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Introduction
Why Xenotransplantation?
The Fear of Xenotransplantation
The First Xenotransplant Trials
Dr. Joshua Lederburg, The Rockefeller University, USA Opening Remarks
Dr. Michael Oborne, OECD, Paris, France Welcome - OECD Perspectives
Dr. David Harper, Department of Health, London, UK Conference Goals and Objectives
Dr. John Wallwork, Papworth Hospital, The Need for Alternatives to Allotransplantation
Dr. Blanca Miranda, National Transplant Organization, Madrid, Spain International Issues in Transplantation
Professor Randall E. Morris, Stanford University, USA New Developments in Allo/Xenotransplantation
Dr. Jay A. Fishman, Massachusetts General Hospital, USA Xenotransplantation: Risk of Infection
Professor Dr. Frans van Knapen, Utrecht University, The Netherlands Parasitic Issues in Xenotransplantation
Dr. Jonathan P. Stoye, National Institute for Medical Research, UK Endogenous Retroviruses
Dr. Joachim Denner, Paul Ehrlich Institute, Germany Immunosuppression by Retrovirus
Dr. Jonathan Allan, Southwest Foundation for Biomedical Research, USA The Risk of Baboons as Transplant Donors
Dr. Marian Michaels, Children's Hospital of Pittsburgh, USA Xenotransplant Associated Infections: Patient Issues
Dr. Nelson A. Wivel, Institute for Human Gene Therapy, USA Lessons from Public Oversight of Gene Therapy Research
Mr. André La Prairie, Health Canada, Ottawa, Canada Public Confidence and Government Regulation
Dr. Louisa E. Chapman, CDC, USA Guidelines on the Risk of Infectious Agents during Xenotransplantation
Dr. James Whitehead, Stellar Systems, USA Development of Databases and Registries: International Issues
Dr. Jeffrey L. Platt, Duke University, USA Xenotransplantation: Historical Perspective and Future Promises
Professor Dr. Claus Hammer, Ludwig Maximillians Universität, Germany Physiology of Xenografts
Dr. David H. Sachs, Massachusetts General Hospital, USA Tolerance and Cloning Strategies
Bartha Maria Knoppers, McMaster Meighen, Canada The Ethics of Xenotransplantation
List of Workshop Speakers and Participants
 

Introduction

Xenotransplantation is an emerging medical technology that offers enormous promise for the treatment of human disease.  Today, we are witnessing the birth of a new branch of medicine, in which tissue and organs from animals will be transplanted into people to replace essential functions lost through myriad diseases.  Because of the international implications of xenotransplantation, the Organization for Economic Co-operation and Development (OECD) and the The New York Academy of Sciences (NYAS) sponsored the International Workshop on Xenotransplantation which brought together researchers, clinicians, regulators, ethicists, advocates,  legal experts, and economists to achieve a common understanding of the benefits and risks associated with xenotransplantation.

For people with diabetes, xenotransplantation may represent the only hope for a cure in the near term.  Specifically, the most promising technology today is the transplantation of insulin-producing islets from pigs into people, without the use of immunosuppressive drugs.  Therefore, any regulatory impediments to the advancement of xenotransplantation would have serious consequences for those seeking to end diabetes.  With several countries threatening to impose moratoria on xenotransplantation, it was essential that our voice be heard in an international forum where such regulatory arguments would be aired.

I am happy to report that I do not believe we will face a moratorium in most countries of the world.  It was generally recognized that the benefits of xenotransplantation are enormous, and the risks manageable.  In the United States, the Food and Drug Administration stated very clearly that it would not impose a moratorium, as such a move is unnecessary and would only drive people seeking treatment to countries where the practice was not banned.

The conference lasted for 3 days, each day packed with speakers and panels.  The following report is compiled from my notes taken at the conference, as well as informal discussions with attendees.  Since our main interest is in diabetes, the report will focus on that specific application, rather than provide comprehensive coverage of all the material presented.

Dianne Terry from London, Ontario and I were present representing the interests of the diabetic community.  At the end of the conference, Dianne gave a very pointed challenge to the researchers and regulators saying, in effect, "Now it's time for some action. By this time next year there should be some real progress, and we must not find ourselves still talking about the same things.  This is all about clinical trials, not about endless process."

Why Xenotransplantation?

Allotransplantation, the grafting of organs from human donors, has been a victim of its own success.  The transplanting of organs such as kidneys, hearts, livers, lungs, pancreases, and lungs has saved so many lives that the demand for human organs is outstripping the supply by an accelerating margin.  There were several speakers who operated the organ donation systems in their respective countries, and the message was always the same: More people are dying each year while waiting for a suitable organ donor.  All the speakers agreed that they knew of no way to significantly increase the availability of human donor organs, and that the number of deaths would grow in the coming years.

To bridge the gap between organ supply and demand, it was agreed that xenotransplantation was the only real hope.  In addition, xenotransplantation offers the possibility of treating diseases, such as diabetes and Parkinson's disease, that were hitherto not considered treatable through transplantation.

The Fear of Xenotransplantation

Xenotransplantation, like any new medical technology, comes with enormous promise and some unknowns.  The one risk identified was zoonotic infection resulting from a virus or other pathogen that crosses the species barrier and infects the human host. The remote chance of an infection that causes disease only in the new host would not necessarily create any ethical concern, since the recipient was deriving benefit from the transplant.  The ethical issue centered on the possibility that the zoonotic disease could be spread to other humans who did not derive the same benefit as the recipient.

Several speakers expressed concern about the use of non-human primates, especially baboons and monkeys, as organ donors, as well as the fact that the recipient would be heavily immunosuppressed.  At this point it was important to make the point to the audience that xenotransplantation is not a lumpen mass of science, uniform in its risk and benefit.  In fact, xenotransplantation reflects a whole spectrum of activity, ranging from pig islets without immunosuppression at the safest end of the spectrum, to baboon heart transplants with immunosuppression at the riskiest end of the spectrum.  The difference between those two extremes of xenotransplantation is greater than the difference between xenotransplantation and allotransplantation.  To regulate and practice these extremes as if they shared the same risk/benefit profile would squander a unique opportunity to safely deliver demonstrable benefit from xenografts in the near term.
 
The following table compares the extremes in xenotransplantation.  The obvious difference in risk profiles clearly demonstrates that one set of guidelines targeting the worst case will never work.
 

	Safest End of  Xenotransplantation Spectrum	Midrange of  Xenotransplantation Spectrum	Riskiest End of  Xenotransplantation Spectrum
Disease Treated	Diabetes	Kidney Failure	Heart Failure
Organ Transplanted	Pancreatic Islets	Kidney	Heart
Donor Animal	SPF pig	SPF transgenic pig	Baboon
Immunosuppression	None (Immunobarriers)	Systemic (Lifelong)	Systemic (Lifelong)
Graft Failure	Return to insulin injections	Dialysis	Death

 

The First Xenotransplant Trials

Xenotransplantation is a relatively new science with great promise.  The question arises: What should the first clinical trials of xenotransplantation be?  Just as nobody started selling tickets to cross the Atlantic immediately after the Wright brothers managed 20 seconds of bumpy flight on Kitty Hawk, the first xenografts should be selected for the maximum chance of success and the minimum risk of an adverse outcome.  I had an opportunity to make the case strongly to the audience that islet xenografts were the logical first choice.  Although whole organ xenografts will provide tremendous life-saving potential, they represent a greater challenge and more unknowns that islet xenografts.  By demonstrating success and safety in the least challenging end of the xenotransplantation spectrum, both governments and the public will be more friendly to the promise of whole organ xenografts.

The following table compares islets to whole organ xenografts in terms of challenge, risk, rejection potential, efficacy, track record, compatibility, and public response.  The whole field of xenotransplantation would benefit from an early success, such as reversing diabetes.
 

	Islet Xenotransplantation	Whole Organ Xenotransplantation
Donor Animal	Specific-pathogen-free (SPF) pigs only (lowest risk of zoonotic infection). Transgenic pigs are not required.	Both transgenic SPF pigs (lowest risk of zoonotic infection) and non-human primates (higher zoonotic infection risk), depending on organ.
Immunosuppression	No immunosuppression - Immunobarriers protect transplanted tissue. Recipient retains healthy immune system. Risk of infection from all sources is minimized, and adverse effects such as cancer are precluded.	Systemic immunosuppression  - Higher risk of infection and adverse effects. Immunosuppression is cited as a major risk factor associated with xenografts.  The use of transgenic pigs may allow immunosuppression comparable to allografts.
Hyperacute Rejection	None - Since islets do not contain endothelial cells, hyperacute rejection typical of non-human organs does not occur.	Strong - Because of endothelial cells and species mismatch, whole organs will experience immediate hyperacute rejection, unless the recipient is sufficiently immunosuppressed.
Acute Vascular Rejection	None - Since islets are free tissue not connected directly to the recipient's vascular system, acute vascular rejection is avoided.	Strong - Organs such as hearts, liver, or kidney must be connected to recipient's vascular system, resulting in immediate destruction of the blood vessels unless the recipient is sufficiently immunosuppressed.
Physiologic Differences	Minimal - Normal blood glucose range is 70-100 mg/dl for humans, 70-105 mg/dl for pigs. Pig islets would maintain a normal blood glucose setpoint in humans. Organ matching is not an issue, as it is impossible to transplant too many islets.	Variable - Pigs and humans differ significantly in most physiological parameters. It is not known if these differences will lead to problems in liver, heart, kidney, or other whole organ xenografts.
Historical Efficacy	Compelling - Pig insulin has been used for 77 years to control blood glucose in people with diabetes.	None - There is no track record comparable to pig insulin for any animal whole organ.
Consequence of Failure	Minimal - The recipient will revert to normal injected insulin therapy.	Severe - Failure of a whole organ may result in death or serious illness.
Retransplantation	Minor - Injection or simple surgery to add additional islets, or to remove islets for examination.	Major - Intrusive and risky surgery to retransplant in event that recipient survives graft failure.
Clinical Trials	Some - Several thousand people have already been transplanted with living pig tissue, including islets, hepatic cells, neurons, and skin. In 8 years, there has been no disease manifestation.	None - Other than some early failed attempts, there has been no short or long term experience with a xenografted animal organ.
Economic Impact	High - Diabetes costs the US $30B/year in direct costs, and over $100B/year total costs.	High - Xenografted whole organs will reduce costly organ waiting times and return patients more quickly to productive health.
Organ Demand	Positive effect - Islet xenografts will reduce demand for kidney transplants, many of which are a direct consequence of diabetes.	Positive effect - Organ xenografts may reduce demand for all human organs, and will meet need without costly and often lethal delays.
Organ Donation	No effect - Islet xenografts will have no effect on normal organ donation, as there is no expectation today that donated organs are for curing diabetes.	Possible negative effect - Many administrators of national organ donation systems fear that conventional organ donation will diminish if people believe that animals can meet the demand for organs.
Public Message	Safe - Graft failure would be a "quiet" event. Reversing diabetes would create public support for xenotransplantation in general.	Risky - Failure of early whole organ xenografts and the likely death of recipients may create public antipathy for xenotransplantation in general.

 
It now appears that clinical trials of xenotransplantation will be allowed to proceed in most countries under guidelines that assure adequate record keeping, reporting of adverse events, archiving of donor and recipient biologic samples, safe and humane animal management, long-term monitoring of recipients, and other procedures intended to reduce or eliminate risks.

The following sections provide highlights from some of the speakers and panel participants.

Dr. Joshua Lederburg
Professor Emeritus
The Rockefeller University, NY, NY, USA
Opening Remarks

• Expressed concern over the use of non-human primates as organ donors, as well as the endogenous retroviruses that are part of the DNA of most pigs.
• Felt that pigs were the safest source or organs, and that breeding and proper handling could produce a clean source of specific-pathogen-free (SPF) tissue.
• Described the ethical dilemma of allocating human organs to dying recipients, and the illegal trade of organs that has arisen. These terrible problems could be eliminated through xenotransplantation.
• Discussed the accepted risks of allografts, including disease transmission and public health threats from immunosuppressed patients.

• OECD is a permanent conference of governments based in Paris formed after World War II for the reconstruction of Europe. Today, OECD has global membership and deals with issues which must be managed on a global, as opposed to a national, scale.
• Discussed the early fear surrounding Recombinant DNA technology, and the implementation of a moratorium in 1974. The moratorium was terminated after 16 unproductive months.
• Suggested that today's fears of xenotransplantation are much like the earlier fears of DNA engineering.

• Today there are over 1,000,000 allograft recipients alive worldwide, and the demand for organs is massive and cannot be met from human donors.
• Would like to see sensitive assays developed for early detection of zoonotic infection of a recipient.
• Pointed out that gene therapy had also raised similar concerns, namely the possibility that a replication-competent virus could create a public health issue.
• Discussed the fact that 700,000 dialysis patients are awaiting kidney transplants, and that transplants are 60% cheaper than dialysis and much more humane.
• Suggested that allograft market is now $10B worldwide. In addition, there is a serious problem in illegal organ trade.  Xenotransplantation could eliminate or curtail this illegal and unethical trade.

• Cardiac transplant surgeon with xenograft experience and co-founder of Imutran, developer of the transgenic pig.
• Described massive and growing gap between supply and demand for organs.
• Even after careful screening of ideal transplant recipients, over 20% still die waiting for an organ.
• Stated allograft irony: "Well people must die so that sick people may live".
• Believes that transgenic pigs will be the organ donors of the future.
• A kidney from a transgenic pig is still functioning normally after 78 days in a monkey.
• Mascot is Pigasus -- "It will fly!"

• Runs the most successful organ donation organization in the world. Spain has the highest organ donation rate of any nation.
• In the US, 40,000 people are waiting for 12,000 kidneys, creating a tragic situation.
• No matter what is done to enhance the rate of organ donation, the improvement will be negligible.
• Artificial organs such as heart and pancreas are not a solution, as there are massive unresolved problems with power supply, thrombosis, infection, biocompatibility, and reliability.
• Only solution is to source organs from pigs

• Discussed current technology options to thwart rejection of whole organs.
• New immunosuppressive drugs, such as FK506, MPA, CyA, offer both greater defense against rejection and fewer adverse effects. Traditionally, the more effective the immunosuppressant, the worse the adverse effects such as infection and cancer.
• Feels that Tacrolimus and Cyclosporin-A will be used for whole organ xenografts.
• Did not discuss immunobarriers for cells, but was very interested in their potential during private discussion, and agreed that islets may be the closest to clinical reality, and that immunobarriers are the preferred solution over drugs. Dr. Morris's work has mainly focused on whole organ xenografts.

• Focused on the potential for infection in xenotransplantation.
• Cited the obstacles to whole organ xenografts being hyperacute rejection (HAR), acute vascular rejection (AVR), chronic rejection, complications of immunosuppression, and social acceptance.
• Stated that the species barrier reduces the risk of infection, but may also reduce the immune response in the event that infection occurs.
• The risk of infection is proportional to the level of immunosuppression. The lower the immunosuppression, the lower the risk of infection.
• Xenograft infection risk is driven by the amount of tissue transplanted, whether the tissue is a vascularized organ or cells, the duration of the transplant (permanent versus bridge), and the presence of encapsulation in the case of cells.
• Pigs are much safer than non-human primates.
• With pigs, we have a history of long term interaction, extensive study, absence of illness among meat packers, and no infection in existing pig xenograft recipients.
• Xenografts offer advantages over allografts: Avoid transmission of human diseases such as HIV, Hepatitis B/C, CMV, and EBV; avoid the use of marginal human donors since supply is unlimited; decrease the ischemic time between harvesting and transplanting an organ; and possibly vaccinate the recipient against known and predictable donor-borne viruses.
• Recipients of xenografts should be monitored closely, possibly for the rest of their lives. Must continue to develop better assays for detecting zoonotic infection.
• Dr. David White of Imutran/Novartis stated that hundreds of people have now been transplanted with pig cells without adverse consequence.  He asked how many such human sentinels are needed before we say that porcine xenografts are safe? Dr. Fishman agreed that the data was very supportive, but the possibility of long viral latencies means that we have to remain vigilant.
• Dr. Randall Morris asked if the thousands of people who received pig skin as a treatment for burns have been monitored for infection.  Dr. Fishman said that these patients are being studied using sensitive PCR (Polymerase Chain Reaction) assays to look for even minuscule levels of infection.
• Privately, Dr. Fishman told me that he felt the FDA guidelines would assure safety for clinical trials, but that the requirements made it difficult for small companies and universities to participate without first forming strategic alliances, generally with major pharmaceutical companies.  I pressed for actual budgetary numbers, but he was not able to offer specific cost figures.

• Dr. van Knapen presented data on parasitic infections from animals that was enough to to turn the audience into vegetarians.
• These parasitic infections occur mainly as a result of eating and handling meat, but could also be transmitted through infected transplanted tissue.
• It is essential that animals be birthed and handled to assure the absence of parasites, an achievable goal.
• Parasites are not a public health issue, but could compromise the health of the recipient or damage the transplanted organ itself.
• Immunosuppression increases risk of parasitic infection from all sources, such as water.

• Dr. Stoye presented several anti-xenotransplantation arguments.
• He asked several questions regarding Pig Endogenous Retrovirus (PERV): (1) Can PERV infect human cells? Robin Weiss has shown infectivity in vitro, but never in vivo (in animals or people).  (2) Can the virus be in the germ line of the donor animal?  Yes, PERV is in the genome of every cell in most pig lines. (3) Can PERV infect people? Don't know, has never been shown. He acknowledges that 200 people who received pig tissue have all tested negative for infection, but asked "What about the 201st?"   (4) Will infection lead to high levels of viral replication?  Don't know. (5) Will replication lead to disease?  Don't know.
• In discussing the risk to public health of porcine xenografts, he characterized it as "very, very, very low".
• Dr. Stoye said in a later panel discussion that "We should say no to non-human primates until we can produce primates that are as clean as pigs."

• Dr. Denner made the point that known retroviral infections such as HIV consistently have an immunosuppressing effect on the infected host.  AIDS is the most extreme example of a retrovirus damaging the immune system of its host.
• He speculated that if PERV infection occurred in people, it would also have an immunosuppressive effect.
• Retroviral infection may occur in recipients who are taking large doses of immunosuppressive drugs.
• He speculated that the use of transgenic animal donors might worsen the problem, since the greater similarly of the transplanted tissue may inhibit a vigorous immune response on the part of the recipient.

• Dr. Allan has written extensively about the risks of using non-human primates (NHPs), especially baboons and monkeys, as organ and tissue donors.
• NHPs have been shown to carry simian foamy virus (SFV), simian T-cell lymphotropic virus (STLV), baboon endogenous virus (BaEV), and simian endogenous retrovirus (SERV). As NHPs are very closely related to humans, the risk of these viruses crossing the species barrier is much higher than it would be for pigs.
• Because of the nature of NHPs, it is not practical to apply animal breeding and handling practices that could potentially eliminate these viruses.  Unlike pigs, the long gestation and maturation of NHPs makes such essential animal breeding and production practices impractical.
• Dr. Allan would like to see a moratorium on the use of Non-Human Primates as organ donors.
• He compared pigs to NHPs as organ donors: (1) Long history of NHP infections in people, (2) Genetic relatedness of NHPs to humans, (3) Impossible to apply pig-like controlled production practices to NHPs, (4) Humans have a long history of close contact with pig tissue without infection.
• Dr. Allan said we should use animals with the greatest benefit-to-risk ratio, namely pigs.
• I had a chance to ask the speakers where the pressure was coming from to use baboon and monkey organs.  The answer was unclear, except that organ size was a critical factor for heart transplants in children, and that the genetic relatedness may make the tissue less "foreign", requiring less immunosuppression.

• There are risks of transmitting disease in human-to-human transplants and in animal-to-human transplants.  In fact, all biologic agents carry the risk of infection.  These risks can and have been managed as part of normal medical practice.
• Human-to-human transplants have transmitted diseases such as herpes, hepatitis B and C, bovine spongiform encephalitis (BSE), and others.
• Xenografts using baboons and monkeys have had a poor track record of success.
• Baby Faye who received a baboon heart died from her illness, but did not suffer any infection from the baboon.
• Risk of PERV infection from pigs is very low.
• Jeff Getty, the AIDS patient who received baboon bone marrow, has likewise not suffered from an infection.
• For xenografts, it is essential to (1) Have a multidisciplinary team, (2) Maintain a database that can be accessed and updated by every member of the team, (3) Archive samples of tissue, serum, and blood from the animal and the recipient before transplant, and from the recipient at regular intervals following transplant, (4) Discuss the risks of xenotransplantation with the recipient and his or her circle of intimate contacts, and seek behavioral modification to protect against disease transmission, and (5) Continually adapt xenograft protocols based on new insights.

• In the 1970s, there was a great deal of fear surrounding the emerging science of gene therapy. Many were accusing genetic engineering of manipulating the very building blocks of life, and predicted dire consequences.  A moratorium was actually imposed on gene therapy research in 1974, but was lifted after 16 months.
• In 1976, a group of scientists and their supporters called for legislation to outlaw genetic engineering.  Had that law passed, we likely would have had no recombinant DNA technology today.
• Today, there are 232 gene therapy protocols approved in the United States, and over 300 worldwide.
• The lessons learned from the early days of gene therapy research are (1) Never underestimate the value of public discourse and debate, (2) Oversight should be both by scientists and the public, (3) The scientists should be drawn both from the ranks of basic research as well as clinicians, (4) As technology advances, the patient population targeted by the new medical technology should change, typically going from cases of overt disease to pre-symptomatic disease, and (5) Experience allows the reduction of stringency in the review process.

• Mr. La Prairie spoke eloquently about the need for public confidence in any new medical technology and how that confidence derives from reasonable regulatory safeguards and open communication.
• Moratoria do not work, as they only create a checkerboard of restrictions. If a medical practice has promise, there will a country where it is not banned.  "Transplant tourism" will result in citizens of restrictive countries visiting less restrictive countries where the procedure can be undertaken.  The returning citizen may not have been subject to any safeguards, nor will there be any accessible database of essential information.
• Mr. La Prairie stated that moratoria are not the best for controlling research behavior as they preempt public discussion and remove the issue from the public mind until the new technology suddenly emerges in response to a technological advance. Then it is a fait accompli in which the public will have had no involvement.
• In a later question period, Mr. La Prairie noted that many have discussed the efficacy and adverse outcomes of medical interventions, but has anyone ever considered the efficacy and harm of government regulation? He went on to say that governments should establish clear and reasonable standards that are specific to xenotransplantation, and that clinical trials should adhere to these standards. Regulations and laws will be less effective, as they take a long time to implement, and the underlying technology changes much more quickly than the regulation.

• Dr. Chapman discussed the reaction of the public to the FDA guidelines on xenotransplantation issued in September 1996.
• Of the public comments received:

- 109 disapproved strongly, of which 108 disapproved on the basis of animal treatment and ethics.
- The American Society of Transplant Surgeons felt that regulation was intrusive and ineffective.
- 13 companies said that the tissue archiving requirements would be too costly and difficult.
- The American Society of transplant Physicians, the American College of Cardiology, and 45 medical specialists indicated that they did not approve of the use of non-human primates.
• The voices of patients and their families must be heard.
• Today, xenotransplantation clinical trials can proceed in the United States under an Investigatory New Drug (IND) approval from the FDA.  The sponsor for the trial is responsible for safety.  Before proceeding with the trial, the sponsor needs to show that the pigs are derived from closed herds, birthed by C-section, raised in barrier facilities, and tested regularly for pathogens. In addition, the sponsor must keep proper records of all results, and apply proper diagnostic assays and surveillance procedures. Biologic specimens must be maintained fro 50 years, but this requirement may change as knowledge grows. Adverse events must be reported immediately.
• Final guidelines are expected in 1998.

• Stellar Systems is developing the National Xenotransplantation Database (NXD) for FDA for management of xenotransplantation clinical trials.
• System will be based on Oracle and open standards, and will be accessible globally with suitable firewalls to assure security of private data owned by companies, researchers, and patients.
• Design specification is initially to meet US FDA requirements but can be easily expanded for international requirements.
• Database will cover research data, animal data, specimen archiving, patient registry, patient progress, adverse event reporting, IND applications, corporate database, regulations, and other information required for the safe and efficient management of xenotransplantation clinical trials.
• The project is 4 months into an 18 month completion schedule.
• Sponsors of clinical trials will be responsible for their own record keeping and reporting prior to completion of the NXD.

• Dr. Platt discussed the hurdles successful organ xenografts: (1) Hyperacute rejection - HAR, (2) Acute vascular rejection -AVR, (3) Cellular rejection, and (4) Chronic rejection.
• The development of transgenic pigs has significantly reduced HAR, the most challenging hurdle of the past decade.
• AVR results in the destruction of the blood vessels connected to the xenografted organ.
• New developments in creating central and peripheral xenotolerance enhance graft survival.
• Temporary suppression of the humoral immune response following the xenograft seems to induce a tolerance and the AVR subsides over time.
• New research is focusing on the donor animal and the expression of galactose alpha-1,3 galactose ("gal gal") as a trigger of the heightened immune response.
• Xenografted cells do not seem to experience HAR or AVR.

• There are significant anatomical, physiological, and biochemical differences between pigs and people, and some of these differences may be issues for xenotransplanting organs.
• For example, the physical orientation of the pig results in a different environment for organs such as lung, heart, and liver.
• Dr. Hammer showed a long list of physiological parameters, and it was evident that pigs and humans differ significantly in most of these parameters.
• From the perspective of islet transplantation, it was interesting to note that the one parameter that was nearly identical in humans and pigs was blood glucose (Normal blood glucose range is 70-100 mg/dl for humans, 70-105 mg/dl for pigs). Therefore, pig islets would maintain a normal blood glucose setpoint in humans.  Since pig insulin has proven effective in controlling human blood glucose for 77 years, there is little question as to its compatibility.
• During the question period, many of the researchers agreed that these differences existed, but that trials in monkeys have already shown that many are of little consequence.  In one trial, a pig lung is working successfully in an upright monkey.
• Dr. Hammer agreed that the nearest candidate for successful xenotransplantation is islets.

• Dr. Sachs discussed the use of tolerance induction and cloning as a means of reducing the powerful immune response that a human launches against xenogenic tissue, especially whole organs.
• The ideal source of organs is the inbred miniature swine (350 lbs), as the inbreeding assures an unlimited source of genetically identical donor tissue for induction and maintenance of tolerance.
• Cloning may offer an additional advantage of allowing genetic engineering of the donor cell prior to nuclear transfer.
• Dr. Sachs discussed the transfusion of donor animal bone marrow into the recipient as a means of inducing tolerance. To reduce the risk of graft-versus-host disease (GvHD), the donor bone marrow would be depleted of its T-cells.
• The resultant mixed chimerism in the recipient may gradually create tolerance for the transplanted organ.

• Throughout the conference there was a great deal of discussion surrounding the ethics of xenotransplantation.  Issues have been raised such as: Will a personality be preserved if living animal tissue is transplanted into a person's body? Will xenotransplantation lead to a mechanistic view of humanity, viewing us as little more than a collection of spare parts? Should clinical trials of xenotransplantation be banned until we have satisfied everybody's fear of he unknown? Bartha Knoppers addressed the issue of ethics very succinctly on one of the panels, making the following important points:
• We have not yet done all we need to do to develop public confidence in xenotransplantation.  More discussion and exposure are needed to create an informed and accepting public.
• The public had no previous warning of earlier medical breakthroughs, such as the first test tube baby and Dolly, the first cloned animal. As a result, there was massive resistance to these new developments and some calls for banning such practices.
• A moratorium based on safety will not work. Patients can simply go to other countries.  In addition, no reputable scientist will risk his or her reputation and career with a trial where risk/benefit is not clearly favorable.
• A moratorium based on ethics will not work, since the ethical issues that lead to the moratorium will not change with the passage of time.

 CHAIRS

Dr. Louisa E. CHAPMAN   Retrovirus Diseases Branch  Division of AIDS, STD and TB Lab. Research  National Center for Infectious Diseases  Centers for Disease Control and Prevention  UNITED STATES	Dr. Rachel LEVINSON  Assistant Director  Life Sciences  Office of Science and Technology Policy  UNITED STATES  E-mail: levinson@ostp.eop.go
Dr. Mike CRUMPTON  Deputy Chief Executive  Imperial Cancer Research Technology  ICRF  UNITED KINGDOM 1	Dr. Amy P. PATTERSON  Interim Deputy Director and Medical Offcer  Division of Cellular and Gene Therapies  US Food and Drug Administration  UNITED STATES  E-mail: pattersona@A1.cber.fda.gov
Professor Abdallah S. DAAR  Chairman  Department of Surgery  College of Medicine  Sultan Qaboos University  SULTANATE OF OMAN  E-mail: asdoc@gto.net.om	Dr. Jeffrey L. PLATT  Department of Immunology  Duke University  DURHAM NC 27710  UNITED STATES  E-mail: platt00l@mc.duke.edu
Dr. David HARPER  Chief Scientist  Department of Health  UNITED KINGDOM  E-mail: dharper@doh.gov.uk	Dr. Elettra RONCHI  Biotechnology Unit  Directorate for Science, Technology and Industry  OECD  E-mail: elettra.ronchi@oecd.org
Professor Ian KENNEDY  Professor  School of Public Policy  University College London  UNITED KINGDOM  E-mail: i.kennedy@ucl.ac.uk	Dr. Calvin R. STILLER  Microbiology and Immunology  Department of Medicine  University of Western Ontario  CANADA  E-mail: cstiller@cmdf.com
Dr. Joshua LEDERBERG  President Emeritus  The Rockefeller University  UNITED STATES  Email: lederberg@rockvax.rockefeller.edu	Dr. David WHITE  Imutran Limited  UNITED KINGDOM  E-mail: david.white@pharma.novartis.com