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Washington Post, Monday March 20, 2000
By Rick Weiss, Staff Writer (sent in by a correspondent)
The announcement last week that scientists
had created the world's first litter of cloned pigs marked
a milestone in the century-long quest to use animals as a
source of organs for transplantation into humans.
But significant technical hurdles will
have to be cleared if pigs are to solve the chronic organ
shortage that allows tens of thousands of patients to die
on waiting lists every year.
Scientists trying to overcome those difficulties
are focusing on pigs because pig organs are about the right
size to fit inside people, and because porcine physiology
is reasonably similar to human physiology. That means a pig
kidney, for example, can probably do for a person everything
a human kidney is designed to do.
But that doesn't mean those organs are
welcome in the human body. Most animal organs are subject
to an intense rejection reaction mounted by the recipient's
immune system. To make matters worse, that reaction is actually
a series of attacks, each involving a different biological
weapon and each having to be countered individually if an
animal organ is to survive inside its new host.
"There are all kinds of molecular
roadblocks," said Harvard immunologist Fritz Bach, an
expert in cross-species, or "xeno," transplants.
Even if the initial rejection reaction is overcome, Bach said,
delayed and chronic rejection reactions will remain to be
tackled. "It may be quite a problem," he said.
The first challenge is the "hyperacute"
rejection reaction--a horribly rapid and intense response
that can leave a transplanted organ black, bloated and dead
Just five years ago, researchers discovered
the molecule that triggers this initial reaction. They found
that with the exception of primates--the group that includes
people, apes and monkeys--all mammalian blood vessel cells
bear a sugar molecule on their outer membranes called alpha
1-3 galactose, or "alpha gal."
Alpha gal is like a red flag, beckoning
human antibodies to the network of blood vessels that laces
through every transplanted pig organ, be it a kidney, heart
or lung. The antibodies attach themselves to alpha gal molecules
on the vessel walls, and in doing so they become slightly
bent, or distorted. That change exposes a usually hidden part
of the antibody, which in turn attracts a human blood substance
When a molecule of complement attaches
itself to an antibody, it makes a potent toxin that eats away
at an organ's blood vessels. The vessels grow leaky, and the
body tries to stanch the blood loss by sending platelets (cell
fragments that plug leaks like chewing gum) and various clotting
factors. Before long the besieged vessels have become totally
clogged, strangling the oxygen-needy transplant to death.
To overcome this problem, scientists
a few years ago learned how to "knock out" the gene
that allows pig cells to make alpha gal. But as is so often
the case with biology, that solution did not quite work as
As it turns out, pig cells that are denied
the opportunity to make alpha gal make another kind of protein-sugar
complex--one that is just as visible and objectionable to
the human immune system as alpha gal. Now, researchers are
experimenting with another approach: They are adding a gene
called H transferase, which helps pig cells make a sugar molecule
commonly found on human cells.
The H transferase gene appears to "out-compete"
the pig's own alpha gal gene, making the cell surface look
about 95 percent human. Now that researchers know how to clone
a pig from a single cell, they plan to do so from a cell that
has been engineered to contain this human gene. The result
may be a pig with humanized organs that won't trigger a hyperacute
But no scientist believes that this alone
will be sufficient. Other immune system mechanisms also promote
complement toxicity and blood clotting around xenotransplants,
and they too must be stopped if the new organ is to live.
One approach under investigation is to
add a gene called DAF, which endows cells with the ability
to block complement. Unfortunately, DAF has recently been
found to play another role: It can help certain viruses invade
cells. That infection-enhancing side effect could be problematic
for transplant recipients, most of whom are already at increased
risk of infectious diseases because of the immune system-suppressing
drugs they must take to prevent a later stage of organ rejection.
Scientists have also learned how to add
to pig cells two other genes, which they hope will reduce
the second-tier problem of "delayed graft rejection,"
in which blood clots gradually clog and kill an organ in the
weeks and months after transplantation. One of those genes
serves as a local anticoagulant, or blood thinner. The other
interferes with the hormonal signals by which white blood
cells and platelets are attracted to injury sites.
Again, though, this approach turns out
to be not as simple as it seems. Pigs bearing these genes
may themselves have trouble surviving long enough to become
donors. So scientists are adding molecular "switches"
that will turn on the added genes in an organ only after that
organ has been removed and transplanted. One clever approach
uses the difference in body temperatures between pigs and
people as the signal that tells the new genes to turn on.
Finally, there will remain the problem
of chronic rejection, a persistent immunological campaign
mounted not by antibodies and complement but by specialized
white blood cells called T lymphocytes. It is these cells
that immune-suppressant drugs, such as cyclosporin, take aim
at. And xenotransplant recipients will almost certainly face
a lifetime on these medicines, which have the unfortunate
effect of preventing not only unwanted immune system reactions,
but helpful ones, too.
To get around that last problem, some
researchers are pursuing a strategy called tolerization, which
might stop the immune system from attacking a transplant but
would not suppress the body's defenses overall. The idea is
to infuse some pig cells into a person's blood or bone marrow
around the time of transplantation. Done properly, researchers
believe, such an infusion might "persuade" the immune
system to accept similar cells as "self" instead
Even if scientists overcome all these
difficulties, the door to xenotransplantation will not necessarily
swing open. Pig cells typically contain DNA from pig viruses
that some scientists suspect could merge with human viruses
if given the chance in a recipient's body. Scientists and
regulators are looking into whether that might lead to the
creation of an entirely new and possibly contagious virus--one
that poses a threat not only to the recipient, but also to
the public at large.
A SAFE HEART OUT OF A SOW'S EAR?
Re-engineering swine genes may convert
hogs into human organ banks.
- A cell is removed from the hog to be cloned.
- Genes that trigger human immune systems
are removed and genes are inserted that either make the
cell appear more human or block immune-system-alerting genes.
- The altered cell is fused with a gutted
- The combined cells grow into an embryo.
- Several embryos are transferred to a surrogate
- A litter of identical clones is born to
supply spare parts for humans.
© 2000 The Washington Post Company
AGENCY FAILED TO MONITOR PATIENTS IN
New York Times, February 2, 2000
By Sheryl Gay Stolberg,
Officials at the National Institutes
of Health said yesterday that they had failed to keep track
of how patients fared during gene therapy experiments and
had outlined steps to ensure that scientists followed rules
requiring them to report information about harmful side effects.
"We were receiving only a small
number of adverse event reports, and we certainly should have
recognized this as a sign of underreporting," Dr. Ruth
L. Kirschstein, acting director of the institute, wrote yesterday
in a letter to a congressman.
In an interview, a senior official at
the institute said, "There is no excuse for it, and it
should have been noticed."
The admission by Dr. Kirschstein, in
a letter to Representative Henry A. Waxman, Democrat of California,
came on the eve of a Congressional inquiry into lapses of
federal oversight into gene therapy in general and the death
of a patient in an experiment at the University of Pennsylvania
In an exchange of letters with Mr. Waxman,
officials at the health institute had acknowledged that of
691 serious side effects experienced by patients in a particular
type of gene therapy experiment, only 39 were reported immediately,
as required by the agency. Other reports were received only
after an inquiry into the death of the Pennsylvania patient,
Jesse Gelsinger, 18, who enrolled in a trial to test a treatment
for an inherited enzyme deficiency.
In a letter on Jan. 10, Mr. Waxman complained,
"This is a failure rate of roughly 95 percent."
In her reply, Dr. Kirschstein said scientists
might have been confused about the reporting requirements.
"Nevertheless," she wrote, "while this is an
explanation for inadequate reporting, it is not an excuse."
The admissions came amid increased scrutiny
of the 10-year-old field of gene therapy.
Mr. Gelsinger died after an overwhelming
immune reaction to an infusion of corrective genes. Last month,
the Food and Drug Administration shut down all gene therapy
experiments at the university.
Today, Senator Bill Frist, Republican
of Tennessee, will convene a hearing into the death. Mr. Gelsinger's
father, Paul, will testify, as will officials from the Food
and Drug Administration and the health institute.
"I think the oversight system is
failing to prevent serious violations of patient protection,"
Senator Frist said. "Let's have full transparency in
In recent months, it has become clear
that the system is not as transparent as federal rules require.
Typically, researchers experimenting with drugs and therapies
are monitored by the drug agency, which is required to keep
all patient safety information confidential. Gene therapy
has always been an exception; because it is so novel, it is
also monitored by the health
institute through a panel of medical and ethics experts called
the Recombinant DNA Advisory Committee.
Federal rules require that all serious
side effects, whether or not directly related to gene therapy,
be disclosed immediately to the health institute. But even
before Mr. Gelsinger's death, members of the advisory committee
had expressed concerns that the requirements were not being
To force scientists to comply, Dr. Kirschstein
said the institute would begin inspections of laboratories
that conduct gene therapy research. The agency has also repeated
its rules to all scientists conducting gene therapy research
and is receiving weekly reports about side effects.
The biotechnology industry is expected
to oppose an efforts to force greater disclosure. Michael
Werner, a lawyer for the Biotechnology Industry Organization,
a trade group, said today that companies want to comply but
are concerned that their research may become public and available
to their competitors.
Most patients in the experiments are
already seriously ill, often with cancer, and many die during
the research from problems related to their diseases.
Mr. Gelsinger's case was unusual in that
he was not particularly sick; he suffered from a mild form
of an enzyme deficiency. The Pennsylvania
experiment was designed to test the safety of a treatment
for babies with a fatal form of his disorder. It involved
an infusion of corrective genes, encased in a weakened cold
The 691 reports gathered so far include
a range of side effects, from high fever to serious infection
to seizures, but most appeared to be related to the patients'
underlying diseases, the institute official said.
But, the official said, until the agency
has completed a review of the reports it would be impossible
to determine if any patients have been harmed in gene therapy
The reports are from all studies that
used adenovirus; such studies account for one quarter of all
the gene therapy clinical trials that have been conducted
over the past decade. So it is possible that there are many
more reports outstanding. Mr. Waxman said today that he was
trying to press the health institute to obtain the additional
Copyright 2000 The New York Times Company
MAD COW DISEASE AND HUMANS
When a new form of an old human disease
appeared in England in 1995, some medical specialists immediately
suspected that it might be a human version of "mad cow
disease," but they had no proof. Mad cow disease had
appeared in British dairy cattle for the first time in 1985
and during the subsequent decade 175,000 British cows had
died from it. British health authorities spent that decade
reassuring the public that there was no danger from eating
the meat of infected cows. They said a "species barrier"
prevented mad cows from infecting humans. A "species
barrier" does prevent many diseases from crossing from
one species to another -- for example, measles and canine
distemper are closely related diseases, but dogs don't get
measles and humans don't get distemper.
While the British government was placing
its faith in the species barrier, British citizens began to
die of a new disease, called "new variant Creutzfeld-Jakob
disease" or nvCJD. A similar disease, CJD (Creutzfeld-Jakob
disease) had been recognized for a long time but it almost
never occurs in people younger than 30; nvCJD, on the other
hand, strikes people as young as 13. There are several other
differences between CJD and nvCJD, so nvCJD represents something
new. To date, nvCJD has killed 48 people in England and one
or two others elsewhere in Europe. The main feature of both
mad cow disease and nvCJD is the progressive destruction of
brain cells, inevitably leading to total disability and death.
New research published late in 1999 showed
that nvCJD is, in fact, a human form of mad cow disease,
dashing all hope that a species barrier can protect humans
from this deadly bovine affliction.
Mad cow disease is formally known as
"bovine spongiform encephalopathy" or BSE. BSE is
the cow version of a larger class of diseases called "transmissible
spongiform encephalopathies," or TSEs. TSEs can afflict
sheep, deer, elk, cows, mink, cats, squirrels, monkeys, humans
and other species. In all species the symptoms of TSEs are
the same -- progressive destruction of brain cells leading
to dementia and death.
Traditional Creutzfeld-Jakob disease
(CJD) is a rare human affliction. The visible symptoms are
similar to Alzheimer's disease; in fact, CJD is sometimes
diagnosed as Alzheimer's and therefore may go unrecognized.
CJD strikes one in a million people almost all of whom are
older than 55. In people younger than age 30, CJD is extremely
rare, striking an average of 5 people per billion each year,
worldwide (not counting the recent outbreak in England).
In cows, the latency (or incubation)
period for mad cow disease is about 5 years, meaning that
cows have the disease for five years before symptoms begin
to appear. No one knows the latency period for nvCJD in humans,
but it is thought to be around 10 years. Because of this uncertainty,
no one is sure how many people in England already have the
disease but are not yet showing symptoms. The British government's
chief medical officer, Professor Liam Donaldson, said December
21, 1999, "We're not going to know for several years
whether the size of the epidemic will be a small one, in other
words in the hundreds, or a very large one, in the hundreds
The epidemic of mad cow disease was caused
by an agricultural innovation -- feeding dead cows to live
cows. Cows are, by nature, vegetarians. But modern agricultural
techniques changed that. Cows that died mysteriously were
sent to rendering plants where they were boiled down and ground
up into the consistency of brown sugar, and eventually added
to cattle feed. It was later determined that mad cow disease
was being transmitted through such feed, and especially through
certain specific tissues -- brain, spinal cord, eyes, spleen
and perhaps other nerve tissues.
Ten new cases of nvCJD were reported
in England in 1999, bringing the total to 48. It has been
more than 10 years since government authorities banned the
use of the particular parts of cows thought to transmit mad
cow disease. The appearance of new cases of nvCJD in 1999
implies either that the latency period for the disease is
longer than 10 years, or that infected meat was not effectively
eliminated from the food chain when government authorities
said it was, or both.
The SUNDAY TIMES of London reported in
late December that some meat banned for human consumption
is still being marketed in England. After the mad cow scandal
erupted, the British government attempted to eradicate the
disease by requiring that all cows older than 30 months be
slaughtered. As a result, by last September more than 2.5
million British cows had been killed. But the TIMES reported
that British investigators have documented at least 50 cases
of farmers and cattle dealers using bogus identity documents
to falsify the ages of cows in order to sell them for human
consumption. Furthermore, the Agriculture Ministry acknowledged
that as many as 90,000 cattle could not be accounted for.
About 1600 new cases of mad cow disease are still being reported
each year in England.
In December, French health authorities
announced finding a second case of nvCJD, a 36-year-old woman
in Paris. France has continued to refuse to import British
beef, even though the European Union on August 1, 1999, formally
declared British beef as safe as any in the European Union.
The European Union said in December it will take France to
the European Court of Justice to force it to import British
beef. Germany is also refusing to import British beef.
The U.S. government says mad cow disease
has never been observed in any U.S. cows. However, a closely-related
TSE disease, called chronic wasting disease (CWD), has been
increasing for almost 20 years among wild deer and elk in
northern Colorado and southern Wyoming. Since 1981, CWD has
been spreading slowly among wild deer and elk herds in the
Rocky Mountains and now afflicts between 4% and 8% of 62,000
deer in the region between Fort Collins, Colorado and Cheyenne,
During 1999, CWD erupted among a herd
of elk on the David Kesler Game Farm near Philipsburg, Montana,
which raised elk commercially. A few of Mr. Kesler's elk had
been shipped to Oklahoma and Idaho, and perhaps elsewhere,
and CWD was discovered in some of those animals, too. In early
December, Montana health authorities slaughtered 81 elk on
Mr. Kesler's farm. They initially announced plans to incinerate
the carcasses, but later decided that incineration would be
too expensive. The animals were finally buried at the High
Plains Sanitary Landfill north of Great Falls. Equipment used
to feed, water and care for the animals was also buried in
the landfill. Montana authorities announced that the fenceline
at the elk farm would be decontaminated, but they did not
say what procedure they would use. Nor did they announce what
would become of Mr. Kesler's contaminated land. The disease
agent that causes CWD -- a prion protein -- is very hardy
and resists destruction by traditional sterilization techniques
like alcohol and heat.
The diseased elk carcasses in the High
Plains landfill have been buried under a mound of garbage
but will still be accessible to rainwater and perhaps to scavenging
In northeastern Colorado and southeastern
Wyoming, state officials are urging hunters to protect themselves
when dressing wild deer and elk they have shot. Hunters should
wear rubber gloves, minimize contact with brain and spinal
cord tissues, discard the brain, spinal cord, eyes, spleen
and lymph nodes and definitely not eat them. There is no evidence
that CWD can cross over from deer and elk to humans, but there
was no firm evidence that mad cow disease could afflict humans
until 1999, so wildlife officials in the Rocky Mountain states
say caution is warranted.
Writing in the BOSTON GLOBE, Terry J.
Allen reported in late 1999 that, since 1996, Creutzfeld-Jakob
disease has been identified in 3 Americans younger than age
30. All three are known to have hunted extensively or eaten
venison. There is no evidence that CWD disease has jumped
from deer or elk to humans, but the appearance of this extremely-rare
disease in young people was the first evidence of a problem
in England, so health authorities in the U.S. say they are
aggressively investigating all the possibilities.
A statistician at the federal Centers
for Disease Control (CDC) in Atlanta told Terry Allen that,
if one more case of CJD had surfaced in a person younger than
30 in the U.S., it "might tip the balance," meaning
it might convince authorities that something truly unusual
was occurring. Dr. Michael Hansen of Consumer's Union says,
"Given how rare the disease is in young people and how
difficult it is to make a diagnosis, the possibility that
some cases go undetected cannot be ruled out."
Indeed, of the 3 cases detected in the
U.S. since 1996, one nearly went undetected. Last year in
Utah, Doug McEwan, 28, began to show an array of mysterious
symptoms: loss of memory, loss of motor control, mood swings,
and disorientation. His wife, Tracey, says his doctors conducted
hundreds of tests but could not diagnose his disease. She
happened to see a TV program on mad cow disease and she insisted
that Doug's doctors must test for CJD. A brain biopsy confirmed
One of the three young CJD victims had
eaten deer shot near Rangely, Maine, so last November federal
officials took samples of brains from 299 deer shot in western
Maine. Authorities said at the time they were quite sure Maine
deer are not harboring CWD. So far, test results have not
Federal authorities have quarantined
two herds of sheep in Vermont because they say the sheep may
have been given feed that contained parts of animals afflicted
by mad cow disease. The sheep had been imported into Vermont
from Belgium and the Netherlands, where they may have been
fed improperly. A similar herd of sheep in New York state
was recently purchased by the federal government and slaughtered.
Meanwhile, a 68-year-old Indiana man
with a fondness for beef-brain sandwiches died of CJD last
summer. Beef-brain sandwiches are a local delicacy in Indiana,
introduced years ago by German immigrants. The EVANSVILLE
(INDIANA) COURIER reported that John Hiedingsfelder, a forensic
pathologist in Evansville, said he had seen three cases of
CJD in the past year. No connection to mad cow disease has
been established in the Indiana cases. Roberta Heiman, a staff
writer for the EVANSVILLE (INDIANA) COURIER reportedly received
a warning from a cattleman's association not to publish any
further articles about this subject. ============
 Unless a specific source is cited,
information in this issue of Rachel's was taken from www.mad-cow.org,
a web site maintained by Thomas Pringle of Eugene, Oregon.
Sources of information are cited at www.mad-cow.org.
 Michael R. Scott and others, "Compelling
transgenic evidence for transmission of bovine spongiform
encephalopathy prions in humans," PROCEEDINGS OF THE
NATIONAL ACADEMY OF SCIENCES Vol. 96, No. 26 (December 21,
1999), pgs. 15137-15142.
 Terry J. Allen, "Rare, Animal-Borne
Disease a Medical Mystery; Officials Examine Maine Deer in
Hunt for Clues," BOSTON GLOBE December 12, 1999, pg.
 Matthew Taylor, "Mad Cow Fears,
Anger on Farms; Two Imported Sheep Herds Quarantined in Vermont,"
BOSTON GLOBE October 31, 1999, pg. F24.
BABOON LIVED WITH HUMANIZED PIG HEART
The Daily Telegraph (Canada), Friday, October 29, 1999
By Roger Highfield (sent in by Alix Fano)
A milestone in the effort to implant
genetically modified pig hearts into people was passed this
week when a Cambridge, England-based team told a conference
that it had kept a baboon alive for up to 40 days with a "humanized"
pig heart, the longest period achieved to date. The use of
humanized animal organs is being pursued to meet a shortage
of donor organs and, when perfected, is expected to make the
biggest impact on transplant medicine since anti-rejection
drugs. The work was presented by Dr. Conrad Vial, of Stanford
University, who is working with Imutran, the Cambridge company
pioneering the use of pig organs humanized by genetic modification.
Dr. Vial told the Congress of the International Xenotransplantation
Society in Nagoya, Japan, of the latest research on six baboons.
If subsequent work is as encouraging, trials on patients could
start in at least two years. The research that led to the
advance in "humanized" pig heart transplants dates
back to 1992, when a white piglet called Astrid was born in
Cambridge. Imutran hopes that Astrid and hundreds of her progeny
-- "A74 pigs" -- could begin to fill the gap left
by the shortage of human donors. Conventional heart transplants,
or allografts, are made successful by using the closest possible
tissue matching and immuno-suppressant drugs. But for pig
hearts to work, they have to be humanized. The size of a pig
heart is about right for transplant, as is the anatomy and
blood pressure. But if human blood is pumped through an ordinary
pig heart, "it will go black and fail within one or two
hours," said David White, Imutran's research director.
Pig hearts can be "humanized" by the introduction
of human genes to persuade the human immune system to accept
the foreign organ, work that Imutran has pursued since 1984.
Note from Alix Fano:
I'd say this article will further help
the case against xenotransplantation. Check out: 691 serious
side effects from gene therapy experiments, a 95% failure
rate, and NIH failing to track these patients. The way things
are going, (Secretary's Advisory Committee on Xeno under jurisdiction
of NIH Recombinant Advisory Committee) NIH would also have
juridisction over xeno experiments.
Note from Emanuel Goldman:
40 days! Wow. Call the Guiness Book of World
What about the size of the pig capillaries versus that of
the host lymphoctes and red blood cells? I don't know the
values for baboons, but we do know that human cells are too
large for pig capillaries. Emanuel Goldman
XENOTRANSPLANTS & PORCINE MENANGLE
From: Dr. Raymond G. Whitham
Date: Mon, 23 Aug 1999
The study referred to in the first ProMED
post [ref. above] concerning xenotransplants does not reassure
me in the least. I do however see that the 3 major public
health problems involving xenotransplants are still at risk
of being drowned in the euphoria of the moment.
1. The main risk of xenotransplants is
not to the relatively few transplant patients, but to the
entire human species. No matter how small the number of transplants
being allowed by the FDA at the moment, it only takes one
transplant patient to be able to transmit a virus to another
human being, and from there to others in the population. How
can this be avoided? Do we
isolate them for life?
As for the comment
".....since not everyone is an organ donor, but every
life is precious, maybe this is the solution to saving those
we love. The world is not perfect."
try telling that to public health officials in the Third World
and to those who have lost friends and relatives to the AIDS
2. The keyword in the discussion is "UNKNOWN".
The known viruses are not a problem when compared to "UNKNOWN"
viruses. It never ceases to amaze me how officials rely on
the erroneous assumption that you can "WATCH" a
xenotransplant in order to PREVENT a catastrophe. The only
thing you can watch are the CONSEQUENCES of an unknown viral
infection. How can you prevent the consequences of a virus
you know nothing about?
In order to diagnose a viral infection,
you need antigens of or antibodies directed against the virus.
With an UNKNOWN virus, you have neither. Find a universal
viral antigen and you may have something (but then, how can
you know it actually IS universal?).
And what will you do to the transplant
patient and their close contacts (i.e. the family) if there
IS transmission of a pathogenic virus?
3. The problem researchers wish (exclusively)
to address is the rejection of the transplant. Bigger and
better immunosuppressant drugs not only mean a higher PATIENT
survival rate, but higher VIRUS survival rate as well.
Until public health take precedence over
the almighty dollar and the need to publish more and more
scientific articles, we peons of the general public will have
to suffer the consequences.....or do we?
Dr. Raymond G. Whitham
Zoonosis & Infections Web Site for the General Public
[Raymond is not completely correct with
respect to the need for a universal antigen. One could design
sets pf random primers and look by PCR. That, however, is
still the needle in the haystack story - Mod.CHC]
From Emanuel Goldman
I've been meaning to comment on the incident
you posted, about a human volunteer for an attempted gene
therapy cure who died as a result of the vector used, even
though the vector had been presumed safe due to animal testing.
Quite apart from the issue you focused on, i.e., the unreliability
of animal tests as a predictor of responses in humans, there's
also a very important paradigm with respect to xenotransplanatation.
The vector used was a "weakened" adenovirus, which
is a common human virus that causes cold or flu like symptoms,
and is not fatal in immuno-competent adults. What's so scary
about this incident is that this virus, ordinarily not fatal
through its usual routes of entry (respiratory system) became
fatal when given a new route of entry, i.e., direct introduction
into the bloodstream.
The analogy to the risks in xenotransplantation is evident.