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Imagine a world where there’s no need for matching potential organs with anxiously waiting recipients — without ever getting on a waiting list. Several events are shaping the future of organ transplantation and could ultimately mean an end to the shortage of available organs. In April, the Scottish biotechnology company that created Dolly the sheep revealed it has created the world’s first transgenic-cloned pigs.
The biotechnology company, PPL Therapeutics, has the ability to produce a pig that could become the industry’s standard for xenotransplantation, says PPL’s research director Alan Colman. The five piglets, born in its United States laboratory in Blacksburg, VA, have a foreign marker gene within their DNA structure.
The company actually cloned its first pigs last year, but they were not transgenically modified. The modification is vital because it prevents the human immune system from rejecting transplanted pig organs. The piglets are called knock-out pigs because the alpha 1-3 gal transferase gene is inactivated.
Critics of xenotransplantation no doubt remain skeptical of PPL’s achievement. Critics argue that xenotransplantation opens the risk of animal viruses being transmitted to humans, also known as graft versus host disease (GVHD). The U.S. Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research recently issued a draft of proposed guidelines for public comment. The 62-page set of guidelines, titled Guidance to Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans, appeared in the Feb. 7, 2001, Federal Register.
The FDA draft guidelines suggest the benefits and risks of xenotransplantation should be evaluated for the recipient and the welfare of public health. Here’s what the guidelines say about potential risks: "Infectious disease is among the potential risks both to the recipient and to the public posed by the use of xenotransplantation products. Trans-mission of microbial agents from xenotransplantation products could lead to systemic disease (for example, infection or neoplasia) or failure of the xenotransplantation product in the recipient. Immunological risks include rejection of the live xenogeneic cells, tissues or organs, and in some cases, GVHD. In addition, transmission of infectious agents could result in outbreaks of zoonotic disease, silent transmission of latent viruses, or emergence of new strains of pathogens. Experience has shown that widespread horizontal or vertical transmission of new pathogens is possible before the pathogens are recognized (such as HIV)."
The Chicago-based American Medical Association’s Council on Ethical and Judicial Affairs recently issued a report on xenotransplantation: The Ethical Implications of Xenotransplantation. (See "Excerpt from The Ethical Implications of Xenotransplantation," in this issue.)
Xenotransplantation may sound years away from being a reality, but the New England Medical Center in Boston is taking a more contemporary but unusual approach to organ transplantation. Called Hope Through Sharing, the program was approved in February after nine months of review by the Richmond, VA-based United Network for Organ Sharing (UNOS). The program, which some physicians say is unethical, allows a patient to move up on the waiting list if a family member donates one of their kidneys to a stranger. Currently, the program only involves kidneys.
The program does not violate any ethical issues because the only benefit the donor receives for their kidney is another kidney for the loved one, says Richard Rohrer, MD, the chief of transplant surgery at New England Medical Center. "It is assigning a value to a kidney donation, and the value is exactly a kidney. On that basis, we feel very comfortable," he says.
Mark D. Fox, MD, a medical ethicist at the University of Rochester (NY) Medical Center, says everyone benefits from this program in the end. He likens the process to a "good-faith donation." Fox served on the UNOS panel that evaluated the program.
Kidneys are distributed by waiting time, unlike other organs that are distributed based on urgency. This program could cut down the amount of time for many patients, says Richard Luskin of the New England Organ Bank in Boston. "It’s really an addition to the total available pool of organs," adds Luskin.
The national waiting time averages five years, but in Massachusetts, it’s only three to four years, according to UNOS data.
In yet another advancement, researchers at the Lahey Clinic Medical Center in Burlington, MA, are determining what factors constitute a successful match for livers between donor and patient and whether the procedure is safe for donors. The main obstacle to live donor transplantation between adults is determining how much liver one can take from a donor and not harm them, and whether it is sufficient for the person who needs it, explains Elizabeth Pomfret, MD, PhD, director of live donor liver transplantation at Lahey.
Results of the research appear in the April issue of the Archives of Surgery.1 Ultimately, 15 of 66 volunteers completed the surgery. Donors regenerated 80% of their livers within a month following surgery and 90% a year later, notes Pomfret.
"This is a feasible operation, but needs to be done in centers where there is a strong commitment to doing this," adds Pomfret. Many volunteers were disqualified after their health was evaluated. The most common cause for disqualification was having a liver that was too small. Potential donors diagnosed with hepatitis C or other liver disorders also were disqualified.
1. Pomfret E, Pomposelli J, Lewis D, et al. Live donor adult liver transplantation using right lobe grafts. Arch Surg 2001; 136:425-433.
For more information on the FDA draft guidelines, contact:
• Stephen Ripley, Center for Biologics Evaluation and Research, HFM-17, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448. Telephone: (301) 827-6210. Web: www.fda.gov/cber/guidelines.htm.