Earlier this month researchers announced the use of CRISPR-Cas9 genome editing technology to successfully eliminate a porcine retrovirus that served as a stumbling block in organ transplants between pigs and humans.
Currently there are more than 117,000 people on the waiting list for an organ transplant in the United States. It is estimated that another person is added every 10 seconds, and that more than 20 people die per day due to a shortage of transplantable organs. Using chimera organ transplants could help to solve this problem.
Because pigs have organs roughly the same size and with the same function as human organs, they are considered prime candidates for inter-species organ transplants. However, the presence of active Porcine Endogenous Retrovirus (PERV) has stymied research thus far. PERV is a polytropic virus released from pig cells and is the result of the incorporation of a viral genome into a pig’s own DNA. The incorporated viral DNA is then passed on to future generations of pigs through their own genetic material.
Humans have their own form of an endogenous retrovirus, called HERV (human endogenous retrovirus). Unlike PERV, HERV is primarily inactive in the body. Like PERV, HERV is the result of a viral genome being incorporated into the human genome, likely millions of years ago.
Top 10 Hospitals by # of All-Payor Kidney Transplants Performed in 2015
|Hospital||State||# Kidney Transplants|
|Jackson Memorial Hospital||FL||966|
|New York Presbyterian Hospital||NY||718|
|Medical University of South Carolina||SC||554|
|University of Wisconsin Hospital||WI||520|
|Emory University Hospital||GA||498|
|Tampa General Hospital||FL||488|
|Auxilio Mutuo Hospital||PR||485|
|Vanderbilt University Hospital||TN||484|
|St Barnabus Medical Center||NJ||473|
Fig 1 Data from Definitive Healthcare using ICD-9 codes 5561 and 5569. Most recent CMS data available.
PERV has been one of the major roadblocks in testing the transplant of pig organs into the human body. Now, using CRISPR-Cas9, researchers have been able to remove PERV from pig genomes entirely. A new generation of genetically engineered piglets shows no sign of having inherited the retrovirus.
Despite the elimination of PERV, the human immune response still poses a significant barrier to successful organ transplant between species. But this hasn’t stopped researchers from testing chimera transplants in other animals.
Scientists have successfully used pluripotent mouse cells to grow a pancreas in fetal rats. Once the chimera rats are born, they have a fully functional, rat-sized pancreas made entirely of mouse cells. Sections of the pancreas can then be transplanted into diabetic mice, curing their illness for about a year—or half their life.
Similarly, intermediate stem cells have been used in human-pig tests. Researchers inserted human intermediate stem cells into a pig embryo. When the pig was born, about 1 of every 100,000 cells was human rather than pig. The human cells composed about 10 percent of the pig’s heart cells, and about 1 percent of the pig’s liver and kidneys.
These kinds of tests are promising, as they prove that pig and human cells can coexist and function together to form organs and other body tissue. This chimera pig, however, was dubbed “highly inefficient” by researchers. But it is one step closer to solving the problem of organ shortages.
In addition to the physiological barriers to research, there are also ethical concerns. Many of the obstacles researchers face involve the inability to test organ harvesting and preservation methods on humans. In the case of brain-dead donors, doctors have only minutes to remove the still-functioning organs from a cadaver before they start deteriorating.
Top 10 Hospitals by # of All-Payor Heart Transplants Performed in 2015
|Hospital||State||# Heart Transplants|
|Cedars-Sinai Medical Center||CA||134|
|Newark Beth Israel Medical Center||NJ||109|
|Baylor University Medical Center at Dallas||TX||89|
|Hospital of University of Pennsylvania||PA||88|
|Montefiore Medical Center Main Campus - Henry and Lucy Moses Hospital||NY||86|
|Memorial Herman - Texas Medical Center||TX||74|
|Tampa General Hospital||FL||67|
|Nebraska Medicine - Nebraska Medical Center||NE||67|
|Ronald Reagan UCLA Medical Center||CA||61|
Fig 2 Data from Definitive Healthcare using ICD-9 code 3751. Most recent CMS data available.
In these situations, it could be beneficial to use certain drugs or procedures to preserve the organs for longer periods of time until they can be removed and stored properly. But the issue of informed consent proves complicated. The patient cannot give informed consent if they are brain-dead. Would the question move to the surviving family? To the patient receiving the organ(s)? One cadaver can often supply organs to recipients living hundreds or thousands of miles apart, and it would be nearly impossible to contact them in such a short window.
Because organ preservation tests would have to be performed on living humans, review boards must approve the procedures and methodology to ensure it is ethical and poses minimal risk to all involved.
In a 2015 trial at the University of California San Francisco (UCSF), researchers wanted to test the idea that cooling a cadaver to hypothermic temperatures would help maintain ideal organ function during removal and transportation. The UCSF research board determined that the organ donors involved in the trial were dead, and therefore did not qualify as human research subjects. Doctors then did not require informed consent to carry out their tests.
UCSF consequently suffered major backlash from the medical community, resulting in a request by Public Citizen for a federal investigation from the Office for Human Research Protections in April 2016.
One of the major barriers in organ transplant research is a disagreement between institutional review boards and surgeons on what qualifies “human subjects research.” In a hypothetical scenario published by New England Donor Services in 2016 involving dead organ donors, 82 percent of institutional review board members considered the trial to be human subjects research compared with 58 percent of transplant surgeons.
For now, researchers are strictly limited when it comes to researching organ transplant methods on humans. But the mouse-rat chimeras and PERV-inactivated pigs can serve as a springboard for new trials and innovations in the world of organ transplants.
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