Gene editing brings pig organ transplant closer

Friday August 11 2017

The process of animal-to-human donation is known as xenotransplantation

Many pig organs are similar to human organs

“Gene editing to remove viruses brings transplant organs from
pigs a step closer,” The Guardian reports after researchers
used the new CRIPSR gene editing technique. CRIPSR acts like a
set of molecular scissors that can cut out potentially harmful
infectious genes.

Despite the difference in size and shape, many of the pig’s
internal organs are remarkably similar to human organs, making
them a candidate for organ donations. The drawback is that some
pigs carry what are known as porcine endogenous retroviruses
(PERVs).

Retroviruses are a group of viruses that can cause various
cancers and immunodeficiency illnesses, including HIV, which
affect people. This has been found to make any attempt to use
“unedited” pig cells for donation unsafe.

The researchers showed they could use CRIPSR to target the
areas of the pig DNA that carried the retroviral code. Using
this technique they were able to successfully remove all
retroviruses from the pig cells.

These gene-edited cells were used to create pig embryos, which
were implanted into surrogate sows. The resulting piglets were
free from PERVs.

This research is a promising step forward in the possible use
of pig organs to meet the massive shortage of human organ
donors. However, there are many more stages of research to go
and there are likely to be other practical, ethical and safety
issues to overcome before using pigs as organ donors.

Until further progress is made you can help by signing up to
the NHS Organ Donation register. You can sign up online, it takes just
a few minutes.

 

Where did the story come from?

The study was carried out by researchers from eGenesis Inc in
the US, Zhejiang University, China, and other institutions in
China, the US and Denmark. The study was mainly funded by
eGenesis Inc. and the US National Institute of Health, with
other funding grants awarded to individual researchers.

eGenesis Inc is a US biotech firm working on trying to make
animal-to-human organ transplant safe and effective. This
technique is known as xenotransplantation.

The study was published in the peer-reviewed
journal Science.

The UK media give balanced coverage of this research by making
it clear there were a number of hurdles to be cleared before
xenotransplantation could become a reality.

 

What kind of research was this?

This laboratory study aimed to see whether it was possible to
remove porcine (pig) retroviruses, which can infect human
cells, from genetically modified pigs.

Retroviruses are a group of viruses that carry their genetic
material in ribonucleic acid (RNA) and are named because of the
enzyme reverse transcriptase that transforms RNA into DNA. The
retrovirus group can cause various cancers, neurodegenerative
disorders and HIV.

Pigs show potential as organ donors for humans as their organs
are similar in size and function and they can be bred in large
numbers. Porcine retroviruses (PERVs) are currently one of the
big safety barriers preventing us using pigs as organ donors.

 

What did the research involve?

The researchers first demonstrated that porcine retroviruses
are transferred to human cells. They transferred pig epithelial
cells (which line organs and other surfaces in the body) to
human embryonic kidney cells. When the human embryonic cells
(cells derived from embryos developed from eggs fertilised in
the lab) were monitored for four months, the number of porcine
retroviruses increased over time. They showed that these
viruses had integrated into the human DNA and could be
transmitted to other human cells.

The researchers then showed they were able to inactivate all 62
copies of porcine retroviruses from the pig epithelial cells,
which safely eliminated virus transmission to the human
embryonic cells.

The focus of the current study was to demonstrate that they
could achieve the same results and inactivate porcine
retroviruses from pig foetal fibroblast (connective tissue)
cells.

Firstly they mapped the 25 viruses present in the genetic code
of these cells. They then used the technique of “CRISPR Guide
RNA” which guides enzymes to cut the DNA at specific locations,
effectively editing out the genes carrying the virus.

 

What were the basic results?

With some modifications to the CRISPR Guide RNA technique, the
researchers were eventually able to completely edit out of all
retroviruses from the pig fibroblast cells. They also confirmed
that the technique did not lead to unwanted alterations
elsewhere in the DNA.

They then used these gene-edited fibroblasts to create pig
embryos (using a technique called somatic cell nuclear
transfer, SCNT). After confirming the resulting embryos were
completely free from retroviruses, they were then transferred
to surrogate sows.

From about 200-330 embryos per sow transferred across to 17
sows, they produced 37 piglets, of which 15 remained alive up
to four months. The piglets from successful pregnancies were
confirmed to have no retroviruses in their DNA. They also
confirmed there weren’t any abnormal structural changes to
these piglets.

The researchers are continuing to monitor the longer term
effects in these animals.

 

How did the researchers interpret the results?

The researchers conclude that they have shown porcine
retroviruses can be passed from pig to human cells in the
laboratory, highlighting “the risk of cross-species viral
transmission in the context of xenotransplantation.”

To work towards eliminating this risk, they used a technique
called CRISPR Guide RNA to produce pig embryos, foetuses and
live pigs free from the retroviruses.

 

Conclusion

This promising research shows that it can be possible to use
gene editing techniques to eliminate retroviruses from pigs,
removing one of the potential barriers to using genetically
modified pigs as organ donors for humans.

There are a few points to note. As the researchers say, though
they have shown that pig retroviruses can be passed onto human
cells in the laboratory, we don’t know what the effects would
be in real life. We don’t know whether pig retroviruses would
be transferred to humans and whether they could cause cancers
or immunodeficiency illnesses, for example.

The research is at an early stage. The study has shown that
they can produce retrovirus-free piglets but moving onto pig
organ donation is another step. While some pig tissues have
been in medical use for decades, such as pig heart valves and
insulin, there are likely to be various practical, ethical and
safety steps to overcome when it comes to transplanting whole
large animal organs into humans.

A number of experts responded to the news – highlighting
both the positives and negatives.

Prof Darren Griffin, Professor of Genetics, University of Kent,
says: “This represents a significant step forward towards the
possibility of making xenotransplantation a reality,” while
Prof Ian McConnell, Emeritus Professor of Veterinary Science,
University of Cambridge, cautions: “[Organ transplant] is a
huge unmet need of modern medicine. But the use of animal
organs such as pig kidneys and hearts is not without serious
ethical and biosecurity concerns.”

When it comes to organ donation, demand far outstrips supply in
the UK. You can help with this problem by signing up to
the NHS Organ Donation register.

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