This little piggy might save your life
Process of cloning pigs for transplants offers hope, questions
By JOHN FAUBER
of the Journal Sentinel staff
Veterinarian Gail Lange checks out several transgenic cloned pigs on a
rural Wisconsin farm. The pigs were developed by Infigen of DeForest
and the company is continuing research and development of the pigs in
hopes that someday pigs may provide organs for humans in need of
organ transplants.

DeForest - In a nursery pen at a secret location not far from here, a
dozen piglets scamper around, cute and oblivious to their status as
pioneers in modern medicine.

Not only are these little porkers some of the world's first cloned pigs, but
they also have a human gene inserted in their DNA, making them
transgenic.

Other than sheer madness, why would scientists want to add human
genes to a pig?

Because someday, one of the 100 million or so pigs slaughtered in this
country may save your life.

Researchers here at Infigen Inc. are trying to genetically alter and clone
pigs to produce organs that will not result in massive organ rejection
when transplanted into humans.

Just how many lives are saved, extended or improved may well depend
on the success of the experiments taking place at Infigen and other
research sites around the country, including the University of
Wisconsin-Madison.

In the nextfive years, porcine hearts, kidneys, livers and even brain cells
probably will be transplanted into sick, dying or injured people in hopes
of giving them a new lease on life, some scientists say.

The official term for when animal organs or cells are transplanted into a
human is "xenotransplantation." Some scientists think that millions of
people could someday benefit, and that xenotransplantation could act as
a bridge to the kind of human tissue advancements that stem cell
research may yield.

But there are obstacles and risks.
First, more work is needed to genetically alter and clone pigs to produce
organs that will not be rapidly rejected by their human hosts, although
many scientists now believe that day is near.

Beyond that, there is unknown risk lurking.
What if a hidden virus or other unknown infectious agent in pigs
attacked the person who received a pig organ? Worse yet, what if that
person spread the virus to large numbers of other people before
scientists realized it was deadly to humans?

It is believed that HIV, for example, jumped from chimpanzees to humans
sometime during the first half of the 20th century, eventually leading to
the worldwide AIDS epidemic.

Infections from animals
In their cells, nearly all pigs carry   porcine endogenous retrovirus
(PERV), a pathogen that has shown the ability to infect human cells, at
least in a laboratory dish. The virus does not make pigs ill; its effect on
humans remains unknown. But in a 1999 study of 160 people who had
been exposed to living pig cells, none showed any evidence of being
infected by PERV.

Still, PERV is just one known virus; other animal pathogens may not
have been identified yet. For example, scientists already know that pigs
play a unique role in the spread of flu viruses. Most of the viruses
originate in birds, then infect animals such as pigs, which can recombine
the flu virus DNA in novel ways before spreading it to humans.

"We don't want to unleash a pandemic on the world," said David
Cooper, a professor of surgery and immunology at Harvard Medical
School and president of the   International Xenotransplantation
Association.

But the pig already may be out of the pen.
Already, more than 200 experiments involving pig cells or organs have
taken place.

In one of the early cases, Rebecca Draeger, then a 17-year-old Iron
Ridge resident, had her blood infused through pig livers at the
University of Wisconsin Hospital and Clinics in Madison to keep her
alive for more than a day until a human liver could be transplanted.
At the time, she was less than 24 hours away from brain death,
according to her doctor. A catheter was inserted into the femoral vein in
her leg, near her groin. Her blood was pumped out into a mechanical
oxygenator, a blood warmer and then into the main vein of the pig liver.
"The liver was in a sterile container at her bedside," said UW transplant
surgeon   Tony D'Alessandro.

As the blood circulated through the pig's liver, toxins and bile were
removed, and the blood was returned through the jugular vein in her
neck. When one liver reached its limit, a second was used.

Today, Rebecca, 22, is married and doing fine; she gave birth to a son
about a year ago.

Draeger's operation was a stopgap measure, not an actual
transplantation. However, much more permanent and bold experiments
have been devised and tested in the last several years.

Brain cells substitute
In September 1999,   Maribeth Cook had 30 million brain cells from a pig
fetus injected into her brain.

Cook, 40, of Saratoga Springs, N.Y., had suffered a debilitating stroke
five years earlier, and she and her doctors hoped the neural cells from
the pig fetus would take over the functions of her neural cells that died
as the result of her stroke.

Less than two years after the operation, Cook said she has seen
noticeable improvement. Her speech and walking have improved, she
said.

But more important: "My cognitive thinking is better," she said. "I'm
thinking clear, and I'm reading."

Before the operation, she said, she remembered virtually nothing when
reading.

Cook is one of five stroke victims and 10 Parkinson's disease sufferers to
have neural cells from pigs injected into their brains in clinical trials
being conducted by Diacrin Inc., a biotech company in   Charlestown,
Mass.

The results from those trials have been mixed.
The stroke trial was stopped after two of the patients suffered seizures,
even though one of them later reported a significant improvement in her
condition and the cessation of seizures.

In the Parkinson's trial, there was an average 28% improvement in the
condition of the 10 patients. It is believed the pig neural cells can help
Parkinson's patients produce dopamine, a brain chemical they lack.

However, there also was a 21% improvement in a group of eight
"placebo" patients who had small holes drilled in their heads - "just a
little divot," according to a Diacrin official - but who received no pig
brain cells.

Over the next three months, Diacrin researchers will analyze the data and
decide their next step, said Doug Jacoby, the company's director of
research.

For the rest of their lives, some of the patients also will have to be tested
for signs of the porcine endogenous retrovirus.

In the meantime, the company   last month started a trial involving the
injection of pig fetal nerve cells into the spinal cords of six paraplegics
and quadriplegics.

Animal experiments suggest that such a procedure may help repair the
spinal cord and restore some function. However, the spinal cord study is
a trial designed primarily to test the safety of the procedure.

Other researchers have transplanted or scheduled trials involving the
transplantation of pig pancreas cells into diabetics in hopes of helping
them produce their own insulin. At one time, insulin used by humans to
control their disease came from pigs.

Need for organs
One of the big reasons why xenotransplantation may become a
necessary therapy is the vast numbers of people in need of life-saving
organs.

Last year, 22,827 people donated organs, but more than 75,000 people
needed an organ. About 15 people die every day in the United States
while waiting on an organ donation list.

Pig organs are the most likely source because anatomically they are
similar to human organs, and there is virtually an unlimited supply. Pigs
produce large litters in a little more than three months, and the animals
mature quickly.

Non-human primates such as chimpanzees and baboons are not likely to
provide organs for people because they take longer to raise, and some
are considered endangered. As close relatives to humans, they also
harbor viruses that could easily be transmitted to people.

The Food and Drug Administration - with input from the National
Institutes of Health and the Centers for Disease Control and Prevention -
 has regulatory authority over xenotransplantation experiments. Former
Gov. Tommy G. Thompson, as secretary of the Department of Health
and Human Services, oversees those agencies.

Thompson now has an 18-member group, the Secretary's Advisory
Committee on Xenotransplantation, helping him with that responsibility.
The committee had its first meeting in February.

Thompson said xenotransplantation offers "tantalizing" possibilities and
the potential to provide a much greater supply of organs and tissues.
But there are concerns, especially the risk of transmission of infectious
diseases from animals to humans, he said.

"As high as some of our hopes are for xenotransplantation, this is an
area where care and thoroughness are especially important," he said in a
statement to the Journal Sentinel.

Organs made to order
Permanent transplantation of whole animal organs into humans could be
three to five years away, said Cooper, of Harvard Medical School and co-
author of   "Xeno: The Promise of Transplanting Animal Organs into
Humans."

In fact, xenotransplantation could become one of the greatest medical
advances of the 21st century, he said.

In his book, Cooper, a longtime heart and lung transplant surgeon,
describes a scenario that he says could be repeated daily at "donor
centers" around the country. Surgeons arrive, scrub, enter sterile rooms
and begin removing organs to order. Those organs quickly are perfused
with a cold saline solution, put on ice and shipped by plane.

The donor centers would not be hospitals, but rather "veterinary
institutions" on farms where special pigs would be bred and raised by
the thousands.

"The potential benefits are absolutely immense, and it could prove to be
the next great medical revolution," he writes.

However, science still needs to address some issues.
Even organs from humans are often quickly rejected when transplanted
into other people. Organs and tissue from other people are viewed as
foreign by the body's immune system, which begins to attack the organs
as soon as they are transplanted.

In human-to-human organ transplants, doctors are able to avoid part of
the problem by selecting organs from donors who are a good match to
the recipient, such as those from someone with the same blood type,
and by using immune-suppressing drugs, which must be taken for the
rest of the recipient's life.

But there is a violent, hyperacute rejection that takes place when animal
organs are transplanted into people.

"It is a dramatic immune attack," Cooper said.

To avoid hyperacute rejection, researchers are trying to genetically alter
pigs, both by adding certain human genes and by knocking out pig
genes to make the organs appear more human-like to the body's immune
system.

Experiments abound
Infigen already has succeeded in adding a human gene to the DNA of
pigs and then cloning those pigs, said Michael Bishop, president of
Infigen. However, the first gene that was added was done just to prove
that the concept worked. It was not a gene that would make pig organs
more suitable for human transplantation.

Other researchers have been able to add another human gene to pig
DNA as another possible means of preventing hyperacute rejection
problems.

Infigen also has been able to clone embryos with a "knockout" or
inactivated pig gene, a development researchers hope will lead to organs
that won't be rapidly rejected by humans. Piglets with the knockout gene
are expected to be born in July, Bishop said.

So far, more than 40 cloned pigs, including several with the human gene
added, have been born at Infigen, Bishop said.

"We've got so good at cloning pigs, we had to quit," Bishop said. "We
had so many of them around."

More genetic tampering probably will be needed to prevent other organ
rejection problems.

While that research is going on, better immune-suppressing drugs are
being developed.

Last year, UW researchers received a $1.3 million grant to test drugs
designed to prevent rejection of pig kidneys transplanted into baboons.
Before pig organs are transplanted into humans, they will be tested in
non-human primates such as baboons.

Researchers at other universities also are testing immune-suppressing
drugs that can be used in xenotransplantation.

Hans Sollinger, head of the UW organ transplant program, said much
work still needs to be done and scientists need to be careful not to give
false hope.

Nevertheless, he said, xenotransplantation "looks like the only promise
we have" in addressing the imbalance between the number of human
organs available and the number of people needing them - at least until,
or unless, stem cell research opens up new opportunities to use human
tissue.

"Ultimately, we will be using animal organs to transplant to humans,"
Sollinger said. "It will change the face of medicine."

Appeared in the Milwaukee Journal Sentinel on May 6, 2001.

http://www.jsonline.com/alive/news/may01/pig06050501.asp

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