The Transplantation Xeno-Derby
|The greatest problem in transplantation medicine -- what to do about the organ shortage -- is getting worse. While the number of organ donors follows a barely upward trend, the list of those desperate for an organ transplant gallops ahead at 15 percent per year. With no cavalry of human donors riding to fill the gap, biotech companies are forging ahead to implement their own solution -- organs from pigs.|
Making a silk purse from a sow's ear might be easier, however, for the human immune system destroys pig organs with a tiger-like ferocity that standard immunosuppressive drugs are powerless to prevent.
But the problem is being solved, mainly by clever genetic engineering schemes that make pig organs more acceptable to the immune system. So much progress has been made towards that goal that it now seems only a matter of time -- a few more years -- before pig organs start saving lives. And with the arrival just a few months ago of a technique for cloning pigs, which will almost certainly mark a milestone in transplantation, that day has drawn much closer.
Transplantation today embraces therapies that seemed like science fiction when the field began almost a hundred years ago. Thanks to immunosuppressive drugs and tissue typing, transplants of major organs -- heart, kidney, lung and pancreas -- are established medical procedures. Twenty-five different body parts can be transplanted, and new ones keep joining the list. Just two years ago, the first successful hand transplant was performed.
But as transplantation medicine heads into its next century, its great accomplishments are overshadowed by an enormous shortage of donor organs. Demand runs so far ahead of supply that each year several thousand people die while waiting for organs that never come.
A solution is on the horizon -- xenotransplantation, the use of animal organs by humans. Since the early 90s, a handful of biotech companies have been quietly working on the challenge of transplanting organs from the animal of choice, the pig. To do this, pigs have to be genetically engineered so their organs will be tolerated by the human immune system. The clever competitors in this race have made so much progress that the opening of a billion-dollar xenotransplantation market is now more than likely just a few years down the road.
This year, about 5,000 living donors will contribute organs. There will be a similar number of donations after death. That is not nearly enough to meet demand -- the national waiting list now tops 70,000 names, according to the United Network For Organ Sharing (UNOS). Little surprise, then, that a wait for a kidney can stretch to 5 years, or that some 4,000 patients this year will expire for want of transplant organs.
Type Of Transplant
Number Of Transplants Performed In 1999
Number Of Patients Waiting For Transplant (as of 7/8/00)
Pancreas (islet cell)
Data courtesy United Network For Organ Sharing (UNOS).
* Based on UNOS Scientific Registry data as of 6/10/00. Double kidney, double lung and heart-lung transplants are counted as one transplant.
**Note that some patients are waiting for more than one organ; therefore the total number of patients is less than the sum of patients waiting for each organ.
That animal organs are the solution to the problem has been evident to farsighted researchers since long before organ transplants became successful. Attempts to put animal organs into humans, in fact, coincide with the development of techniques for vascular surgery. The most celebrated early xenotransplantation experiments were those performed in Paris in the early 1920s by a Russian surgeon named Voronoff. In several dozen experimental surgeries, he claimed to rejuvenate elderly men with grafts of monkey testicles.
Monkey ball transplants set smiles on many faces. A popular café ashtray of the time was decorated with a monkey covering his privates and the inscription “Non, Voronoff, tu ne m’auras pas!” [“No, Voronoff, you won’t get me!”]. If any grandpas were turned into gigolos, though, it was more for emotional than physiological reasons: Successful transplantation did not begin until the 1960s, with the advent of immunosuppressive drugs and an understanding of the genetics of transplantation, which is the basis for tissue typing.
Experiments eventually revealed clear differences between transplanted organs from pigs and non-human primates. To a small extent, kidney, liver and heart transplants from baboons and chimpanzees worked; the record for the length of time one of their organs can keep a human alive is about 70 days. Pig organs, however, failed decisively -- inside humans, they survived at most a couple of hours; frequently they lasted only minutes.
So biotech’s bet that pig organ transplants have a big future flies squarely in the face of an abysmal performance. Several reasons explain why what plainly has not worked may burgeon into a bonanza.
First, baboons and chimpanzees are not going to satisfy the demand for organs. They are exorbitantly expensive to raise in the numbers needed. The similarity of HIV to endogenous primate viruses, moreover, leaves a strong fear that baboon or chimp organs could transmit serious infections to humans. Just as importantly, many consider it immoral to use primates for xenotransplantation. Pigs, on the other hand, are economical to breed, even under the GMP conditions that would be required for transplant organs. And few object to transplanting organs from a species already used for food.
Most importantly, however, the cause of rapid rejection of pig organs is now understood and a variety of things can be done about it. The problem traces to a carbohydrate on the surface of pig cells called alpha 1,3-galactose. Humans have circulating antibodies against alpha gal, as it is called, because of prior exposure to bacteria that coincidentally bear the same sugar. The intense, rapid destruction of transplanted pig tissue is due to these antibodies. The fierce immune response, in fact, has a special name: hyper acute rejection, or HAR. Every xenotransplantation company has a strategy to prevent HAR.
Once HAR is overcome, the remaining problems are the ones human organ transplantation grapples with every day -- acute and chronic rejection. Research on these problems is the leading edge of the field. With solutions, similarities between pig and human physiology make it a reasonable assumption that pig organs will work well enough to keep humans alive for long periods of time.
"Everything about pig embryology is more difficult than in any other livestock species," says David Ayres, explaining why it took until this year for his company, PPL Therapeutics, of Blacksburg, VA, to become the first to clone pigs.
Ayres, who is vice president of research and development at PPL, saw the project start in 1998, when cloning technology was transferred to Blacksburg from PPL's labs in Scotland. The Scottish branch of the company, in collaboration with the Roslin Institute, was the first to clone a mammal from an adult cell. In 1997, news photos of that animal, a sheep named Dolly, trumpeted the feat around the world. Dolly was created by substituting the nucleus of an unfertilized sheep egg with the nucleus of a cell from an adult ewe’s udder. The altered egg was then implanted into a foster mother, who brought the famous animal to term.
Cloning, also called nuclear transfer, can be used to turn genetically altered pig cells into pigs. It is more versatile than the older technology of DNA microinjection into pig eggs, which lets scientists give pigs new genes. Cloning can do that and something more -- it can also delete them. Pig cloning allows a broader range of genetic engineering techniques to be brought to bear on the xenotransplantation challenge.
PPL’s pioneering work with other animals only took the company so far when cloning pigs. “The method used for cattle didn't work in pigs,” says Ayres. “We had to change all aspects of the nuclear transfer and try various strategies to maintain pregnancies with small litter sizes. Cows, sheep and goats can carry one offspring, but a pig has to keep at least four implanted in the uterus [or the pregnancy aborts]. So you have to be very successful in your nuclear transfer.”
Success came this past March: Five little sows, pretty and pink, the first cloned pigs: Millie, Christa, Alexis, Carrel and -- in envious tribute to what internet stock hoopla can do for company valuations -- Dotcom. Work has already started on the HAR problem, using cloning to inactivate the alpha-1, 3-galactosyltransferase gene (GT) that creates the alpha gal sugar. When GT goes, HAR goes.
Photo courtesy PPL Therapeutics.
In Ayres’ view, that is just the beginning: “We don’t believe combating hyper acute rejection is the end of the story. We have a more comprehensive program that deals with delayed rejection, which occurs not within minutes, but within hours into the first week, and then we have strategies to deal with chronic rejection. Once we have a knockout animal for alpha gal, we will breed in another five or six genes to combat the whole rejection process. We don’t want to put an organ into a human and then have it last only three months. That would not only be bad for the patient, but bad for the whole industry. It would be perceived that it wasn’t good therapy.”
PPL will add two genes to inhibit human complement. Complement refers to a group of plasma proteins that in concert with an activating antibody (such as one against alpha gal) can kill foreign cells. (HAR starts when human antibodies react with alpha gal, but the pig cells do not die until the antibodies bring complement into play.)
Two other genes will inhibit blood clotting around the xenograft. On the endothelial cells lining transplant organs’ blood vessels are anticoagulant proteins that prevent clot formation. But in the delayed immune response that comes after HAR, those proteins are lost. Without them, blood clots form, oxygen and nutrient delivery shut off and the graft dies. PPL will also add genes that inhibit pig Vcam1, an adhesion protein that recruits immune inflammatory cells into the transplant.
PPL does not clone alone. Hot on its heels are Advanced Cell Technology Inc. (ACT), of Worcester, MA, and Infigen Inc., of DeForest, WI. Robert Lanza, ACT’s vice president of medical and scientific development, says his company, the first to clone cattle, will soon clone pigs too. “It’s really just a matter of getting the embryos a little further along,” he says. Lanza is co-author of Xeno, an excellent book about xenotransplantation.(Xeno, by David K. C. Cooper and Robert P. Lanza. Oxford University Press. 2000.)
Michael D. Bishop, president of Infigen, is coy, not stating outright that his company has cloned pigs. He confines himself to serving notice that Infigen has applied for pig cloning patents. “We’ve been a bit more successful than they have,” is how he scores the pig race with PPL. “They just don’t know it yet.”
PPL is the only one without a partner in the xeno-derby. ACT’s partner is another competitor in the field, BioTransplant Inc., of Charlestown, MA. Infigen works with Imutran, of Cambridge, England. The partnerships and PPL have the same objective: Knock out GT. The race is underway.
Cloners have a straightforward attack on HAR. The strategies of companies formed in the era BC (before cloning) are by force more devious.
Nextran Inc., of Princeton, NJ, has direct experience with pig organs functioning with humans. In 1996, less than a year after it had been acquired by Baxter Corp., Nextran began a small clinical trial to test transgenic pig livers as bridge organs for patients with fulminant hepatic failure. The pig livers, connected outside patients’ bodies, were meant only to keep them alive until human livers became available. For three people, the pig livers worked; two others, too far gone to hold on, died.
The livers still had alpha gal. Not being able to get rid of it, Nextran instead created transgenic pigs with two human complement inhibitor genes. Since Nextran could not prevent the first step in pig cell destruction, it tried to stop the second, when anti-alpha gal antibodies activate complement.
The strategy worked, coming quite close to conquering HAR, says John Logan, vice president of R&D at Nextran. When the company tested the transgenic pig organs in primates, “we found they didn’t go into hyper acute rejection.” With transgenic transplants, only 5-10 percent of primates had HAR. The clinical trial “essentially verified what we had done in the non-human primate work,” he says. “The trial showed us that at least in a temporary situation, these organs could function physiologically and actually bridge people to a transplant.”
The trial ended last year on a positive note, but Nextran will not pursue liver transplants further. Logan thinks the physiological match between pigs and humans should be considered on an organ-by-organ basis. On those grounds, “an organ that is mechanical in function, like the heart, is a great choice,” he says. “The kidney, mechanically somewhere between the heart and the liver, is also a good choice because it performs a physical function, which is filtration of the blood; it does perform a few biochemical functions, but not too many.” But he suspects that pig and human livers are too biochemically different for good compatibility.
For the short term, where compatibility seems less important, pig liver bridging is moving full steam ahead, although not at Nextran. Circe Biomedical Inc., of Lexington MA, is in Phase III trials with its HepatAssist liver support system. Instead of an entire pig liver, Circe uses pig liver cells in a hollow fiber bioreactor outside the body. The system separates plasma from blood cells, diffuses plasma through the bioreactor for cleaning, adds it back to the cells, and then returns everything to the body. The bioreactor protects the pig cells from the human immune system.
Nextran is now looking beyond HAR to the next problem, acute rejection, which can start as early as a week after surgery. Here, differences in acute rejection of pig and human organs call for different immunosuppressive drug regimens. “With the pig there is a more strong antibody-mediated reaction against the graft. A human organ is rejected by a cellular-based mechanism,” he says. "And a lot of immunosuppressive agents developed for human grafts don’t function very well against an antibody-mediated response. So the challenge is to find the appropriate mix of immunosuppressive agents that can work.”
Nextran will also try immunopheresis -- physical removal of human anti-alpha gal antibodies before surgery. “We will use it in combination with transgenics to assure that we can overcome hyper acute rejection in 100 percent of the cases,” Logan says. The process will have to be carried out again in the first week or two post-transplant; afterwards Logan believes it may be less critical. "That is what we are trying to optimize now,” he says, “when to use immunopheresis and when to use immunosuppressants.”
BioTransplant’s approach to transplantation is immune system re-education, which co-opts transplant rejection by teaching the immune system to recognize donor tissue as belonging to the body. After re-education is successful, an organ can be transplanted without long-term need of immunosuppressive drugs. BioTransplant’s re-education procedures are in clinical trials for human organs and at the research stage for pigs.
The company has several re-education strategies. One involves giving donor bone marrow to the patient in order to create a mixed immune system, blended from donor and recipient. The cells that comprise the immune system develop from stem cells that reside in bone marrow. Of particular importance, new T cells migrate from the bone marrow to the thymus, where any that might attack donor or recipient tissues are deleted. Consequently, the patient’s immune system recognizes both donor and recipient tissues as self.
Normally, however, the patient’s T cells destroy donor bone marrow. BioTransplant prevents this by inactivating them with a proprietary humanized monoclonal antibody, MEDI-507 (which binds to the CD2 receptor found on T cells and natural killer cells), in effect wiping the T cell slate clean. New T cells arising in their place learn to tolerate donor tissue. BioTransplant recently used this procedure to allow a kidney transplant patient to stop using immunosuppressive drugs.
Another procedure in development uses a pig thymus to teach human T cells to tolerate pig tissue. BioTransplant’s thymo-kidney illustrates the idea. “A good way to transplant a pig kidney,” says Elliot Lebowitz, the company’s CEO, “would be to take thymic tissue from a donor pig and place it under the kidney capsule. When you transplant the kidney, the thymus is carried along to do the re-education. You put everything in one place.” Lebowitz calls thymo-kidneys “very promising” in experiments with baboons.
This does not deal with alpha gal and HAR, however. So BioTransplant is developing procedures that will deplete antibodies against alpha gal, a tactic similar to Nextran's.
In partnership with Imutran, BioTransplant will try taming HAR with transgenic mini-pigs that expresses human complement inhibitor genes. BioTransplant is the only company to use mini-pigs, which grow to no more than 250 pounds and better match human organ size requirements. The two companies will test organs from the transgenic mini-pigs in conjunction with BioTransplant’s reeducation procedures.
At Alexion Pharmaceuticals Inc., of New Haven, CT., a clever insight linking alpha gal and human blood types is the basis for a strategy against HAR. The major human blood types A, B, AB and O designate sugar structures on red blood cells and the epithelial cells lining blood vessels. For organ transplantation, blood types must be matched between donor and recipient even more closely than tissue types. Blood type mismatches can cause hyper-acute rejection due to circulating antibodies against carbohydrates A and B. The exception to this rule is that tissue of type O can be transplanted to someone of a different blood type (provided tissue types match sufficiently). That is why type O is called “the universal donor.”
Alexion is exploiting an insight that an enzyme can be added to the biochemical pathway that forms alpha gal so that the type O fucosyl sugar is formed instead. This is the basis for the company’s UniGraft concept. As Steve Squinto, Alexion’s senior vice president of research, explains, this “refers to genetically engineering the graft so that it will be evasive to the human immune system and have the ability of being transplanted into any recipient.”
Diagram of the central features of the complement cascade.
Courtesy Alexion Pharmaceuticals.
Alexion made a UniGraft transgenic pig with the gene (called the H-gene) encoding the type O conversion enzyme (alpha 1,2 fucosyltransferase). The pigs express type O, providing, Squinto says, “a pretty significant barrier to rejection.” Still, pigs have other molecules to which antibodies react that over a longer period could provoke rejection. So Alexion, like some of its competitors, will inhibit human complement. The company has added three human complement inhibitor genes to its type O pigs. “We see a combination of these inhibitors as being the appropriate strategy,” Squinto says. The pigs are now in preclinical testing.
The dark pig in the race is Ari Marshall’s Cryobiogenics, which suffers from the perception that Eastern European science is not very good. Marshall, of course, sees things otherwise. He may profit hugely if he is right.
Cryobiogenics is what might be called a cold war spin-off. A businessman by background, Marshall started a bank in Bulgaria after the end of the cold war. He was soon asked if he was interested in financing xenotransplantation technology developed by a group of Bulgarian scientists. Marshall performed due diligence by asking some American scientists to evaluate the Bulgarians’ research. He liked what he found out.
“At the collapse of the communistic regime, everything was for sale,” he remembers. “We met the right people at the right time and were able to acquire the technology. Actually, the technology is not new -- it started in the 80s. But it was all hush-hush because of the cold war. They never publicized what they were doing.” And, he adds, they never realized its commercial value. Marshall did, though, and started Cryobiogenics Corp. in Woodbridge, NJ, with an American management team in order to bring it to several markets -- kidneys, hearts, and vein and artery transplants.
According to Marshall, Cryobiogenics' pig veins and arteries can be stored in lyophilized form for as long as ten years. When reconstituted using a process that is a trade secret, the vessels can be transplanted without need of immunosuppressive drugs. Cryobiogenics will start a Phase II trial on vessel xenotransplantation this year in Eastern Europe. If it goes well, the Phase III trial will be conducted in the U.S. As well, a Phase I trial for kidney xenografts starts this year in Eastern Europe.
The Bulgarian connection is still active and, indeed, is essential in enabling the company to move things forward while saving a bundle in salaries. “The president of Bulgaria makes $600 a month,” Marshall notes, succinctly illustrating the Bulgarian wage scale.
The Bulgarians never dreamed of being concerned with FDA regulations when they did their original trials with humans. Little wonder, then, that their documentation is totally unacceptable to regulatory authorities and that Cryobiogenics must repeat the trials while measuring up to the highest standards. “Whatever we do in Europe, we do to FDA standards,” Marshall emphasizes.
Marshall is close-mouthed about why Cryobiogenics’ pig tissues are tolerated by the human immune system. Three strains of transgenic pigs are interbred to arrive at hybrid animals “completely compatible to the human immune system.” The pig organs have been tested in animals, “especially dogs, and we have had tremendous success so far.” GT is taken care of; he is mum on how. Other genes are added; he is mum on which. In fact, with no patents filed or awarded on its technology, Cryogenics has all the more reason to rely heavily on its trade secrets.
After Phase I trials in Eastern Europe, Marshall figures that someone will see that his company is successful and finance the next trials in the U.S. With clear data and strong documentation, he will finally stop being treated as “this guy who comes in from the woods.”
Marshall's entrepreneurial venture has been a long haul. “We put what we have and what we don’t have in this company to succeed; it’s been extremely hard,” he says with a touch of weariness. No VC money here -- private financing only. “The venture capitalists want your blood, you know. We’re not going to give it away. That’s the reason we’re suffering. It’s not easy. A colossal project.”
A world away from bootstrapping Cryobiogenics is well heeled Imutran, powered by Novartis AG’s money. Novartis bought the Cambridge, England, company in 1996 because it saw the potential market for pig hearts and kidneys.
Imutran is currently testing pig-to-primate transplants using transgenic hearts and kidneys that express two human complement inhibitor genes. The results look good, according to COO Corinne Savill. “In most instances, HAR is no longer a problem,” she says. “If we do see HAR, we are encouraged by the fact that either a soluble complement inhibitor or a carbohydrate which specifically inhibits the anti-alpha gal antibody gives further protection.”
“The aim now is to overcome acute xenograft rejection,” she adds. “Unlike transplantation of human organs, where the major rejection process is with T cells, it appears that in xenotransplantation it is predominantly an antibody response. At the moment, a better therapy for the antibody response is what we are looking for.”
Imutran is not yet ready for clinical trials. Savill says the FDA set quite a high hurdle last year when its xenotransplantation committee recommended that xenografts survive at least six months in primates, and preferably a year, before starting formal trials. (See CBER's Xenotransplantation Action Plan for more details about the FDA's policies.) Some in the industry think that is much too demanding. Certainly, she points out, no such requirement existed when transplants with human organs started.
“I think our published results are probably the longest surviving xenotransplants,” she says. “We have animals that go to one or two months, or very exceptionally three. So we have a way to go to meet the FDA target. Our view of what we have to do is find a good treatment for antibody-mediated acute rejection. Then the survival data will follow and we will be able to have regulatory discussions with people like the FDA.”
“We try to make the problem easier for ourselves,” says Thomas Fraser, CEO of Diacrin Inc., of Charlestown, MA. The company’s clinical progress bears him out: While other companies’ clinical trials are off in the future, Diacrin started trials years ago. Xenotransplantation is, apparently, easier at Diacrin.
And that is because Diacrin transplants pig cells, a much easier proposition than organs. Why? One reason, says Fraser, is that “we are putting in cells that do not give rise to a vigorous immune response. The worst offenders in stimulating the immune response are the endothelial cells that line blood vessels -- they are much more immunogenic than other pig cells. When you put in a vascularized organ, you are putting in endothelial cells, which leads to hyper acute rejection.” By transplanting only an organ’s functional cells and leaving behind those making up its framework, Diacrin lowers the cells’ profile on the human immune system’s radar.
Diacrin further simplifies by transplanting into the central nervous system, sidestepping HAR antibodies. "The blood-brain barrier,” as Fraser explains, “separates the central nervous system from the rest of the body, and does not allow antibodies to pass through. So we completely eliminate the antibody response.”
That leaves only the cellular immune response to deal with, which Diacrin handles in two ways. One is with standard cyclosporin immunosuppression. The other employs an antibody that masks pig MHC class I antigens that are recognized by human Killer T cells; recognition quickly results in the death of the xenograft cells. Masking eventually leads to long-term T cell quiescence, and the transplant becomes permanent. In pig-to-primate experiments using either method, about 75 percent of the primates have good graft survival after 6 months.
Diacrin stands a good chance of being first with a product on the market. In partnership with Genzyme Corp., Diacrin is using pig neural cell transplants to treat Parkinson’s disease, a malady characterized by degeneration of a brain region that controls movement, resulting in shaking and muscular rigidity. The company hopes the pig cells will alleviate the disease by producing dopamine, a compound essential to movement control that the patients’ brains no longer produce. The product is now in a Phase II/III trial. Diacrin’s other neural cell xenograft trials are Phase I tests for epilepsy and chronic intractable pain. There is also an IND submitted for treatment of spinal cord injury.
If there is any problem that could kill the whole field of xenotransplantation, PERV -- porcine endogenous retrovirus -- is probably it. Every clinical trial sponsor is well aware of the need to have good PERV safety data before the FDA will give a green light for tests with humans.
Many copies of PERV genes are present in pig cells, but they are usually inactive and no PERV are produced. When they are produced, however, they can infect human cells. PERV might seem an unlikely worry, considering humanity’s long association with pigs and lack of evidence that PERV causes disease. But given what retroviruses can do -- they are a rare cause of human cancer, and HIV is a retrovirus -- regulators want to be sure that the benefits of pig organs outweigh the risks of PERV.
Diacrin’s Fraser knows the problem well, since his company is has been engaged in clinical trials with pig cell transplants for 5 years. "We have spent a lot of effort to develop PERV assays because we have patients,” he says. “We have about 50 walking around who have received pig cells." Diacrin has found "no evidence of disease caused in pigs or people by this retrovirus.”
Nor has any company. A collaborative study between Novartis and independent scientists is widely quoted within the industry. In a report published in Science last year (Paradis, K. et al. Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. Science 285 (5431):1236-41. Aug. 20, 1999), researchers found no evidence of PERV infection in 160 people exposed to pig tissues.
Nevertheless, PERV goes on being studied. “We know that there are polymorphisms in PERV sequences and between pigs,” says Nextran’s Logan, “so there is still quite a lot of work that remains to be done in terms of how serious a risk it is.”
In the fall of 1997, a 19-year old Texas teenager named Robert Pennington thought he had the flu, and went to a local medical clinic for treatment. There he got a visceral signal that he faced something far more serious than a bout of seasonal virus -- his urine sample was as brown as coffee. Four days later he entered the hospital with fulminant hepatic failure, his life hanging on the hope of a transplant before his liver gave out. But no liver was available.
Pennington lived, thanks to the transplant he received a couple of weeks later. But he never would have lasted that long without a life-sustaining assist from Nextran’s clinical trial testing pig livers as bridge organs. In a procedure called “extracorporeal perfusion,” a transgenic pig liver was attached to Pennington from outside his body. Hooked up, his blood was heated and oxygenated, circulated through the pig liver for cleansing and pumped back into his body.
His savior was a pig named Sweetie Pie. Pennington’s grandmother, who raised him, keeps a Polaroid photograph of the animal that died for the young man she loves.
Many others are going to join Robert Pennington in owing their lives to pigs. The race to bring pig organs into the clinic is in the home stretch.
This means that in a few years we will finally learn how well pig organs function in humans. Will hearts from a sedentary species be up to the demands people will place on them? How much will the biochemical differences between pig and human kidneys matter?
These problems -- if they are problems -- may be solvable thanks to the wider range of genetic engineering techniques that pig cloning now makes possible. For xenotransplantation, that may be the larger significance of cloning. One by one, pig genes will go out, and human genes will replace them. Pig organs that are merely (!) immune tolerable will come first, but later ones will increasingly be humanized to our desires. Sweetie Pie 1.0 will give way to Sweetie Pie, Sports Edition. And we will never look at pigs in quite the same way again.