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December 16, 2019

Advanced Research in the Era of the Chimera

Playing God in a Cleanroom?

animal human chimera

What do you get if you cross a parrot with a centipede? Take a moment…A walkie-talkie! Yes, as anyone with a kindergartener knows, the old jokes really are the best. But when it comes to crossing one animal with another – also known as hybridization – it’s time to get serious. Although the idea of a zonkey (zebra and donkey) or a liger (lion and tiger) sounds like something conjured up by Dr. Seuss, the hybridization of two animals within the same genus is a topic of increasing interest in the scientific community, especially in the areas of medical research. Unlike the natural breeding of animals to emphasize certain physical features, creating a hybrid creature requires leveraging advanced science, high tech equipment, a cleanroom environment and all that goes with that. And given the budgets at stake, you will not see farmers or breed specialists in the room but instead a team of technicians in personal protective equipment (PPE), environmental control, aseptic processing, and more SOPs and HACCP protocols than you could shake a swab at. But what is the goal of this research? Given the advances already made in cloning, why would research shift into the realm of the hybrid? The uptick in interest may be down to one simple reason: cloning inevitably gives you back what you started with; hybridization creates something never before encountered. Arguably, it is as close to playing God as it is possible to come. So let’s take a look at what’s happening in contamination controlled environments, potentially near you…

So when researchers at the Roslin Institute in Scotland announced the arrival of a very important lamb in1997, it may be suspected that they knew this to be merely a first step along a convoluted path of genetics study. Dolly, as she was christened, was produced by engineering a zygote – a fertilized eukaryotic cell with two sets of DNA – combining a mammary gland cell from one sheep with an egg cell from another, and was gestated within a surrogate mother sheep. She made history by becoming the first live mammalian birth from cloning and effectively ushered in the era of intensified research into stem cell science and DNA editing. Potentially, in hinting at the vast possibilities of animal cloning, her birth and survival also illuminated the dark specter of human cloning waiting in the shadows.

So could human clones ever exist?

Perhaps not at this time – despite the claims of the Raelian sect to have produced a cloned child – but the idea seems fascinating, especially to writers of science fiction. Frequently dystopian in nature, authors as diverse as Michael Marshall Smith and Kazuo Ishiguru have focused a critical spotlight on the considerations both ethical and practical – of creating clones as redundancy for existing individuals. Marshall Smith’s Spares – a noir, nightmarish fusion of Coma and Blade Runner, according to Publishers Weekly – depicts a world in which the wealthy are cloned at birth to provide themselves with a spare from which replacement organs may be harvested as needed. Similarly, but with a greater cerebral emphasis, Ishiguru’s Never Let Me Go paints the picture of a quaint English boarding school in which the students are clones created to provide organs and tissues to their ‘possibles,’ – genetically identical individuals who may, at some stage, need to replace their own body parts.

 Outside of the world of literary fiction, the demand for the cloning of individuals is thankfully low and the ethical considerations are still being weighed. Furthermore, for all its science fictional allure, the technique is no longer at the bleeding edge of biomedical research. In a post-Dolly world where those with sufficient funds can now even get genetically identical copies of their beloved canine ‘best friends’ (see ‘Welcome to the New Dawn of Cloning (Gone Are the Days of Boy Meets Girl)’), the newly emerging science is that of hybridization – the creation of an offspring that is genetically different from both parents. And another term for these creatures is a ‘chimera.’

According to the Merriam-Webster dictionary, the root of the noun, chimera, stems from the Greek, chimaira, meaning ‘she-goat.’

In Greek mythology, the name conjured images of a fire-breathing monster with the head of a lion, the body of a goat, and the terrifying tail of a dragon. Understandably furious with her less than flattering body image, she terrorized the human population of Lycia and was ultimately slain in a battle involving Pegasus, the winged horse. Although defeated, this mythical she-goat lived on in popular folklore and her echoes persist today, linguistically, through our adoption of the term to reference not only an imaginary monster but also an organism created through the reproduction of individuals of two different species.

Two different species? If you’re scratching your head and wondering how that is possible, let’s take a step back for a moment. As long ago as the turn of the twentieth century, the idea of the hybridization between species and that of animals with humans has – like that of cloning – captured the literary imagination. In 1896, for example, novelist H. G. Wells published one of his perhaps best-known of works, The Island of Dr. Moreau, wherein the eponymous mad scientist, through outlandish and horrifying vivisection of Frankensteinian proportions, creates a cadre of ‘Beast Folk.’ Narrated by the novel’s main protagonist Edward Prendick, a shipwreck survivor who finds a grim refuge on Moreau’s island, the mutants are described as a combination of animal bodies with human sensibilities but are devoid of the ability to create harm. The depiction of the fictional Moreau’s work saw Wells entering into an increasing important social narrative around ideas of degeneration (the societal slide into decline due to a population’s inferior physical characteristics), Darwin’s theories of evolution, and also a new public outcry against the use of vivisection in scientific research.

And this outcry would be channeled again, almost a century later, in First Born, starring actor Charles Dance which premiered in 1988. Chronicling the work of government geneticist Edward Forester, the story sees the main protagonist fulfilling his lifelong ambition of creating a ‘new species–one with man’s intelligence, but without his homicidal aggression.’(1) Gordon – ‘Gor’ – is a child born to a female gorilla impregnated with human sperm who Forester incorporates into his own family, watching as the chimera develops into an outwardly ‘normal’ human teenager. Only when Gor becomes romantically interested in the scientist’s daughter does the deceit unravel and the truth of the boy’s disturbing genesis come to light.

But, in the real world, would such a hybridization be possible? Although there is little data readily available to suggest research into the creation of a human-gorilla hybrid, several attempts at engineering a combination of humans and chimpanzees are to be found in the scientific literature. In the 1920s, for example, a Russian biologist – Ilya Ivanovich Ivanov – attempted to impregnate three female chimps with human sperm via artificial insemination. He failed and was ultimately sent into exile by the then Soviet authorities. Forty years later, however, experiments in Shengyang, Northeast China are said to have resulted in the successful impregnation of a female chimp. Although the project researchers were redeployed to farm labor camps at the time of the Cultural Revolution, accounts of their work were corroborated by the genetics research bureau of the Chinese Academy of Sciences and, in 1981, one of the original scientists, Ji Yongxiang, announced plans to continue the research. We have yet to find out how successful or otherwise his efforts have been.

With that said, recent news from China does seem to indicate advances in the field.

According to an article in the British press, two monkey-pig hybrids were born in a laboratory in Beijing to a porcine mother.(2)

As embryos, the piglets were injected with primate stem cells from cynomolgus monkeys which became genetic material in their hearts, livers, lungs, skin, and spleen. Of the greater than 4000 embryos used in this research, only these two piglets made it to birth, dying within a week from complications suspected to have arisen from the initial in vitro stage of their creation.

The fact of the live birth of these two individuals, however, has some bioethicists concerned. The official rationale for this research in China is the development of a host animal whose organs would be sufficiently bio-compatible for human transplantation.

After all, as we noted in our earlier article, ‘Tissue Banks and Cleanrooms: The Ultimate Price of Contamination Issues,’ the waiting list for donated organs can be frustratingly – and oftentimes terminally – long. To date, the sale of organs or tissues is illegal within the U.S. and the only way of procuring replacement parts is via donation. As we noted in the referenced article, ‘the Uniform Anatomical Act was drafted by the National Conference of Commissioners on Uniform State Laws in 1968, establishing a donor card scheme that would, in effect, allow the bearer to legally donate their own organs after death and remove the burden of a decision from grieving next-of-kin. This nascent donor card scheme later combined with the Required Request legislation of 1986 that mandated hospitals create policies to request organ donation from the relatives of viable donors. Now, according to OrganDonor.gov, […] 130 million citizens over the age of 18 are registered as donors – that’s a full 51% of the potential donor base in the U.S.’(3)

But it’s still not enough. According to OrganDonor.gov, as of July 2019, more than 113,000 individuals are waiting on the national transplant list, with 1 more being added every 10 minutes. However, only 3 people in every 1000 die in a way that allows for donation of their organs, so the wait can be significant.(4) Furthermore, this shortage of allotransplantation is a problem on a global scale. In China, the use of organs ‘harvested’ from the prison population has become a national scandal, with minority groups targeted for forced harvest. According to the findings of The China Tribunal, a project of the non-profit The International Coalition to End Transplant Abuse in China (ETAC), forced organ harvesting ‘has been committed for years throughout China on a significant scale and that Falun Gong practitioners have been one – and probably the main – source of organ supply. The concerted persecution and medical testing of the Uyghurs is more recent and it may be that evidence of forced organ harvesting of this group may emerge in due course. [There is] no evidence that the significant infrastructure associated with China’s transplantation industry has been dismantled and absent a satisfactory explanation as to the source of readily available organs [the Tribunal] concludes that forced organ harvesting continues till today.’(5)

Clearly this egregious abuse is a significant problem and one which will be alleviated only by the development of alternatives to direct human organ procurement. Alongside the pursuit of knowledge for its own sake, this is why – at least in part – leaders in the field of biomedical science seek alternatives to donor-based systems and is also behind the push to develop bio-compatible chimera for xenotransplantation.

However, this type of research is not without its own series of ethical considerations, especially given a report published in El Pais that a team of American and Spanish scientists have created a human-monkey chimera using Chinese technology. Drawn from the Salk Institute for Biological Studies based in La Jolla, California, and the Murcia Catholic University, Spain, the team was led by biochemist Juan Carlos Izpisúa (previously of the Barcelona Regenerative Medicine Center) and created ‘very promising’ results in a process that involved ‘genetically modified monkey embryos [with deactivated] genes that are essential to the formation of organs. The scientists then injected human stem cells, which are capable of creating any type of tissue, into the embryo.’(6) And although this result stands out for its use of human stem cells, it is not the first time that Izpisúa found success in hybridization. In 2017, his team deployed CRISPR, a genome editing tool, to ‘deactivate genes in mouse embryos that are fundamental to the development of the heart, eyes and pancreas. The team then introduced rat stem cells that were capable of generating these organs. The result was a series of rat-mouse chimera embryos.’(7)

The field of advanced genetics, stem cells, and embryology is a comparatively new one and there is still a lack of unanimous agreement on the scope of its ethical boundaries.

Many critics of the field hold not only ethical but also religious and scientific objections. With the cross-over of disease between species – think of the impact on humans of recent outbreaks of avian and swine flu – chimera may represent ‘the perfect vessel for diseases to overcome the species barrier, because cells from two different species are integrated in the same body. Cases of porcine virus infecting human cells in human-pig chimeras have already been observed.’(8) And this may be the reason why ‘[in] the United States, Senators Brownback and Landrieu have introduced the Human-Animal Hybrid Prohibition Act of 2009, which makes chimera research bureaucratically and financially challenging.’(9)

Moreover, it is scientifically challenging in that the window of time for research is deliberately curtailed. To date, all embryos created as chimera are destroyed at 14 days of gestation – a period considered sufficiently long to yield useful observations but short enough to prevent the development of a human central nervous system. Does a 14-day window seem restrictive?

To some scientists the answer is yes, which may be why the research is increasingly finding a home in Asia, where such limitations are perhaps more relaxed. In Japan, for instance, the ban on transplanting hybrid embryos into surrogate animals in order to bring the pregnancy to term has recently been overturned by the Japanese education and science ministry.

This is good news for stem-cell scientist Hiromitsu Nakauchi, who leads research teams both at the University of Tokyo and at Stanford University, California. Nakauchi’s specific focus is on engineering animals with specific organs comprised of human cells. For instance, like his Spanish colleague Izpisúa, Nakauchi envisions being able to create an embryo devoid of the genes to produce a specific organ – let’s say a liver. By injecting that embryo with human induced pluripotent stem (iPS) cells, scientists can then ‘grow’ a customized animal with a liver that, upon birth, can be harvested for a human patient in need of that organ. Again, this is good news for the researcher team and the patient, but bad news for the animal and perhaps for our broader societal ethics.

And if all of that were not enough to bear in mind in any discussion of chimerism, there’s also the legal implications of having two distinct sets of DNA. In Stephen King’s novel, The Dark Half, struggling author of high-brow literary fiction Thad Beaumont discovers he is a chimera – a physical host to his fraternal twin who was absorbed in utero. In classic Kingian style, the narrative sees Beaumont increasingly tormented by the crimes of his evil twin and a battle ensues for primacy of their shared physical body.

While, in the world outside of literature, the problems of the fictional Beaumont do not exist, other issues have arisen. Take, for instance, the case of Chris Long of Reno, NV. According to an article in the New York Times, suffering from cute myeloid leukemia and myelodysplastic syndromes Long’s only hope was a bone marrow transplant. Working at the Washoe County Sheriff’s Department, Long agreed to have colleagues take DNA swabs prior to the treatment to see how far the new DNA created by the donor bone marrow would migrate. And the results were startling: ‘Within four months of the procedure, Mr. Long’s blood had been replaced by his donor’s blood. Swabs collected from his lip, cheek and tongue showed that these also contained his donor’s DNA, with the percentages rising and falling over the years. Of the samples collected, only his chest and head hair were unaffected. The most unexpected part was that four years after the procedure, the DNA in his semen had been entirely replaced by his donor’s.’(10)

And having two sets of DNA would have implications for law enforcement.

Current forensic techniques rely upon one simple fact: DNA is unique – an identification that can only belong to one individual. However, with a chimera there can be two sets of DNA present which makes confusion, misidentification, or the risk of a miscarriage of justice more possible. Take, for instance, the case presented by Abirami Chidambaram at the Alaska State Scientific Crime Detection Laboratory, based in Anchorage, AK. In a sexual assault investigation, detectives threw doubt upon the victim’s testimony as she described her attacker as a lone individual. Forensic examination, however, revealed two sets of DNA – the second of which was ultimately determined to be that of her bone marrow donor. By the time this was uncovered, however, the psychological damage had been done: the victim survived the attack only to be disbelieved by those charged with bringing her justice.

And in Seoul, South Korea, blood samples taken at the scene identified a road traffic accident victim as a woman. Later, however, it was revealed that the deceased was, in fact, male – as confirmed by analysis of DNA taken from a kidney. The DNA extracted from his lung and spleen, however, was – like that in the blood – female, and had originated in a bone marrow transplant from his daughter. Chimerism is indeed a complex area fraught with potential challenges.

And with that in mind, there is perhaps one final point to make in this inevitably abbreviated discussion of a fascinating but challenging developing branch of scientific inquiry. While it holds out the promise of great benefits in the medical field, it also represents something of an existential threat both to our broader survival and, of course, to our ethics. Throughout this article, we have used the term chimera in its strictly scientific sense, but a second definition of the word also exists. Again, according to Merriam-Webster, a chimera can also be ‘an illusion or fabrication of the mind; an unrealizable dream.’ Although cases like that of Chris Long show chimerism in a basic sense, it may well be that success with the inter-species variant, of the kind envisioned by researchers such as Izpisúa and Nakauchi, will prove to be more elusive. Indeed, it may be that the blending of two animals – or that of non-human animals with humans – remains tantalizingly out of our reach at this time, relegated to the realm of science fiction and fantasy in the vein of H. G. Wells. And given the medical, moral, ethical, and legal impacts of this science, that might not be a bad thing.

Where do you stand? Are you for or against the hybridization of animals? Do you have opinions about organ harvesting? Would you be accepting of animal-human chimera? We’d love to know your thoughts!

References:

  1. https://www.latimes.com/archives/la-xpm-1989-06-17-ca-1687-story.html
  2. https://www.dailymail.co.uk/news/article-7766123/Worlds-monkey-pig-hybrids-born-Chinese-lab.html
  3. https://cleanroom-news.com/2017/01/tissue-banks-cleanrooms-the-ultimate-price-of-contamination-issues/
  4. https://www.organdonor.gov/statistics-stories/statistics.html
  5. https://chinatribunal.com/final-judgement-report/
  6. https://elpais.com/elpais/2019/07/31/inenglish/1564561365_256842.html
  7. ibid
  8. https://www.bu.edu/writingprogram/journal/past-issues/issue-2/yu/
  9. ibid
  10. https://www.nytimes.com/2019/12/07/us/dna-bone-marrow-transplant-crime-lab.html

 

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