The Early Days of Organ Farming Are a Bit Gnarly

University of California, Davis researchers announce the disappointing results of their implantation of human stem cells in pigs.


In June 2016, scientists from the Salk Institute for Biological Studies at University of California, Davis announced that they’d ambitiously implanted human cells into a whopping 1,500 proto-embryonic pig blastocysts. They were attempting to create a hybrid, a “chimera,” that would be a pig with a pancreas made of human cells. In theory, it would be a pancreas that could be transplanted into a person in need of that organ. Scientists have been investigating the use of animals as incubators in which to cultivate healthy human organs since the 1970s —it’s called “organ farming.” In late January 2017, the team published the results of their experiment in Cell

The UC scientists had used CRISPR gene editing to remove from a newly fertilized pig embryo the DNA responsible for growing a pancreas, creating a ”niche,” or a gap, into which human cells could be inserted. Next, they took human induced pluripotent (iPS) stem cells — adults stem cells regressed so that they can once again grow into any kind of human tissue — and slotted them into the niche.

This isn’t the first chimera the team had attempted. They’d injected rat cells into mouse embryos — the resulting mice had rat gall bladders— and rat cells into pig embryos, which didn’t work at all.

Rat-mouse chimera (JUN WU)

They had also tried introducing human cells into pig embryos before, though without creating a niche. They later found human cells throughout the pig, but they were fairing poorly in competition with the pig’s own cells. 

There are plenty of unresolved ethical concerns about organ farming, of course. Obviously there’s the question of whether it’s morally defensible to breed an animal strictly as a source for human parts, and there are worries about the treatment of organ-farm animals. There’s also the possibility of new diseases and/or conditions in humans and pigs that could result from tinkering with the intermingling of their DNA. And some are afraid human cells might wind up in a pig’s brain, causing who-knows-what kind of problems. One of the UC researchers, Pablo Ross, told the BBC last year, "We think there is very low potential for a human brain to grow, but this is something we will be investigating."

So. The new report reveals that though the human stem cells seemed at first to be successfully attaching and growing, they eventually failed. Four weeks after the fetuses had been implanted in mothers, there were only traces of human cells left behind. Principle UC investigator Juan Carlos Izpisua Belmonte tells Gizmodo, “The ultimate goal is to generate cells for human tissues. We feel that due to the first results we got, we are far way.”

Human cells are green in this image. (JUN WU)

The relative success of the rat-mouse chimera leaves scientists wondering why this experiment failed. It could be that rats and mice are closer genetically than humans and pigs. Human and porcine gestation times are also very different, so there may be a disconnect there. Paul Tesar, associate professor in genetics at Case Western, speaking to Gizmodo, suggests that selecting just the right kind of stem cells might also be a factor.

For Tesar, it’s not a total loss, though: “I think the paper is well done... It’s a huge amount of work, and the number of embryos they tested here is a pretty impressive tour-de-force. The end result might not be what they’re hoping for... but now we can move on from these studies and build upon them to get to the next level of analysis.”

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Yale scientists restore brain function to 32 clinically dead pigs

Researchers hope the technology will further our understanding of the brain, but lawmakers may not be ready for the ethical challenges.

Still from John Stephenson's 1999 rendition of Animal Farm.
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  • Researchers at the Yale School of Medicine successfully restored some functions to pig brains that had been dead for hours.
  • They hope the technology will advance our understanding of the brain, potentially developing new treatments for debilitating diseases and disorders.
  • The research raises many ethical questions and puts to the test our current understanding of death.

The image of an undead brain coming back to live again is the stuff of science fiction. Not just any science fiction, specifically B-grade sci fi. What instantly springs to mind is the black-and-white horrors of films like Fiend Without a Face. Bad acting. Plastic monstrosities. Visible strings. And a spinal cord that, for some reason, is also a tentacle?

But like any good science fiction, it's only a matter of time before some manner of it seeps into our reality. This week's Nature published the findings of researchers who managed to restore function to pigs' brains that were clinically dead. At least, what we once thought of as dead.

What's dead may never die, it seems

The researchers did not hail from House Greyjoy — "What is dead may never die" — but came largely from the Yale School of Medicine. They connected 32 pig brains to a system called BrainEx. BrainEx is an artificial perfusion system — that is, a system that takes over the functions normally regulated by the organ. Think a dialysis machine for the mind. The pigs had been killed four hours earlier at a U.S. Department of Agriculture slaughterhouse; their brains completely removed from the skulls.

BrainEx pumped an experiment solution into the brain that essentially mimic blood flow. It brought oxygen and nutrients to the tissues, giving brain cells the resources to begin many normal functions. The cells began consuming and metabolizing sugars. The brains' immune systems kicked in. Neuron samples could carry an electrical signal. Some brain cells even responded to drugs.

The researchers have managed to keep some brains alive for up to 36 hours, and currently do not know if BrainEx can have sustained the brains longer. "It is conceivable we are just preventing the inevitable, and the brain won't be able to recover," said Nenad Sestan, Yale neuroscientist and the lead researcher.

As a control, other brains received either a fake solution or no solution at all. None revived brain activity and deteriorated as normal.

The researchers hope the technology can enhance our ability to study the brain and its cellular functions. One of the main avenues of such studies would be brain disorders and diseases. This could point the way to developing new of treatments for the likes of brain injuries, Alzheimer's, Huntington's, and neurodegenerative conditions.

"This is an extraordinary and very promising breakthrough for neuroscience. It immediately offers a much better model for studying the human brain, which is extraordinarily important, given the vast amount of human suffering from diseases of the mind [and] brain," Nita Farahany, the bioethicists at the Duke University School of Law who wrote the study's commentary, told National Geographic.

An ethical gray matter

Before anyone gets an Island of Dr. Moreau vibe, it's worth noting that the brains did not approach neural activity anywhere near consciousness.

The BrainEx solution contained chemicals that prevented neurons from firing. To be extra cautious, the researchers also monitored the brains for any such activity and were prepared to administer an anesthetic should they have seen signs of consciousness.

Even so, the research signals a massive debate to come regarding medical ethics and our definition of death.

Most countries define death, clinically speaking, as the irreversible loss of brain or circulatory function. This definition was already at odds with some folk- and value-centric understandings, but where do we go if it becomes possible to reverse clinical death with artificial perfusion?

"This is wild," Jonathan Moreno, a bioethicist at the University of Pennsylvania, told the New York Times. "If ever there was an issue that merited big public deliberation on the ethics of science and medicine, this is one."

One possible consequence involves organ donations. Some European countries require emergency responders to use a process that preserves organs when they cannot resuscitate a person. They continue to pump blood throughout the body, but use a "thoracic aortic occlusion balloon" to prevent that blood from reaching the brain.

The system is already controversial because it raises concerns about what caused the patient's death. But what happens when brain death becomes readily reversible? Stuart Younger, a bioethicist at Case Western Reserve University, told Nature that if BrainEx were to become widely available, it could shrink the pool of eligible donors.

"There's a potential conflict here between the interests of potential donors — who might not even be donors — and people who are waiting for organs," he said.

It will be a while before such experiments go anywhere near human subjects. A more immediate ethical question relates to how such experiments harm animal subjects.

Ethical review boards evaluate research protocols and can reject any that causes undue pain, suffering, or distress. Since dead animals feel no pain, suffer no trauma, they are typically approved as subjects. But how do such boards make a judgement regarding the suffering of a "cellularly active" brain? The distress of a partially alive brain?

The dilemma is unprecedented.

Setting new boundaries

Another science fiction story that comes to mind when discussing this story is, of course, Frankenstein. As Farahany told National Geographic: "It is definitely has [sic] a good science-fiction element to it, and it is restoring cellular function where we previously thought impossible. But to have Frankenstein, you need some degree of consciousness, some 'there' there. [The researchers] did not recover any form of consciousness in this study, and it is still unclear if we ever could. But we are one step closer to that possibility."

She's right. The researchers undertook their research for the betterment of humanity, and we may one day reap some unimaginable medical benefits from it. The ethical questions, however, remain as unsettling as the stories they remind us of.