Looking to cure a host of neurodegenerative diseases, StemCells, a Palo Alto, Calif.-based company, has transplanted human neural stem cells into the brains of thousands of mice. The mice are technically chimeras, or is a mix of two or more species. (The word "chimera" refers to the Greek mythological creature that has a lion's head, a goat's body, and a serpent's tail.) President and CEO Martin McGlynn says his biotech company is now waiting for the FDA's permission to test human neural stem cells – the ones already tested in mice – in human patients.
Such animals, especially mice, have been used to search for ways to cure human diseases including Parkinson and Alzheimer disease. "Having the ability to evaluate human cells in a mouse or other animal is critical to translating scientific discoveries into therapeutic medicine," says McGlynn. "It's the key. It's the bridge to the clinic."
However, the use of such chimeric animals is the focus of a complicated patent case that is raising legal and ethical questions. In this case, opponents to the patenting of living things applied for a chimera patent. The US Patent and Trademark Office (USPTO) recently refused to issue a patent for the human-animal chimera in the application, on the grounds that it would have been too nearly human.
In the volatile debate over bioengineered life forms, many disagree about the ramifications of the recent case. The critics of the biotechnology industry who applied for the patent say the case has serious business and research implications. But some leading scientists and industry observers say the case is just another effort to grab attention in a field rife with more heat than rational discussion.
THE PATENT AS A FORM OF PROTEST
Stuart Newman, a professor of cell biology and anatomy at New York Medical College in Valhalla, says he opposes the patenting of living things. Newman, working with Washington, DC, activist Jeremy Rifkin, filed a patent application in 1997 for a theoretical creature he never actually made. For "tactical reasons," Newman says he eventually split his patent application into two: one involving primates and the other focused on other animals.
Using what he calls the "embryo chimera technique," Newman sought to patent a creature combining human embryo cells with cells from the embryo of a monkey, ape, or other animal to create a blend of both. Other scientists have used similar methods to create a "geep" (part goat, part sheep) says Newman, adding that his chimera could be used for drug testing and as a source of organs to transplant into humans.
After seven years and several rejections and appeals, the USPTO turned down both of Newman's patent applications in August 2004, saying, among other things, that his creatures would be too close to human. Newman and Rifkin let the six-month appeals period lapse and declared victory in February 2005. Both Rifkin and Newman say they expect the ruling to prevent scientists and biotechs from obtaining similar patents for 20 years, the time a patent is usually viable. Rifkin says crossing species boundaries is a form of animal abuse and a violation of nature and human dignity.
"The ruling has significant implications for the future of the biotech industry," says Rifkin, president of the nonprofit Foundation on Economic Trends, and one of the most vocal critics of biotechnology products such as genetically engineered organisms. "The implications for commercial interests are far-reaching. It means anyone applying for a patent for human-animal chimeras ought to be turned down."
Newman says he expects the ruling to affect stem cell researchers, too. "There are people who are producing or who express their intention to produce mixtures of humans and mice for research purposes in order to test the potential of human stem cells. This decision does not block their ability to do that in their labs," says Newman, "but if they wanted to patent and market these mixed human and animal organisms, it would be more difficult for them to commercialize it." However, some leading stem cell researchers say the case is unlikely to stop work on chimeric animals.
CAN YOU PATENT A MOUSE WITH A HUMAN BRAIN?
Twenty-five years ago, US scientist Ananda Chakrabarty, who worked for General Electric at the time, obtained the first patent on a living organism, a genetically engineered bacterium that consumes oil spills. The patent office originally denied the application, believing it could not patent living organisms, according to Brigid Quinn, USPTO spokesperson. The case landed in the US Supreme Court, which in 1980 ruled that patents could be awarded on anything that was human-made.
Since then, some 436 transgenic or bioengineered animals have been patented, including 362 mice, 26 rats, 19 rabbits, 17 sheep, 24 pigs, two chickens, 20 cows, three dogs, and many more. Many say the 1980 ruling led to the birth of biotechnology in the United States.
However, Quinn notes that US law clearly prohibits the patenting of people. "One reason we denied the case was the examiner believed one or more of the claims encompassed human beings." Asked whether the case will affect future patent applications for chimeric lab animals, Quinn says examiners always decide first if it is patentable subject matter. "Humans aren't. Anything found in nature is not patentable subject matter," says Quinn. "It has to be new, useful, nonobvious, and fully disclosed in writing."
Quinn wouldn't comment on whether the case will affect future chimera patent applications. "Each patent application is reviewed on its own merits."
Irving L. Weissman, a professor of cancer biology, pathology, and developmental biology at Stanford University has created mice with brains that contain about 1% human tissue. Weissman says recent news reports that he plans to create a mouse with a 100% human brain are "inaccurate." A pioneer in the field of stem cell research, Weissman is credited as being the first scientist to identify and isolate hematopoietic stem cells from mice and humans. He says that the news reports were fueled by an academic inquiry he made to find out, in theory, what his university ethics panel thought of the idea. He says he has no current plans to create such a mouse.
The Newman/Rifkin patent is "a new attempt to block science," while the "use of human-mouse chimeras is old," Weissman says. In 1988, J. Michael McCune patented the SCID-hu mouse, "a severe combined immunodeficient mouse with human organs, bones, lymphoid tissue, thymus, and liver," says Weissman, who is also director of Stanford's Institute of Cancer/Stem Cell Biology and Medicine and a cofounder of Stem-Cells and other companies.
"The precedent is there, the discoveries are long published, and people's lives have been affected by those discoveries. Would they take back all those discoveries and be happy if the therapies discovered through them were taken away?" Weissman dismisses the Newman/Rifkin case as "typical Rifkin," adding that "one example doesn't hold. It doesn't invalidate the others, so it's a hollow victory. The case is not the precedent they think."
CHIMERAS AND STEM CELLS
Austin Smith, director of the Institute for Stem Cell Research at the University of Edinburgh, agrees. The case is "irrelevant to mainstream stem cell research and the companies interested in this area. They're not interested in creating monsters. It's absurd. The idea of using them to create body parts is just ludicrous."
Smith notes that the point of much of stem cell research is to develop cells that can be transplanted into patients to cure disease. "You can only test the medication by injecting it into animal models – an already made animal, not an early embryo – which means part of the animal will be chimeric," he says. "Of necessity, it will have some human cells in it."
While there is a legitimate ethical discussion concerning the mixing of very early cells from a human embryo and an animal embryo, such as a chimpanzee, it's not an application anyone is pursuing, says Smith. "Nobody's ever proposed doing that. It's like some dark fantasy. No scientist would ever think of doing that because there's no reason to do that," he says.
"I can't see any business use of primary embryo chimeras," says Smith. "For late chimeras, yes, it's an important testing system to research and test therapies for degenerative diseases like Parkinson's or juvenile diabetes, so a company might want to use it, absolutely. To get it into the clinic, you need commercial involvement."
Robert Lanza, medical director at Advanced Cell Technology, Worcester, Mass. says the patent case is most likely "a publicity stunt." Certain changes are acceptable, such as introducing a specific human gene into pigs to prevent transplant patients from rejecting pig organs, he says. However, he adds that it's "inhumane to create any chimeric animal that causes it distress or solely for entertainment purposes, such as glow-in-the-dark fish." In 2002, a Taiwanese company inserted DNA from jellyfish into zebrafish, creating glow-in-the-dark fish.
To address ethical issues, Canada passed the Assisted Human Reproduction Act last year, which bars the transfer of a nonhuman cell into a human embryo or of human cells into a nonhuman embryo. In the United States, the National Academy of Sciences is expected in the spring to issue voluntary guidelines for researchers who work with human embryonic stem cells.
Lila Feisee, director for intellectual property for the Biotechnology Industry Organization, a trade group, says companies are aiming to provide life-saving treatments, not patent people. "No one from our industry that I'm aware of has applied for a patent on a human being."
McGlynn says chimeric animals, and patents, are crucial to a biotech's ability to develop cures for human diseases. To protect its investment, for example, StemCells has more than 43 US patents on its stem cell technology, though none are on bioengineered mice. "If the private sector cannot receive a patent on all its work and invention," he says, "it's unlikely to engage in the work because it takes so much time and effort and money."
"The ability to retain a return on your investment is crucial," says McGlynn, adding: "Mice are the backbone of biotechs, pharmaceuticals, and drug development."