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These are individual opinions sent in by our email correspondents and do not necessarily reflect DLRM policy.

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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 within minutes.

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 called complement.

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 planned.

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 rejection response.

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 of "other."

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.


Re-engineering swine genes may convert hogs into human organ banks.

  1. A cell is removed from the hog to be cloned.
  2. 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.
  3. The altered cell is fused with a gutted egg.
  4. The combined cells grow into an embryo.
  5. Several embryos are transferred to a surrogate mother.
  6. A litter of identical clones is born to supply spare parts for humans.

© 2000 The Washington Post Company

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 particular.

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 the system."

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 met.

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 virus, adenovirus.

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 research.

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 information.

Copyright 2000 The New York Times Company


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.[1] 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,[2] 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 of thousands."

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, Wyoming.

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 animals.

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.[3] 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."[3]

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 the diagnosis.

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 been released.

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.[4]

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. ============

[1] Unless a specific source is cited, information in this issue of Rachel's was taken from, a web site maintained by Thomas Pringle of Eugene, Oregon. Sources of information are cited at

[2] 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.

[3] Terry J. Allen, "Rare, Animal-Borne Disease a Medical Mystery; Officials Examine Maine Deer in Hunt for Clues," BOSTON GLOBE December 12, 1999, pg. C26.

[4] Matthew Taylor, "Mad Cow Fears, Anger on Farms; Two Imported Sheep Herds Quarantined in Vermont," BOSTON GLOBE October 31, 1999, pg. F24.

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 Records.
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

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 epidemic.

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.


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