the general idea, at least. In reality, the process is much trickier.

One of the first problems is finding cells to do an engineer's bidding, said Robert S. Langer, a pioneer of tissue
engineering at the Massachusetts Institute of Technology. Then there's the challenge of creating just the right matrix
to nurture and support the cells while they grow into the correct shape. The organ must function correctly and avoid
rejection by the body.

Tissue engineers already have grown skin that is used to treat burn victims, Langer said. Engineered bone, cartilage
and corneas are in clinical trials, he said. Spinal cord repair kits and new blood vessels could follow soon.

But no one, not even Langer after nearly 20 years of trying, has been able to grow a liver. Or a pancreas. Or a kidney.
Much work remains before that is possible, Langer says.


"Self-assembling" organs

But maybe engineers don't have to do all the work.

"The most beautiful term one can use in describing a biological system is 'self-assembling,'" said Gabor Forgacs, a
physicist-turned-tissue engineer at the University of Missouri at Columbia.

Forgacs is working out a method that gets organs to build themselves.

Armed with a machine that works something like a dot matrix printer, a variety of gel recipes that the makers of Jell-O
probably never dreamed of, and a few clumps of cells, Forgacs is printing organs.

The machine Forgacs uses is not a printer like the one linked to your personal computer. Instead, it's a device that
spots drops of "bio-ink" in a pattern on a thin layer of gel "paper."

The organ printer's ink is composed of living cells. Each drop is packed with thousands of cells. The cells act like a
fluid, flowing together and merging into a structure Continued on A17
without boundaries. This liquid behavior is important to get cells in the right place at the right time during
development, Forgacs said.

The physicist and his team demonstrated their technique in a report published last month in the Proceedings of the
National Academy of Sciences. The scientists printed 10 dots containing 925 Chinese hamster ovary cells each in a
circular pattern. The cells produced a protein called N-cadherin on their surface. The protein is an adhesion molecule,
a type of molecular glue that helps cells stick together.

The dots of cells began to expand. As the dots touched, they merged with each other, forming a solid ring of cells. The
experiment is the first step toward building a blood vessel. The next step is to build a tube of tissue by stacking
alternating layers of gel and cells. The rings of cells will merge into a three-dimensional tube.

Forgacs uses a special thermal gel matrix that will dissolve when the scientists raise the temperature, leaving the
organ behind for transplant. Other tissue engineers have experimented with biodegradable scaffolds that melt inside the
body once the replacement tissue is transplanted.

In the earliest printing experiments, Forgacs used a single variety of cells for the bio-ink. But blood vessels contain
at least two types of cells - epithelial cells lining the inside and smooth muscle cells forming the outer wall.

Printing a blood vessel may be no more complicated than creating a ring of hamster ovary cells. Forgacs doesn't need to
print separate rings of epithelial cells and muscle cells and then figure out how to glue them together. Instead, he
plans to mix two kinds of cells and let them sort themselves into the proper arrangement.

Forgacs and colleagues have shown previously that drops of epithelial cells and muscle cells will sort themselves to
create an island of epithelia ringed with muscle, or vice versa, depending upon the gel matrix that surrounds the
cells.

If the technique works, scientists one day may be able to remove damaged blood vessels from patients, grind the veins
into bio-ink and print a new vessel.

Use of stem cells

Stem cells are a possible source of cells for tissue engineering.

Stem cells are primitive cells that specialize to form all the body's tissues. The cells contain all the instructions
for forming every organ or tissue in the body but haven't determined yet what they will be when they grow up.
Scientists use chemicals and more mature cells to coax the stem cells into becoming certain kinds of tissues.

Embryonic stem cells can reproduce indefinitely, generating huge numbers of pliant cells that could be perfect for
building new organs, Langer said.

But as the old adage states, more is not always better. During development, cells respond to certain cues and become an
organ or tissue. Biologists have not learned all of the cues and don't always know how to prompt a stem cell into
becoming a certain organ, said Dr. Leonard Zon, a pediatrician at Children's Hospital Boston and president of the
International Society for Stem Cell Research.

If stem cells don't develop fully, they could grow into tumors when transplanted in a patient, some researchers fear.

Other scientists prefer to start with more advanced stem cells - so-called adult stem cells - such as the cells in bone
marrow that will give rise to all the types of blood cells in the body, Zon said. Those cells don't need as much
prodding to make the right type of tissue, but they aren't as plentiful as the embryonic cells. And scientists have
found only a few varieties of adult stem cells. For instance, "we don't know if kidney stem cells exist," Zon said.

Simple tissues, such as cartilage, blood vessels, heart valves and cardiac muscle patches that could heal large scars
in the heart, are likely to be the first products of stem cell engineering, said Dr. Catherine Verfaillie, director of
the Stem Cell Institute at the University of Minnesota. But more complex organs, such as livers, kidneys, and lungs,
which require many types of cells to arrange themselves in complicated three-dimensional structures, "will obviously
take quite a bit more time to accomplish," she said.

Treating diabetes

Scientists can transform stem cells into insulin-producing cells. Such cells hold great potential for treating
diabetes. There's just one problem. The cells don't make insulin in response to glucose the way insulin-producing cells
in a healthy pancreas would, said Dr. Marc Hammerman, an endocrinologist and director of the Renal Division at
Washington University School of Medicine.

For 25 years, doctors have implanted adult pancreatic islet cells into diabetics, hoping to cure the disease. The
procedure is still considered experimental and doesn't work well or for very long, Hammerman said. In 1991, doctors at
Washington University performed the first successful islet cell transplant. Since then, doctors there have given 42
diabetics new islet cells. Only one patient was able to forgo insulin injections for more than a year.

Even if the transplants worked perfectly, there still would not be enough pancreases to go around, Hammerman said.
Doctors harvest cells from about three pancreases to get the 700,000 to 1 million islets needed for a single
transplant. And the transplant recipients must take powerful drugs to keep their bodies from rejecting the new cells.

Hammerman is treading a middle ground between stem cells and adult cell transplants. His path may help him avoid some
of the pitfalls of each.

In Hammerman's lab recently, a quartet of white rats reared up on their hind legs and poked pink noses through the
metal bars covering their transparent plastic cage. Each rat has six kidneys - one of their own and five others taken
from embryonic pigs.

The kidneys are not full-size pig organs. They start as organ primordia - pinhead-size collections of cells that form
the first recognizable rudiments of an organ.

When transplanted into a rat, the organ primordia carry out their programming, growing into functional organs without
additional instructions from the scientists.

Transplants of pancreas primordia have completely cured diabetic rats of their dependence on insulin, Hammerman said.
The kidney primordia don't work as well, he admitted.


Problem of rejection

But the greatest advantage to using organ primordia may be the ability to avoid rejection.

The immune system grants special clearance to embryonic tissue, Hammerman said.

The researchers withheld immune suppressing drugs from some rats in a control group. Those rats kept their new
pancreases and were cured of their diabetes just like the rats that got drugs to prevent rejection.

But the ability to rebuff rejection also could be in the blood system. Organ primordia don't yet have a blood supply.
As the organs develop, they attract veins and arteries.

Pig primordia implanted in a rat won't develop pig veins and arteries, Hammerman said. The new organs will hook up to
rat blood vessels. Using the host's own blood vessels may cloak the transplanted organ from the host's immune system.

The researchers don't yet know whether pig organs will work as well in primates and people as they do in rats,
Hammerman said.

Tissue engineers don't know how long patients will have to wait to get a designer organ. But stem cells, pig parts and
printers one day could replace the need for donor organs.

Reporter Tina Hesman
E-mail: [log in to unmask]
Phone: 314-340-8325

SOURCE: The St. Louis Post-Dispatch, MO
http://tinyurl.com/yw9xw

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