After Frankenswine ... the brave new world of human-animal hybrids

How it all started: the rise of the hybrids

BACK in 1984, Time magazine announced, It’s A Geep!, as Cambridge University scientists revealed they had produced the world’s first sheep-goat chimera. A brave new world of hybrid animals had arrived, and soon the new chimeras were being created thick and fast: with, amongst other creations, the arrival of a 'human-mouse' called SCID-hu - with a human thymus, liver, and lymph nodes, and mouse everything else - the insertion of human DNA into a rabbit embryo in 2003, and, in 2007, at the University of Nevada, a sheep whose blood contained 15% human cells and 85% sheep cells. Questions soon started to be raised around the new technology, which fast seemed to be becoming a moral minefield. What, some critics started saying, if the animals became that bit too human?

It’s against this backdrop that the news arrives that the science to save the countless people who die because they are waiting for transplants could reside in pig-human chimeras. These, of course, will not be strange semi-mythological creatures with the tail and snout of a pig, with the bi-pedal body of a human. Rather, they will look just like plain ordinary pigs.

The science around pig-human transplants has long been controversial, even without the introduction of chimeric research. For several decades now, scientists have been trying to produce organs in pigs to transfer into humans, but, until recently, most resources and energy have been channelled into research around genetic modification of what are still essentially pig organs so that they are not rejected by the human body. But with announcements from both Japan and California of progress in the development of chimeric pigs which will grow fully human organs inside them, a whole new strand of promise has opened up, as well as a stream of questions. What if human genetic material gets into the brain and they become more human? What if the transplant process creates zoonotic diseases, the transfer of pig viruses into humans? How would people feel about having something from a pig put in them? Will we start thinking twice about eating a bacon roll?

Yet, we already, as Dr David Shaw, a bioethicist who has worked on a paper on xenotransplantation, puts it, have transplant tissue from pigs – many people have had pig valves transplanted into their hears. “Arnold Schwarzenegger,” Shaw notes, “is walking round with bits of pig in him.” Pigs, since their physiology closely maps humans, have often been the animals science turns to for harvesting such organs and tissues.

Shaw interviewed scientists in the field of xentransplantation several years ago, and recalls that at that point genetic modification of organs seemed to offer the most hope. “But now,” he says, “people seem to think the chimeric route seems more promising.” The science seems to be progressing more, and researchers say there is slightly less concern around the risk of zoonosis.

Bruce Whitelaw, professor of animal biotechnology at the University of Edinburgh’s Roslin Institute - of Dolly the Sheep fame (Dolly was the first cloned animal) - has indicated that British scientists are interested in carrying out their own experiments. “It is scientifically fascinating and of potential commercial interest, and offers much for healthy, productive social debate."

In fact for Roslin, the creation of chimeric animals of various sorts, is business as usual. As Whitelaw put it: “We have been generating chimeric mice for many years. This is a standard methodology. We are now exploring the formation of chimeric animals by introducing cells – usually stem cells – to the developing embryo. We are working with experimental animals including mice, rats, chickens and sheep. This is achieved by introducing stem cells into the pre-implantation embryo which is an established methodology in mice and extensively used worldwide to produce transgenic mice. We are exploring this methodology in livestock.”

Chimeras: the future?

ARE chimera’s the future for organ transplantation? In the mid-term, probably. But many believe they are only a stop-gap solution, until the real breakthrough happens and it is possible to grow organs independently, outside any animal, within the lab. “I do think such lab-based technology will happen in a few decades,” says Scottish bioethicist Dr David Shaw. “But I don’t think that in the meantime we should let people die."

In the mean time, if the science does deliver and prove to be safe, how will it be rolled out? Shaw suggests there are two ways of doing this. “You could either just have factories producing different types of organs or the more expensive option would be just to take specific stem cells from someone and grow them a tailored organ just for them. Of course if you do that the organ is very unlikely to be rejected.”

There is, however, no doubt that chimeric science, in the absence of regulation, is likely to deliver more and more breakthroughs and news stories in the years to come. One of the reasons for this is that it features strongly in human stem cell research – and scientists are interested in unlocking the potential of stem cells to regenerate damaged tissue and cure heart disease, diabetes and many other ailments. The investigation of the behaviour of these cells, however, has to be done on animals – and this involves the creation of chimeras.

Frog skins and monkey mojo: a history of animal transplants

DOCTORS have been using the organs and tissues of animals to treat humans for centuries now. Back in 17th Century France, Jean Baptiste Denis, began the clinical practice of transfusing animal blood, from various species, into humans and, in the 19th century skin grafts, particularly from frogs became a popular treatment. Perhaps most bizarre, from our current perspective, was the work of Serge Vornoff, who in the 1920s, began developing procedures involving the transplantation of chimpanzee testes into older men who had lost their “zest for life”. Vornoff had, previous to this, carried out over five hundred transplantations on sheep, goats and a bull, grafting testicles from younger animals to older ones, and observed that this caused the older animals to regain the vigour of younger animals.

The 1960s brought attempts to transplant organs from chimpanzees. Famously, in America in 1983, Dr Leonard Bailey, transplanted a baboon heart into an infant girl, known as Baby Fae. The surgery caused a media sensation, though many experts objected to it as unethical, and some claimed that there were other options available – for instance an infant human heart. The graft was rejected and Baby Fae died three weeks later. Bailey would perform the first successful infant heart transplant (with a human heart) the following year, in 1985

A question of ethics

IN the UK, every day, three people die while waiting for a transplant and across the world there is an organ shortage. As Edinburgh University bioethicist, Dr Sarah Chan puts it: “Organ transplantation and the need for donor organs is a growing health crisis. I think you only have to meet a few people who are waiting for transplants, and potentially going to die if they don’t get organs, to know that this is an important health problem.”

Nevertheless there remains a great deal of opposition to chimera science. It has long had its critics: those, for instance, like Jeremy Rifkin, who was so determined to prevent its progress that he submitted a US patent application for the “humanzee” and the “humouse” in the hope that this would keep others from attempting to create and patent such creations.

Last year, in the United States, the brakes were really thrown on this science. The National Institutes of Health (NIH) announced a moratorium on funding of studies involving “human-animal chimeras” until it had reviewed the scientific and social implications more closely. So we might have to wait a little longer for these theoretical Frankenswines to harvest organs from.

Meanwhile, in the UK, chimeric research has been banned till recently. However, guidelines published in January suggested that three-year licences for hybrid experiments could be given – as long as it could be proved there was no other viable method. This is a sign that the UK Government appears keen to keep the country at the forefront of such developments. Britain last week became the first country to license the genetic editing of human embryos.

Among the concerns that the NIH had was the chance that animals’ “cognitive state” could be altered if they ended up with human brain cells. Others say the chances of this happening are low. “I don’t think there’s any evidence there would be leakage of that type,” says Scottish bioethicist Dr David Shaw. “If we’re only interested in organ development you can knock out the developmental niche for brain development and stop that happening. Also the scientists have said that even if there was some human, neural DNA in there, it would still be in a pig brain. They wouldn’t be performing human neural functions.”

But nevertheless, some ethicists and scientists, do believe it is an issue worth addressing. Bioethicist Dr Sarah Chan, for instance, says that she is willing “to accept that it’s quite unlikely” but that she also thinks "we need to be aware of the possibility and say what does that tell us ethically about what we’re doing here, about how we are treating these animals.” Our discomfort with the idea, she believes, is partly down to the fact that a pig is a "sentient creature".

Meanwhile, critics also express the worry that transplanting an organ from a pig to a human increases the risk of zoonosis. “Humanising animals,” says John Robins of Animal Concern Advice Line, “to make their organs less likely to be rejected by humans increases the risk of existing or new diseases (for which humans have no immunity or medication) crossing from animal to human. Researchers often argued that someone dying of say kidney failure would take that small risk rather than face certain death. However my fear is not than an organ recipient could become infected but that any lab worker could pick up a disease just by being close to the animals.”