When Will Xenotransplantation of Pig Organs Be Possible?
We recently profiled eight companies creating exotic lab-based foods. Dubbed cellular agriculture, the technology to grow meat from animal cells has advanced swiftly in just a few years. One of the first commercial products just hit the menu at a Singaporean restaurant. At $23 for four chicken nuggets, it’s still more of a novelty than a nourishing meal for investors hungry for a return on their investments. But the technology is moving closer to scalability. Another once far-fetched and futuristic idea that involves manipulating animals in a lab is also inching closer to reality – harvesting organs from genetically modified pigs into human hosts. In this article, we want to learn when will xenotransplantation of pig organs be possible?
What is Xenotransplantation?
Xeno, what? It’s definitely a mouthful, but the concept of xenotransplantation is pretty straightforward. We’ll start with the textbook definition from the U.S. Food and Drug Administration (FDA), the federal agency that would need to approve these sorts of procedures when they become scientifically feasible:
Xenotransplantation is any procedure that involves the transplantation, implantation or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues or organs.
In other words, xenotransplantation involves removing animal parts and sticking them into human bodies for medical purposes. The concept isn’t exactly new. It was first mentioned in the mid-1600s concerning transfusing blood from lambs to humans (insert your own joke here about Peter Thiel, blood transfusions, and evil immortals). In 1905, someone apparently transplanted a rabbit kidney into a human, and Bugs Bunny has been making us all laugh with his antics ever since.
Pigs and Xenotransplantation
The most obvious choice for harvesting non-human organs would seem to be our primate relatives, and research through much of the 20th century focused on these animals. However, there were just too many challenges, from cross-species infections and organ disparities to ethical concerns raised by Tarzan and other leading conservationists of the day. There’s also the problem of being able to breed enough non-human primates to meet demand. More than 107,000 people in the United States alone are on the national transplant waitlist, with 17 on average dying every day before a viable organ becomes available.
Since the 1990s, researchers have focused on pigs as the most appropriate candidate for xenotransplantation. There are a few reasons, beginning with the fact that they are physiologically similar to us, and we’re not just talking about the people pigging out on the
trough buffets in Las Vegas. Another bonus is that we can prolifically breed pigs. And most of us have absolutely no qualms about slaughtering millions of them for a crispy bacon addition to our Bloody Marys. Some people are already part porker, as heart valves from pigs are already used to replace damaged or diseased versions in people.
Of course, xenotransplantation of pig organs still comes with challenges, mostly involving infection from and rejection of the transplant. But the latest gene-editing technologies such as CRISPR are helping solve those problems by tweaking the porcine genome to improve compatibility. While current research is still preclinical – meaning no one has tried it in humans yet – experts say we’re tantalizingly close. A team of Chinese researchers wrote a great recap of the current status of xenotransplantation (from which we gleaned and slightly embellished the history above) just last year. They concluded:
With recent achievements and the accumulation of experience with xenotransplantation in preclinical research, the first-in-human clinical trial may be possible in the near future. It is an inevitable trend that pigs modified with multiple genes are to be used as donor animals for xenotransplantation. New gene-editing technologies enable the production of multiple genetically engineered pigs in shorter periods of time and with greater efficiency.Some big brains in China
This means those suffering from organ failure may soon have alternatives to buying a $50,000 kidney on the black market in Pakistan.
The First FDA-Approved Genetically Altered Pig
In fact, the FDA just approved in December 2020 the first-of-its-kind “intentional genomic alteration” in a line of domestic pigs, known as GalSafe pigs, for both food and human therapeutics. You’ll notice the wording here – intentional genomic alteration. That refers to the fact that the pig’s genome has been edited without using genetic material from another species, one of the advantages of CRISPR gene-editing technology. In contrast, the first genetically modified salmon, which the FDA only recently approved after two decades, spliced genes from one species into another to create a faster-growing, more sustainable seafood. (Read our primer on the differences in genetic techniques here.)
The genetic tweak in this case eliminated an alpha-gal sugar on the surface of the pigs’ cells that causes allergic reactions in some people. That change to the genome opens up a wealth of medical possibilities, such as developing blood-thinning drugs. And, the FDA noted, “tissues and organs from GalSafe pigs could potentially address the issue of immune rejection in patients receiving xenotransplants, as alpha-gal sugar is believed to be a cause of rejection in patients.” However, the agency also noted that its approval does not extend to xenotransplantation until more paperwork has been submitted.
A Publicly Traded Xenotransplantation Company
The company behind the genetically altered GalSafe pigs is an outfit called Revivicor, a regenerative medicine company that survived the demise of its parent company, PPL Therapeutics, the British biotech that cloned Dolly the Sheep but eventually went out of business in 2003. Revivicor itself was acquired for $7.6 million a decade ago by United Therapeutics (UTHR), a company that we previously profiled on our first piece on xenotransplantation of pig organs.
United Therapeutics has an interesting story of its own, starting with the fact that it’s a $7 billion biotech that is profitable. However, all of its current revenue is not from relocating pig organs to humans but from five drug therapies for disease, mainly for treating forms of pulmonary arterial hypertension (marked by shortness of breath and dizziness) and neuroblastoma (a cancer that affects young children). In 2017, when we wrote about United Therapeutics, it had been enjoying higher returns than the Nasdaq over the previous five years. Since that piece (roughly X months ago), United Therapeutics returned +21% compared to a Nasdaq return of +118% over the same time frame.
No doubt part of the doldrums is because of falling sales in one of its flagship drugs, Adcirca, due to increasing competition from generic versions. Speaking of which, here’s what their revenue track record looks like for the past four years.
The company only increased revenue slightly from 2019 to 2020, snapping their losing streak and showing they’re fully capable of managing through The Rona. Profitability also came back, as the company went from a net loss of $104.5 million in 2019 to a net gain of $514.8 million last year. Note that the losses of 2019 were also something of an anomaly, with United Therapeutics handing over $800 million up front to Arena Pharmaceuticals (ARNA) to license the latter’s pulmonary arterial hypertension drug therapy.
Three Types of Organ Transplant Technologies
When not handing out Xprizes, futurist and billionaire Peter Diamandis writes about moonshot technologies like xenotransplantation. He is quite bullish on the regenerative medical potential of United Therapeutics, which was founded back in 1996 by Dr. Martine Rothblatt. Founder of Sirius Satellite Radio, Rothblatt started United Therapeutics after her daughter developed a rare lung disease. The company seems to be a step closer to its goal of beginning clinical trials on xenotransplantation of pig organs thanks to the success of Revivicor. Indeed, United Therapeutics has made a number of even bigger investments, including $100 million into Synthetic Genomics back in 2014-15. Synthetic Genomics was once considered to be one of the most exciting synthetic biology companies around, given that its founder, Craig Venter, figured out how to create a synthetic, self-replicating organism. Today, we’re having a hard time figuring out what they’re up to as their last press release is dated August 2018.
United Therapeutics has several types of organ xenotransplantation therapies in the works, including for the heart, kidney, and lungs. The latter is called the Unilobe, an engineered lung generated with a porcine lung scaffold and human lung cells, so something beyond the standard GalSafe pig lung. As the company explains, “Porcine lungs undergo a process of decellularization and washing prior to being recellularized with human allogeneic lung cells.” Sounds difficult.
However, United Therapeutics isn’t ready to go hog wild on xenotransplantation as the only way to replace failing human organs, especially the lungs. The company is also pursuing 3D bioprinting and even lung rejuvenation. The latter technique involves perking up human donor lungs that originally fail to measure up for transplant by perfusing and ventilating them at normal body temperature. That allows surgeons to reassess whether transplant is possible.
United Therapeutics and Synthetic Genomics
One of our premium subscribers asked us about a March 2017 piece we published on How to Indirectly Invest in Synthetic Genomics Stock. In that piece, we noted that United Therapeutics held $100 million worth of Synthetic Genomics stock. From the UTHR 10-K filed in February 2017:
As of December 31, 2016, we maintain in the aggregate, non-controlling equity investments of approximately $173.2 million in privately-held companies, including a $100.0 million investment in the preferred stock of Synthetic Genomics, Inc. (SGI), which we purchased in two separate $50.0 million transactions in May 2014 and September 2015.Credit: United Therapeutics 10-K filed February 2017
That’s the last we heard of that holding. A search of the SEC filings after that date, particularly, the 10-K filings, shows nothing relating to this position existing or not existing. As we noted before, Synthetic Genomics was working with United Therapeutics on xenotransplantation of lungs. In December 2020 we emailed Synthetic Genomics, and in January 2021, United Therapeutics, inquiring about the present relationship between these two companies. We’re still waiting for a response from both companies. Until then we can only speculate as to whether or not United Therapeutics still holds a position in Synthetic Genomics.
Two Xenotransplantation Startups with One Goal
United Therapeutics isn’t the only company that’s making progress on xenotransplantation of pig organs. In the same article from four years ago, we also briefly covered a Boston area startup called eGenesis that had raised $40 million. Today, the company has a war chest of $265 million, including a $125 million Series C just a few days ago. More than two dozen investors have come aboard, including premiere venture capital firms like Khosla Ventures, which also invested in the company’s Series A and Series B. Bayer through its venture arm is another key investor. One of the big drawing cards is co-founder George Church, who is a towering figure in the world of genetics and has become famous for his quest to bring back (a genetic hybrid of) the woolly mammoth, among other grand schemes.
The new round of funding will be used to bring the company’s lead programs into human proof-of-concept studies, according to a press release, as well as continue development of the eGenesis gene-editing platform. The company’s most advanced research efforts have focused on kidney and islet cell transplants. Islet cells are clusters of cells found throughout the pancreas. They are made up of several types of cells, including one that makes insulin. The idea is to transfer islet cells from a healthy donor to a host with incurable type 1 diabetes.
Church is also co-founder of yet another xenotransplantation biotech company in China called Qihan Biotech, which was founded by Luhan Yang (who, in turn, is a co-founder of eGenesis). Founded in 2017, the startup has raised about $33 million, with a $25.5 million Series A in 2019. The company has developed its own proprietary genome-editing platform. Some of its latest work, published in Nature Biomedical Engineering in September 2020, involved using CRISPR and other genetic tools to create pigs with 13 independent genetic modifications.
Among the improvements (at least from the human point of view) was the complete eradication of DNA viral sequences embedded into the pig’s chromosomes. These sequences, porcine endogenous retroviruses (PERVs), could be potentially infectious to the human host. Other modifications lessened the chance of organ rejection while improving blood-coagulation compatibility.
Dubbed Pig 3.0, Qihan Biotech claims its latest creation, in collaboration with eGenesis, is the most extensively gene-edited pig yet. Besides cell and organ therapies, Qihan plans to apply its genome-editing technology in other areas, such as producing animals with enhanced agronomic traits or multi-disease-resistant crops in agriculture.
Update 03/29/2021: Qihan Biotech has raised $67 million in Series A funding to advance their pipeline of novel cell therapies in IND-enabling studies and hypoimmunity projects, and expand their manufacturing facilities. This brings the company’s total funding to $100.3 million to date.
We don’t have a definitive answer to our question of when xenotransplantation of pig organs will be possible, but it’s not too crazy to believe clinical trials will begin in the next three to five years. And based on some of the recent successes of companies like United Therapeutics, eGenesis, and Qihan Biotech, the time could even come sooner. Gene-editing is one of the hottest industries today. Maybe pigs will fly someday.
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