Growing Human Organs Inside Pigs Could Save Lives, But the U.S. Won't Fund the Research
Pigs in a barn.
The shortage of organs is a public health menace. Approximately 120,000 people in the U.S. need a lifesaving organ transplant. Of those, approximately 75,000 patients are on the active waiting list. Every day, nearly 20 individuals die from the shortage of organs in the United States.
Ethical concerns about human-animal chimera research might be dramatically overblown.
Scientists worldwide are developing new methods with potential to save countless patients in need of organs. Such approaches have tremendous potential, if only ethical and regulatory challenges could be overcome first.
One way that scientists are proposing to increase the number of transplantable organs is to produce organs from patient stem cells. Owed to their ability to grow limitlessly in the lab and form all tissue types, pluripotent stem cells from patients, in principle, could supply an infinite amount of cells that could potentially be transplanted back into patients. Unfortunately, all efforts to generate organs that can be transplanted into patients from stem cells to date have been unsuccessful.
A different encouraging approach is to generate patient organs inside livestock species, such as pigs. In the latest methods, interspecies chimeras – animals containing cells from both humans and animals – are generated by introducing human stem cells into early-stage animal embryos. Key genes essential for organ formation are disabled, allowing the introduced human stem cells to fill the empty space. In theory, this strategy will produce a human organ inside pigs or sheep.
Creating chimeras is not new in biology. Chimeras, or animals comprised of tissues from two different individuals, have already been deployed in research. Mouse chimeras are routinely used to create genetically engineered mice to study genes. The concept of generating human organs inside pigs or sheep comes from previous studies involving interspecies chimeras generated between mice and rats. Past experiments have demonstrated that it is possible to generate a rat pancreas inside a mouse.
Scientific and Ethical Obstacles
Unfortunately, chimera research has faced hurdles that have impeded progress. Of note, attempts to generate interspecies chimeras by several groups have failed. The results of these studies indicate that human cells appear unable to grow inside mouse embryos. The levels of human chimerism – the number of human cells inside the host animal embryo – appear too low to support any human organ generation.
Another obstacle is that chimera generation is ethically controversial. Some question the moral status of an animal that is comprised of human and animal cells. The most concerning question is whether human cells will contribute to the host animal's brain, potentially altering the cognition of the animal. These issues have prompted scientists to proceed very cautiously with chimera experiments. However, such concerns might be dramatically overblown. This is because the levels of human chimerism are too low to cause any significant change in animal brain function.
The ethical controversy has affected research policy in the United States. In the United States, the National Institutes of Health (NIH), the major funding body of biomedical research, blocked funding for chimera research while ethical questions were considered. Later, it was proposed that a new review process would be instated for chimera research. However, no change in policy has actually happened. The restrictive NIH policy is a major barrier to chimera research progress because laboratories around the United States cannot obtain funding for it. Lifting the restrictions on NIH funding for chimera research would dramatically accelerate chimera research.
Nonetheless, despite the past and current hurdles that chimera research has faced, new advances are changing the landscape of chimera research.
It is time to lift restrictions on chimera research so that its promise can be fully realized.
Progress on the Horizon
Scientists are developing improved strategies to increase the numbers of cells in animal embryos to the point where it might be possible to generate a human organ in an animal. For example, it has been suggested that the human stem cells researchers have been using cannot grow in animals. Scientists have made advances in generating new types of human stem cells that might have an improved ability to form chimeras.
Additionally, scientists have identified some barriers responsible for the failure to generate chimeras. For example, preventing cell death and enhancing the ability of stem cells to compete with host animal tissues also improves the numbers of human cells to the point where human organs can be generated inside an animal.
Finally, a relaxation of regulatory hurdles in other countries has created a more permissive environment for human-animal interspecies chimera research. In March, the Japanese government approved the first such experiments that could comprise a new way of generating organs from patients for transplantation.
Additionally, in spite of the somewhat negative attention that chimera generation has received, the International Society for Stem Cell Research (ISSCR) supports the new Japanese policies allowing chimera experiments. The ISSCR maintains that research involving the generation of chimeras should be permitted, as long as rigorous oversight and ethics review occur.
Chimera research has the potential to transform medicine. Of all the impediments, the NIH restrictions on funding remain the single most significant barrier. It is time to lift restrictions on chimera research so that its promise can be fully realized. One day, it might be possible to grow patient-specific organs inside of livestock animals such as pigs and sheep, saving thousands of human lives. But to change our current policy, the public, scientists, and bioethicists must first agree that this critical cause is worth fighting for.
Gene Transfer Leads to Longer Life and Healthspan
In August, a study provided the first proof-of-principle that genetic material transferred from one species to another can increase both longevity and healthspan in the recipient animal.
The naked mole rat won’t win any beauty contests, but it could possibly win in the talent category. Its superpower: fighting the aging process to live several times longer than other animals its size, in a state of youthful vigor.
It’s believed that naked mole rats experience all the normal processes of wear and tear over their lifespan, but that they’re exceptionally good at repairing the damage from oxygen free radicals and the DNA errors that accumulate over time. Even though they possess genes that make them vulnerable to cancer, they rarely develop the disease, or any other age-related disease, for that matter. Naked mole rats are known to live for over 40 years without any signs of aging, whereas mice live on average about two years and are highly prone to cancer.
Now, these remarkable animals may be able to share their superpower with other species. In August, a study provided what may be the first proof-of-principle that genetic material transferred from one species can increase both longevity and healthspan in a recipient animal.
There are several theories to explain the naked mole rat’s longevity, but the one explored in the study, published in Nature, is based on the abundance of large-molecule high-molecular mass hyaluronic acid (HMM-HA).
A small molecule version of hyaluronic acid is commonly added to skin moisturizers and cosmetics that are marketed as ways to keep skin youthful, but this version, just applied to the skin, won’t have a dramatic anti-aging effect. The naked mole rat has an abundance of the much-larger molecule, HMM-HA, in the chemical-rich solution between cells throughout its body. But does the HMM-HA actually govern the extraordinary longevity and healthspan of the naked mole rat?
To answer this question, Dr. Vera Gorbunova, a professor of biology and oncology at the University of Rochester, and her team created a mouse model containing the naked mole rat gene hyaluronic acid synthase 2, or nmrHas2. It turned out that the mice receiving this gene during their early developmental stage also expressed HMM-HA.
The researchers found that the effects of the HMM-HA molecule in the mice were marked and diverse, exceeding the expectations of the study’s co-authors. High-molecular mass hyaluronic acid was more abundant in kidneys, muscles and other organs of the Has2 mice compared to control mice.
In addition, the altered mice had a much lower incidence of cancer. Seventy percent of the control mice eventually developed cancer, compared to only 57 percent of the altered mice, even after several techniques were used to induce the disease. The biggest difference occurred in the oldest mice, where the cancer incidence for the Has2 mice and the controls was 47 percent and 83 percent, respectively.
With regard to longevity, Has2 males increased their lifespan by more than 16 percent and the females added 9 percent. “Somehow the effect is much more pronounced in male mice, and we don’t have a perfect answer as to why,” says Dr. Gorbunova. Another improvement was in the healthspan of the altered mice: the number of years they spent in a state of relative youth. There’s a frailty index for mice, which includes body weight, mobility, grip strength, vision and hearing, in addition to overall conditions such as the health of the coat and body temperature. The Has2 mice scored lower in frailty than the controls by all measures. They also performed better in tests of locomotion and coordination, and in bone density.
Gorbunova’s results show that a gene artificially transferred from one species can have a beneficial effect on another species for longevity, something that had never been demonstrated before. This finding is “quite spectacular,” said Steven Austad, a biologist at the University of Alabama at Birmingham, who was not involved in the study.
Just as in lifespan, the effects in various organs and systems varied between the sexes, a common occurrence in longevity research, according to Austad, who authored the book Methuselah’s Zoo and specializes in the biological differences between species. “We have ten drugs that we can give to mice to make them live longer,” he says, “and all of them work better in one sex than in the other.” This suggests that more attention needs to be paid to the different effects of anti-aging strategies between the sexes, as well as gender differences in healthspan.
According to the study authors, the HMM-HA molecule delivered these benefits by reducing inflammation and senescence (cell dysfunction and death). The molecule also caused a variety of other benefits, including an upregulation of genes involved in the function of mitochondria, the powerhouses of the cells. These mechanisms are implicated in the aging process, and in human disease. In humans, virtually all noncommunicable diseases entail an acceleration of the aging process.
So, would the gene that creates HMM-HA have similar benefits for longevity in humans? “We think about these questions a lot,” Gorbunova says. “It’s been done by injections in certain patients, but it has a local effect in the treatment of organs affected by disease,” which could offer some benefits, she added.
“Mice are very short-lived and cancer-prone, and the effects are small,” says Steven Austad, a biologist at the University of Alabama at Birmingham. “But they did live longer and stay healthy longer, which is remarkable.”
As for a gene therapy to introduce the nmrHas2 gene into humans to obtain a global result, she’s skeptical because of the complexity involved. Gorbunova notes that there are potential dangers in introducing an animal gene into humans, such as immune responses or allergic reactions.
Austad is equally cautious about a gene therapy. “What this study says is that you can take something a species does well and transfer at least some of that into a new species. It opens up the way, but you may need to transfer six or eight or ten genes into a human” to get the large effect desired. Humans are much more complex and contain many more genes than mice, and all systems in a biological organism are intricately connected. One naked mole rat gene may not make a big difference when it interacts with human genes, metabolism and physiology.
Still, Austad thinks the possibilities are tantalizing. “Mice are very short-lived and cancer-prone, and the effects are small,” he says. “But they did live longer and stay healthy longer, which is remarkable.”
As for further research, says Austad, “The first place to look is the skin” to see if the nmrHas2 gene and the HMM-HA it produces can reduce the chance of cancer. Austad added that it would be straightforward to use the gene to try to prevent cancer in skin cells in a dish to see if it prevents cancer. It would not be hard to do. “We don’t know of any downsides to hyaluronic acid in skin, because it’s already used in skin products, and you could look at this fairly quickly.”
“Aging mechanisms evolved over a long time,” says Gorbunova, “so in aging there are multiple mechanisms working together that affect each other.” All of these processes could play a part and almost certainly differ from one species to the next.
“HMM-HA molecules are large, but we’re now looking for a small-molecule drug that would slow it’s breakdown,” she says. “And we’re looking for inhibitors, now being tested in mice, that would hinder the breakdown of hyaluronic acid.” Gorbunova has found a natural, plant-based product that acts as an inhibitor and could potentially be taken as a supplement. Ultimately, though, she thinks that drug development will be the safest and most effective approach to delivering HMM-HA for anti-aging.
A new study provides key insights in what causes Alzheimer's: a breakdown in the brain’s system for clearing waste.
In recent years, researchers of Alzheimer’s have made progress in figuring out the complex factors that lead to the disease. Yet, the root cause, or causes, of Alzheimer’s are still pretty much a mystery.
In fact, many people get Alzheimer’s even though they lack the gene variant we know can play a role in the disease. This is a critical knowledge gap for research to address because the vast majority of Alzheimer’s patients don’t have this variant.
A new study provides key insights into what’s causing the disease. The research, published in Nature Communications, points to a breakdown over time in the brain’s system for clearing waste, an issue that seems to happen in some people as they get older.
Michael Glickman, a biologist at Technion – Israel Institute of Technology, helped lead this research. I asked him to tell me about his approach to studying how this breakdown occurs in the brain, and how he tested a treatment that has potential to fix the problem at its earliest stages.
Dr. Michael Glickman is internationally renowned for his research on the ubiquitin-proteasome system (UPS), the brain's system for clearing the waste that is involved in diseases such as Huntington's, Alzheimer's, and Parkinson's. He is the head of the Lab for Protein Characterization in the Faculty of Biology at the Technion – Israel Institute of Technology. In the lab, Michael and his team focus on protein recycling and the ubiquitin-proteasome system, which protects against serious diseases like Alzheimer’s, Parkinson’s, cystic fibrosis, and diabetes. After earning his PhD at the University of California at Berkeley in 1994, Michael joined the Technion as a Senior Lecturer in 1998 and has served as a full professor since 2009.
Dr. Michael Glickman