Tag Archives: chimeras

Need to improve oversight on chimeric human-animal research

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It seems chimeras are of more interest these days. In all likelihood that has something to do with the fellow who received a transplant of a pig’s heart in January 2022 (he died in March 2022).

For those who aren’t familiar with the term, a chimera is an entity with two different DNA (deoxyribonucleic acid) identities. In short, if you get a DNA sample from the heart, it’s different from a DNA sample obtained from a cheek swab. This contrasts with a hybrid such as a mule (donkey/horse) whose DNA samples show a consisted identity throughout its body.

A December 12, 2022 The Hastings Center news release (also on EurekAlert) announces a special report,

A new report on the ethics of crossing species boundaries by inserting human cells into nonhuman animals – research surrounded by debate – makes recommendations clarifying the ethical issues and calling for improved oversight of this work.

The report, “Creating Chimeric Animals — Seeking Clarity On Ethics and Oversight,” was developed by an interdisciplinary team, with funding from the National Institutes of Health. Principal investigators are Josephine Johnston and Karen Maschke, research scholars at The Hastings Center, and Insoo Hyun, director of the Center for Life Sciences and Public Learning at the Museum of Life Sciences in Boston, formerly of Case Western Reserve University.

Advances in human stem cell science and gene editing enable scientists to insert human cells more extensively and precisely into nonhuman animals, creating “chimeric” animals, embryos, and other organisms that contain a mix of human and nonhuman cells.

Many people hope that this research will yield enormous benefits, including better models of human disease, inexpensive sources of human eggs and embryos for research, and sources of tissues and organs suitable for transplantation into humans. 

But there are ethical concerns about this type of research, which raise questions such as whether the moral status of nonhuman animals is altered by the insertion of human stem cells, whether these studies should be subject to additional prohibitions or oversight, and whether this kind of research should be done at all.

The report found that:

Animal welfare is a primary ethical issue and should be a focus of ethical and policy analysis as well as the governance and oversight of chimeric research.

Chimeric studies raise the possibility of unique or novel harms resulting from the insertion and development of human stem cells in nonhuman animals, particularly when those cells develop in the brain or central nervous system.

Oversight and governance of chimeric research are siloed, and public communication is minimal. Public communication should be improved, communication between the different committees involved in oversight at each institution should be enhanced, and a national mechanism created for those involved in oversight of these studies. 

Scientists, journalists, bioethicists, and others writing about chimeric research should use precise and accessible language that clarifies rather than obscures the ethical issues at stake. The terms “chimera,” which in Greek mythology refers to a fire-breathing monster, and “humanization” are examples of ethically laden, or overly broad language to be avoided.

The Research Team

The Hastings Center

• Josephine Johnston
• Karen J. Maschke
• Carolyn P. Neuhaus
• Margaret M. Matthews
• Isabel Bolo

Case Western Reserve University
• Insoo Hyun (now at Museum of Science, Boston)
• Patricia Marshall
• Kaitlynn P. Craig

The Work Group

• Kara Drolet, Oregon Health & Science University
• Henry T. Greely, Stanford University
• Lori R. Hill, MD Anderson Cancer Center
• Amy Hinterberger, King’s College London
• Elisa A. Hurley, Public Responsibility in Medicine and Research
• Robert Kesterson, University of Alabama at Birmingham
• Jonathan Kimmelman, McGill University
• Nancy M. P. King, Wake Forest University School of Medicine
• Geoffrey Lomax, California Institute for Regenerative Medicine
• Melissa J. Lopes, Harvard University Embryonic Stem Cell Research Oversight Committee
• P. Pearl O’Rourke, Harvard Medical School
• Brendan Parent, NYU Grossman School of Medicine
• Steven Peckman, University of California, Los Angeles
• Monika Piotrowska, State University of New York at Albany
• May Schwarz, The Salk Institute for Biological Studies
• Jeff Sebo, New York University
• Chris Stodgell, University of Rochester
• Robert Streiffer, University of Wisconsin-Madison
• Lorenz Studer, Memorial Sloan Kettering Cancer Center
• Amy Wilkerson, The Rockefeller University

Here’s a link to and a citation for the report,

Creating Chimeric Animals: Seeking Clarity on Ethics and Oversight edited by Karen J. Maschke, Margaret M. Matthews, Kaitlynn P. Craig, Carolyn P. Neuhaus, Insoo Hyun, Josephine Johnston, The Hastings Center Report Volume 52, Issue S2 (Special Report), November‐December 2022 First Published: 09 December 2022

This report is open access.

Protocols for mouse-human chimeric embryos

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This work on a type of species boundary-crossing could be very disturbing for some folks. That said, here’s more about the science from a July 2, 2021 news item on phys.org,

A year after University at Buffalo [in New York state] scientists demonstrated that it was possible to produce millions of mature human cells in a mouse embryo, they have published a detailed description of the method so that other laboratories can do it, too.

A July 2, 2021 University at Buffalo (UB) news release (also on EurekAlert) by Ellen Goldbaum, which originated the news item, explains why scientists have created these chimeras,

The ability to produce millions of mature human cells in a living organism, called a chimera, which contains the cells of two species, is critical if the ultimate promise of stem cells to treat or cure human disease is to be realized. But to produce those mature cells, human primed stem cells must be converted back into an earlier, less developed naive state so that the human stem cells can co-develop with the inner cell mass in a mouse blastocyst.

The protocol outlining how to do that has now been published in Nature Protocols by the UB scientists. They were invited to publish it because of the significant interest generated by the team’s initial publication describing their breakthrough last May [2020].

“This paper will enable many scientists to use this new platform to study the human disease of their interest,” said Jian Feng, PhD, professor of physiology and biophysics in the Jacobs School of Medicine and Biomedical Sciences at UB and senior author. “Over time, it will transform biomedical research toward a more effective use of the human model system to directly study virtually any inborn condition of an individual. It will stimulate unforeseen discoveries and applications that may fundamentally change our understanding of human biology and medicine.”

The protocol will allow scientists to create animal models that Feng said provide a much more realistic picture of embryonic development than has ever been possible. These more realistic animal models also will have the potential to reveal the mechaniswms behind numerous diseases, especially those that afflict individuals from birth.

Better mouse models

“This step-by-step protocol will benefit the entire field by enabling other scientists to use our methods to generate chimeras to study human diseases that they are experts in,” said Feng. “It will lead to the generation of better mouse models for various human diseases, such as sickle cell anemia, COVID-19 and many others, or various human developmental disorders.” The paper demonstrates how to generate naive human pluripotent stem cells from existing induced pluripotent stem cells that may be derived from patients with various diseases, how to generate mouse-human chimeras using these cells and how to quantify the amount of human cells in the chimeras.

“Using our method, one can now track the development of naive human pluripotent stem cells in mouse-human chimeric embryos in real-time,” said Feng. These stem cells can then be manipulated either genetically or pharmacologically, providing valuable information about human development and disease.

“For example, one can label naive human pluripotent stem cells by inserting green fluorescent protein in a hemoglobin gene to study the development of human red blood cells in mouse-human chimeras,” said Feng.

Another application is to generate humanized mouse models to study many human diseases.

“These mice contain critical human cells, tissues or even organs so that they more accurately reflect the human condition,” said Feng. “With our method, the human cells are made along with the mouse during the development of the mouse embryo. There would be better matching and no rejections, because there are ways for the human cells to be made where there is no competition from their mouse counterparts.”

Organs for transplant in the future

By allowing others to improve and adapt the method to eventually generate chimeras in larger animals, this protocol may also lead to the generation of human organs to address the dire shortage of organs available for transplant, said Feng.

“If naive human pluripotent stem cells are able to generate significant amounts of mature human cells in other larger species, it could be possible to make human tissues or even human organs in chimeric animals,” Feng explained.

This would be possible using blastocyst complementation where, Feng explained, normal pluripotent stem cells from one species can reconstitute an organ for that species in a blastocyst of another species that been genetically modified not to grow that particular organ.

Feng added: “Ultimately, a better understanding of how human cells develop and grow in chimeras may enable the generation of human cells, tissues and organs in a completely artificial system and fundamentally change how we treat many human diseases. Research using chimeras is a bridge that must be crossed to reach that possibility.”

Here’s a link to and a citation for the 2021 article,

Generation of mouse–human chimeric embryos by Boyang Zhang, Hanqin Li, Zhixing Hu, Houbo Jiang, Aimee B. Stablewski, Brandon J. Marzullo, Donald A. Yergeau & Jian Feng. Nature Protocols (2021) DOI: https://doi.org/10.1038/s41596-021-00565-7 Published 02 July 2021

This article is behind a paywall.

Here’s a link to and citation for the 2020 work, which led to the publication of the protocols,

Transient inhibition of mTOR in human pluripotent stem cells enables robust formation of mouse-human chimeric embryos by Zhixing Hu, Hanqin Li, Houbo Jiang, Yong Ren, Xinyang Yu, Jingxin Qiu, Aimee B. Stablewski, Boyang Zhang, Michael J. Buck, Jian Feng. Science Advances 13 May 2020: Vol. 6, no. 20, eaaz0298 DOI: 10.1126/sciadv.aaz0298

This paper is open access.

Book commentaries: The Science of Orphan Black: The Official Companion and Star Trek Treknology; The Science of Star Trek from Tricorders to Warp Drive

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I got more than I expected from both books (“The Science of Orphan Black: The Official Companion” by Casey Griffin and Nina Nesseth and “Star Trek Treknology; The Science of Star Trek from Tricorders to Warp Drive” by Ethan Siegel) I’m going to discuss by changing my expectations.

The Science of Orphan Black: The Official Companion

I had expected a book about the making of the series with a few insider stories about the production along with some science. Instead, I was treated to a season by season breakdown of the major scientific and related ethical issues in the fields of cloning and genetics.I don’t follow those areas exhaustively but from my inexpert perspective, the authors covered everything I could have hoped for (e.g., CRISPR/CAS9, Henrietta Lacks, etc.) in an accessible but demanding writing style  In other words, it’s a good read but it’s not a light read.

There are many, many pictures of Tatiana Maslany as one of her various clone identities in the book. Unfortunately, the images do not boast good reproduction values. This was disconcerting as it can lead a reader (yes, that was me) to false expectations (e.g., this is a picture book) concerning the contents. The boxed snippets from the scripts and explanatory notes inset into the text helped to break up some of the more heavy going material while providing additional historical/scripting/etc. perspectives. One small niggle, the script snippets weren’t always as relevant to the discussion at hand as the authors no doubt hoped.

I suggest reading both the Foreword by Cosima Herter, the series science consultant, and (although it could have done with a little editing) The Conversation between Cosima Herter and Graeme Manson (one of the producers). That’s where you’ll find that the series seems to have been incubated in Vancouver, Canada. It’s also where you’ll find out how much of Cosima Herter’s real life story is included in the Cosima clone’s life story.

The Introduction tells you how the authors met (as members of ‘the clone club’) and started working together as recappers for the series. (For anyone unfamiliar with the phenomenon or terminology, episodes of popular series are recapitulated [recapped] on one or more popular websites. These may or may not be commercial, i.e., some are fan sites.)

One of the authors, Casey Griffin, is a PhD candidate at the University of Southern California (USC) studying in the field of developmental and stem cell biology. I was not able to get much more information but did find her LinkedIn profile. The other author also has a science background. Nina Nesseth is described as a science communicator on the back cover of the book but she’s described as a staff scientist for Science North, a science centre located in Sudbury, Ontario, Canada. Her LinkedIn profile lists an honours Bachelor of Science (Biological and Medical Sciences) from Laurentian University, also located in Sudbury, Ontario.

It’s no surprise, given the authors’ educational background, that a bibliography (selected) has been included. This is something I very much appreciated. Oddly, given that Nesseth lists a graduate certificate in publishing as one of her credentials (on LinkedIn), there is no index (!?!). Unusually, the copyright page is at the back of the book instead of the front and boasts a fairly harsh copyright notice (summary: don’t copy anything, ever … unless you get written permission from ECW Press and the other copyright owners; Note: Herter is the copyright owner of her Foreword while the authors own the rest).

There are logos on the copyright page—more than I’m accustomed to seeing. Interestingly, two of them are government logos. It seems that taxpayers contributed to the publication of this book. The copyright notice seems a little facey to me since taxpayers (at least partially) subsidized the book, as well, Canadian copyright law has a concept called fair dealing (in the US, there’s something similar: fair use). In other words, if I chose, I could copy portions of the text without asking for permission if there’s no intent to profit from it and as long as I give attributions.

How, for example, could anyone profit from this?

In fact, in January 2017, Jun Wu and colleagues published their success in creating pig-human hybrids. (description of real research on chimeras on p. 98)

Or this snippet of dialogue,

[Charlotte] You’re my big sister.

[Sarah] How old are you? (p. 101)

All the quoted text is from “The Science of Orphan Black: The Official Companion” by Casey Griffin and Nina Nesseth (paperback published August 22, 2017).

On the subject of chimeras, the Canadian Broadcasting Corporation (CBC) featured a January 26, 2017 article about the pig-human chimeras on its website along with a video,

Getting back to the book, copyright silliness aside, it’s a good book for anyone interested in some of the  science and the issues associated with biotechnology, synthetic biology, genomes, gene editing technologies, chimeras, and more. I don’t think you need to have seen the series in order to appreciate the book.

Star Trek Treknology; The Science of Star Trek from Tricorders to Warp Drive

This looks and feels like a coffee table book. The images in this book are of a much higher quality than those in the ‘Orphan Black’ book. With thicker paper and extensive ink coverage lending to its glossy, attractive looks, it’s a physically heavy book. The unusually heavy use of black ink  would seem to be in service of conveying the feeling that you are exploring the far reaches of outer space.

It’s clear that “Star Trek Treknology; The Science of Star Trek from Tricorders to Warp Drive’s” author, Ethan Siegel, PhD., is a serious Star Trek and space travel fan. All of the series and movies are referenced at one time or another in the book in relationship to technology (treknology).

Unlike Siegel, while I love science fiction and Star Trek, I have never been personally interested in space travel. Regardless, Siegel did draw me in with his impressive ability to describe and explain physics-related ideas. Unfortunately, his final chapter on medical and biological ‘treknology’ is not as good. He covers a wide range of topics but no one is an expert on everything.

Siegel has a Wikipedia entry, which notes this (Note: Links have been removed),

Ethan R. Siegel (August 3, 1978, Bronx)[1] is an American theoretical astrophysicist and science writer, who studies Big Bang theory. He is a professor at Lewis & Clark College and he blogs at Starts With a Bang, on ScienceBlogs and also on Forbes.com since 2016.

By contrast with the ‘Orphan Black’ book, the tone is upbeat. It’s one of the reasons Siegel appreciates Star Trek in its various iterations,

As we look at the real-life science and technology behind the greatest advances anticipated by Star Trek, it’s worth remembering that the greatest legacy of the show is its message of hope. The future can be brighter and better than our past or present has ever been. It’s our continuing mission to make it so. (p. 6)

All the quoted text is from “Star Trek Treknology; The Science of Star Trek from Tricorders to Warp Drive” by Ethan Siegel (hard cover published October 15, 2017).

This book too has one of those copyright notices that fail to note you don’t need permission when it’s fair dealing to copy part of the text. While it does have an index, it’s on the anemic side and, damningly, there are neither bibliography nor reference notes of any sort. If Siegel hadn’t done such a good writing job, I might not have been so distressed.

For example, it’s frustrating for someone like me who’s been trying to get information on cortical/neural  implants and finds this heretofore unknown and intriguing tidbit in Siegel’s text,

In 2016, the very first successful cortical implant into a patient with ALS [amyotrophic lateral sclerosis] was completed, marking the very first fully implanted brain-computer interface in a human being. (p. 180)

Are we talking about the Australia team, which announced human clinical trials for their neural/cortical implant (my February 15, 2016 posting) or was it preliminary work by a team in Ohio (US) which later (?) announced a successful implant for a quadriplegic (also known as tetraplegic) patient who was then able to move hands and fingers (see my April 19, 2016 posting)? Or is it an entirely different team?

One other thing, I was a bit surprised to see no mention of quantum or neuromorphic computing in the chapter on computing. I don’t believe either was part of the Star Trek universe but they (neuromorphic and quantum computing) are important developments and Siegel makes a point, on at least a few occasions, of contrasting present day research with what was and wasn’t ‘predicted’ by Star Trek.

As for the ‘predictions’, there’s a longstanding interplay between storytellers and science and sometimes it can be a little hard to figure out which came first. I think Siegel might have emphasized that give and take a bit more.

Regardless of my nitpicking, Siegel is a good writer and managed to put an astonishing amount of ‘educational’ material into a lively and engaging book. That is not easy.

Final thoughts

I enjoyed both books and am very excited to see grounded science being presented along with the fictional stories of both universes (Star Trek and Orphan Black).

Yes, both books have their shortcomings (harsh copyright notices, no index, no bibliography, no reference notes, etc.) but in the main they offer adults who are sufficiently motivated a wealth of current scientific and technical information along with some elucidation of ethical issues.