FRONTLINE presents Organ Farm

the business of xenotransplantation--past and present

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In early 1996, an analyst at Salomon Brothers investment firm, detailed like never before the "unrecognised potential of xenotransplantation": a $6 billion market in transgenic organs by 2010. The report was read by big and small investors alike--biotech venture capitalists (who pumped money into xenotransplant research), as well as newspaper personal investment columnists who featured companies like Imutran, Nextran, Alexion, and BioTransplant as "hot picks." In these heady times, some companies were even suggesting that we might each have our own Astrids, "self pigs" custom-made from our own DNA, "immunological twins" available for any spare parts we might need in the course of our lives.

Some five years later, the big profits have not yet been realized. In late 2000, a number of the original players in the xeno business reorganized their efforts for the next phase of research and development: Most notably,Novartis, the Swiss pharmaceutical giant, merged Imutran with BioTransplant to form a new company, Immerge BioTherapeutics; the new company is allied with another Novartis-funded company, Infigen, for use of Infigen's patented cloning technology. While this move was said to reflect a new commitment to xenotransplanation by Novartis, another company's "refocusing" seemed to start with a vote of no confidence for pig-to-human transplants: In August of 2000, PPL Therapeutics, a Scottish company that set out to commercialize the "Dolly" cloning technology, lost "considerable funding" for its xenotransplantation program from Geron, a California-based company that had been PPL's largest xeno backer. PPL and Geron both denied that the move should be construed as any kind of judgement on the viability of pig-to-human transplants, but PPL has had difficulty finding a new partner for its xeno program.

Here's a look at the major players in the xeno business, past and present:

imutran

This small biotech start-up in Cambridge, England took the early lead in the race toward the organ farm: In December of 1992, at a farm in Cambridgeshire, they created "Astrid," the world's first transgenic pig, who carried human genes within her organs to help prevent rejection by the organ recipient's immune system (one of the thorniest problems facing xenotransplantation). A year and half later, Imutran announced it had produced several generations of Astrids who might be eligible for human trials by 1996. Started by a handful of scientists, the company received early funding from Sandoz pharmaceutical company whose profits were heavily derived from an immunosuppressive drug key to successful transplants. Sandoz eventually purchased Imutran outright. In 1996, Sandoz merged with Ciba-Geigy to form Novartis.

In January, 2001, Imutran completed the relocation of its xenotransplantation research to Charlestown, MA, combining with BioTransplant (another Novartis-funded company) to form Immerge BioTherapeutics. The company denies that the move was motivated by animal rights protests in the UK.

nextran

In the early 1990's, a small biotech company in Princeton, NJ--the DNX Corporation--emerged as one of Imutran's chief rivals. Using a farm in Albany, Ohio, Nextran successfully produced transgenic pigs whose hearts survived for impressive lengths of time in baboons; they were also far along in developing pig livers as filter "bridge" organs for people awaiting transplants. In late August, 1994, the Baxter Health Care Corp. of Deerfield IL partnered with DNX to form a new company--NEXTRAN--with Baxter owning 70% of the partnership. At the time of the formation of Nextran, Baxter's biggest revenue-generator had come from its dialysis equipment, so it took a special interest in DNX, which had been developing transgenic kidneys that might one day make dialysis less necessary. In 1995, Nextran became the first to win FDA approval for human clinical trials involving transgenic pig livers.

In FRONTLINE's report, a Nextran pig saved Robert Pennington's life. It was used outside his body as a temporary "bridge" to filter Pennington's blood while he waited for a human liver transplant. Nextran also is involved in trying to solve the problem of hyperacute rejection problems facing pig-to-human transplants.

ALEXION

Formed in 1992 by a group of Yale University scientists, Alexion was one of the early innovators in finding transgenic solutions to hyperacute rejection in transplant organs. Though initially focused on creating organs (their pigs were grown on farms in West Virginia and Massachusetts, Alexion has had some of its greatest success with implantation of pig nerve cells to repair spinal cord damage. In late 1998, Alexion made headlines worldwide for successfully repairing severed spinal cords in rats and monkeys using pig cells. Alexion's clinical trials continue.

PPL THERAPEUTICS<

Based in Edinburgh, PPL Therapeutics is licensed to commercialize the cloning technology pioneered by the Roslin Institute which surprised the world in 1997 with its creation of "Dolly," the first cloned mammal. In 1998, the company moved its xenotransplantation program to Blacksburg, West Virginia where scientists affiliated with Virginia Tech University were already involved in the research. In March of 2000, PPL's Blacksburg laboratory announced the creation of the world's first cloned pigs. (Later in the year, Wisconsin-based Infigen would be the first to clone transgenic pigs; these pigs were first shown nationally in FRONTLINE's report.)

In August of 2000, PPL Therapeutics' xenotransplantation program lost "considerable funding" from its major backer, Geron corporation of Northern California, who cited a change in "strategic priorities" and a desire to concentrate on stem cell work. PPL executives as well as the director of Edinburgh's Roslin Institute issued press releases denying that the Geron move was a vote of no confidence for xeno: "The institute has had a research programme on pig cloning, one application of which would be the use of pig organs for xenotransplantation. While xeno has raised a number of well-publicised issues, such as possible infection with pig viruses, these were not the basis for the decision to refocus the funding." ). PPL continued to look for partners through the Fall of 2000, but negotiations broke down, largely due to questions about the value of PPL's xeno program.

In early 2001, PPL's Blacksburg, VA lab announced that it had secured new funding--not for xeno, but for stem cell research. It's too soon to tell whether this is one company's story, or a cautionary tale for the industry.

BIOTRANSPLANT

Founded in 1990 and taken public with a stock offering in 1996, BioTransplant was one of the early pioneers of xenotransplantation. Like their rivals, BioTransplant focused on overcoming the hyperacute rejection problem, basing their approach on the bone marrow research of Dr. David Sachs. In August, 2000, the company, which is partnered with Massachusetts General Hospital, announced a breakthrough in breeding transgenic pigs that would not transmit pig viruses, or PERV's.

In January of 2001, BioTransplant spun-off its xenotransplantation program, partnering with Novartis (and the former Imutran) in a new company, Immerge BioTherapeutics, but keeping their offices in the Charlestown Naval Shipyard.

INFIGEN

Infigen was created in 1997 to commercialize the animal cloning techniques developed at American Breeder Service (ABS Global Inc.)--a DeForest Illinois company which is part of W.R. Grace. (ABS describes itself as "the world's leading provider of bovine reproductive services and technologies," a global marketer of dairy and beef cattle semen.) In January of 1999, Infigen and Imutran (Novartis) formed a working alliance that guaranteed Infigen's funding in exchange for use of the company's patented nuclear transfer cloning techniques.

In his FRONTLINE interview,Michael Bishop PhD Infigen's president, explains how genetically modified pigs can be created and cloned.



DIACRIN

Founded in 1990, Diacrin became a public company in early 1996, after the FDA gave the company approval for the first-ever clinical trials of transplanted pig cells into humans. Later in 1996, Diacrin entered a joint venture with Genzyme to develop two products using pig neural cells. .

On March 16, 2001 Genzyme and Diacrin reported that a preliminary analysis of outcomes of Phase II trials for Parkinson's patients found pig neuro cell transplants did not necessarily work better than a placebo treatment. The results are likely not the end of the research trial, but the news triggered a significant drop in stock prices. Jim Finn, a Parkinson's patient featured in FRONTLINE's report, was part of a Phase I trial. Other Diacrin/Genzyme Phase I patients featured in FRONTLINE's report--Maribeth Cook and Amanda Davis--were stroke patients.

IMMERGE BIOTHERAPEUTICS

Beginning operations in January of 2001, Immerge BioTherapeutics is a new company formed from the UK's Imutran and the xeno division of the Boston-based BioTransplant company. Unlike the companies from which it was formed, Immerge is focused squarely on development of cells, tissues, and organs for xenotransplantation, and not on drug therapies or other transgenics.

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