Behind the Scenes / Animal-to-human transplants get closer

Courtesy of Meiji University

A pathogen-free pig that has been developed for pig-to-human organ transplants

By Takashi Ito and Akira Fuyuki / Yomiuri Shimbun Staff WritersA study on growing transplantable human organs in pigs and other animals will likely start as early as this autumn. The project will mark the end of a ban on such research following the publication of a national report on the issue. While the study is expected to lead to a new source of human organs, which have been in short supply, some issues remain, such as technical obstacles and ethical concerns.

5-year discussion

“Many problems [in medical transplantation] would be solved if transplantable organs could be harvested in animals,” Stanford University Prof. Hiromitsu Nakauchi stated during a symposium held in Tokyo in March.

Nakauchi, who is also a distinguished professor at the University of Tokyo, has been researching how to grow human organs in pigs and sheep.

A pancreas, for example, could be created by injecting human iPS cells (induced pluripotent stem cells), which can morph into a variety of different cells, into the embryo of an animal genetically modified to develop without the organ.

Once the fertilized egg has been inserted into the uterus of an animal, the injected iPS cells transform into human pancreatic cells. If the process succeeds, the animal is born with a human pancreas.

In 2010, Nakauchi used this method to develop a rat pancreas in a mouse, which is a different species. He later succeeded in curing a diabetic mouse by growing a mouse pancreas in a rat, before transplanting a section of the organ into the mouse.

In Japan, guidelines prohibit transferring animal embryos with human cells (chimera embryos) into an animal’s uterus. However, in 2013, the government’s Council for Science and Technology Policy approved such transfers and births of animals after considering relevant research developments in the field.

The Education, Culture, Sports, Science and Technology Ministry spent five years discussing how to review the guidelines, and completed its report at the end of March. The report approved the organ development techniques — going so far as to approve the birth of affected animals on the condition that creatures blurring the boundaries between human and animal are not created.

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After the research ban is lifted, the development of animals with human organs could contribute to the study of various disease structures and the effects of medicine, and could help meet demand among patients for organs.

The development of organs using a patient’s own iPS cells could also prevent an immune rejection.

According to the Japan Organ Transplant Network, about 14,000 patients in the country are waiting for donors. Of these, only 300 to 400 are able to receive transplants every year. In the United States, an average of 20 people die each day while waiting for organ transplants.

Nakauchi, who is currently working on a study using sheep in the United States, is considering undertaking a study in Japan on the growth of human pancreases in pigs. “In five years, I would like to reach the point at which we grow human organs,” he said.

Strict monitoring required

However, technical challenges and other issues remain. Although pig and sheep organs resemble those of humans, there are considerable genetic differences. It is not known if the successful recreation of organs in rats and mice can be replicated in these animals and humans.

Research thus far shows that human iPS cells do not sufficiently increase in sheep and pig embryos for the creation of human organs. The ratio of human iPS cells in their embryos is around 0.01 percent — far short of the 1 percent or more required to grow human organs. As such, technical improvements must be made.

It is also possible that human iPS cells could transform into cells for reproductive organs or the cerebral nerve. The guidelines, which are set to be revised as early as this autumn, will likely prohibit the cross-breeding of animals born through this method. They are also expected to ban the fertilization of human reproductive cells harvested in animals.

Although it is extremely unlikely that animals with human-level brain functionality would be born, the guidelines will stipulate that any research be strictly monitored by the government and universities and research facilities involved, to prevent the development of creatures that obscure the boundaries between humans and animals.

Concerns have also been raised over the potential use of animals as tools on a wider scale. Tsutomu Sawai, 32, an assistant professor at Kyoto University who conducts ethical awareness surveys, said, “We need to enhance understanding in society by clearly explaining the purpose and methodology of the research.”

Pathogen-free pigs bred

In the meantime, Japan is moving toward beginning xenotransplantations, which involves transplanting animal organs or cells into humans, rather than harvesting human organs in animals. Pigs are thought to be suitable for the procedure, because their organ sizes and functions are similar to those of humans.

Research on transplanting pig pancreatic cells to diabetes patients began around 1990 in Sweden, China and other countries. Insulin, a hormone secreted from the pancreas, lowers blood glucose levels.

Xenotransplantation is said to trigger more severe organ rejection than human-to-human transplants. Moreover, pig cells contain retroviruses, a form of virus that is extremely difficult to eliminate. Humans infected with retroviruses through xenotransplantation could potentially develop unknown diseases.

However, there have been no reports of retroviral infections in humans among the 200 pig-to-human experimental transplants conducted overseas thus far.

While such transplants have yet to be approved for general treatment due to lingering safety concerns, countries such as Argentina and New Zealand have conducted pig-to-human transplants over the past 10 years. Researchers in those countries modified the procedure to prevent organ rejection, with therapeutic effects observed in diabetic patients who received the organs.

In 2016, the Health, Labor and Welfare Ministry revised its guidelines, which had effectively prohibited xenotransplantation. The ministry opened the door for xenotransplantations to be conducted under certain conditions, such as requiring patients to receive follow-up checks.

A team of researchers from Meiji University, Kyoto Prefectural University and other institutions announced in March that they had bred pathogen-free pigs suitable for pig-to-human transplants. They will begin supplying the pigs at the start of next year in collaboration with private companies.

Clinical research on the transplantation of pig cells to diabetic patients will begin in three to five years at facilities including the National Center for Global Health and Medicine (NCGM), located in Tokyo. “The research framework is under development and will be ready,” said 44-year-old project director Masayuki Shimoda.

Though progress has been slow on discussions over the pros and cons of xenotransplantation, expectations among patient groups are rising. The Saga-based Japan IDDM Network has donated ¥150 million to Meiji University, the NCGM and other facilities for research. The organization represents patients of type 1 diabetes, a disease that often develops in childhood, and their family members.

“For patients, xenotransplantation represents an important option for potential treatment,” said Tatsuo Inoue, the organization’s 66-year-old president.

(From The Yomiuri Shimbun, April 27, 2018)Speech

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