Medicine Research Reproducibility

The Island of Dr Izpisua Belmonte

Human-monkey chimeras arrive to solve the problem of organ shortage. Thank Juan Carlos Izpisua Belmonte, who is ready to cure all possible diseases and even the old age. With chutzpah and Cell on his side.

Scientists create monkey-human chimeras! You saw the news everywhere. But what’s the point? Well, either the sheer pleasure of doing the forbidden thing, or altruistic desire to save the patients in need of organ replacement. Only two labs in the world seem to have successfully published on this topic of growing organs in interspecies chimera. Either it’s superhuman genius, or everyone else in the world is too dumb and incapable to do even mouse-rat thing. NPR quoted the lead scientist behind the recent monkey-human headline:

This is one of the major problems in medicine — organ transplantation,” said Juan Carlos Izpisua Belmonte, a professor in the Gene Expression Laboratory of the Salk Institute for Biological Sciences in La Jolla, Calif., and a co-author of the Cell study. “The demand for that is much higher than the supply.

Human-monkey

This is the paper, published in Cell:

Tao Tan, Jun Wu, Chenyang Si, Shaoxing Dai, Youyue Zhang, Nianqin Sun, E Zhang, Honglian Shao, Wei Si, Pengpeng Yang, Hong Wang, Zhenzhen Chen, Ran Zhu, Yu Kang, Reyna Hernandez-Benitez, Llanos Martinez Martinez, Estrella Nuñez Delicado, W. Travis Berggren, May Schwarz, Zongyong Ai, Tianqing Li, Concepcion Rodriguez Esteban, Weizhi Ji, Yuyu Niu, Juan Carlos Izpisua Belmonte Chimeric contribution of human extended pluripotent stem cells to monkey embryos ex vivo Cell (2021) doi: 10.1016/j.cell.2021.03.020

The authors injected human extended pluripotent stem cells (hEPSCs) into blastocyst embryos of macaques and cultured the resulting chimeric embryos a bit in vitro (as long as these survived, which wasn’t long). The work was done in China and also received the ethics approval in China. Because it’s possible there.

Izpisua Belmonte is Spanish native, his plans on human-monkey chimeras were first announced in El Pais in 2019, where we learn who was originally funding this human-monkey research. The Spanish Catholics namely:

Izpisúa’s research with monkeys in China was financed in large part by the UCAM [Murcia Catholic University, LS], and did not come cheap. “If we combine the human/pig, human/rat and human/monkey research, it is many hundreds of thousands of euros””

The final Cell paper acknowledges UCAM only after the 5 Chinese funding sources. But how did Izpisua Belmonte ended up doing that research in China? In 2016, San Diego Tribune wrote about Izpisua Belmonte’s plans to grow human organs in animals:

Last week [in 2016, -LS], the National Institutes of Health gave Izpisúa Belmonte $2.5 million to advance his research with monkey cells implanted into pig embryos. Since monkeys are biologically similar to humans, analysis of pig-monkey chimeras should yield insights that can be applied to eventual production of human organs, he said. And unlike mice, pigs are large enough to grow usable human organs.

However, the agency didn’t fund Izpisúa Belmonte’s bid to create human-pig chimeras. He calls the new grant a compromise that postpones having to deal with questions about the moral implications of making human-animal life in this groundbreaking way.

Human-pig

It is not clear what Izpisua Belmonte did with that NIH grant, instead of monkey-pig chimeras in USA which apparently never happened (or at least never got published) he announced in 2017 human-pig chimeras from Spain, made at the same catholic university, UCAM. Back then, the embryos were even implanted into pregnant sows and gestated for a month, something which apparently perfectly complies with Catholic dogmas. Maybe not everyone found that cool in the retrospective, because the later 2021 study didn’t even consider implantation (“focused entirely on ex vivo chimeric embryos“). But who cares about ethics when the human-pig chimera story is the best clickbait ever. It was of course covered by media worldwide back in 2017, here by the BBC:

“The process appears very inefficient – of the 2,075 embryos implanted only 186 continued to develop up to the 28-day stage. But crucially there were signs that human cells were functioning – albeit as a tiny fraction of the total tissue – as part of a human-pig chimera.

This is the first time that human cells are seen growing inside a large animal,” Prof Juan Carlos Izpisua Belmonte, from the Salk Institute, told the BBC News website.”

This was the paper, in Cell of course:

Jun Wu, Aida Platero-Luengo, Masahiro Sakurai, Emilio A. Martinez, Pablo Juan Ross, Juan Carlos Izpisua Belmonte Interspecies Chimerism with Mammalian Pluripotent Stem Cells Cell (2017) doi: 10.1016/j.cell.2016.12.036

Mouse-rat chimera no problem, human-pig chimera works also, but rat-pig chimera doesn’t work. Go figure. An accompanying press release mentioned the previous successful work on rat-mouse chimera:

“As a first step, Izpisua Belmonte and Salk Institute staff scientist Jun Wu created a rat/mouse chimera by introducing rat cells into mouse embryos and letting them mature. Other researchers had already created a rat/mouse chimera in 2010. That chimera was a mouse with pancreatic tissue formed from rat cells.”

Thing is, this interspecies chimera technology doesn’t always work in other people’s hands (the bit about “other researchers” and 2010 in a moment). As the authors of the Tan et al Cell 2021 paper write:

Rat and mouse PSCs robustly contribute to chimera formation when introduced into mouse and rat blastocysts, respectively. To date, however, robust chimerism between species that are more evolutionarily distant has not been achieved. Several groups, including ours, have rigorously demonstrated that hPSCs inefficiently contributed to chimera formation in early mouse (E8.5–E17.5) and pig (E17–E28) embryos. Levels of chimerism were far lower than those achieved between rat and mouse (Bayerl et al., 2020; Das et al., 2020; Hu et al., 2020; Salazar-Roa et al., 2020; Theunissen et al., 2014, Theunissen et al., 2016; Wang et al., 2018; Wu et al., 2017; Yang et al., 2017b).”

The first cited paper (Bayerl et al 2020) is about human-mouse chimeric embryos cultured in vitro and comes from the lab of Jacob Hanna, an Israeli scientist I personally would not trust unconditionally (read here). All other referenced papers stem from Izpisua Belmonte’s own lab. Then the authors of Tan et al 2021 admit:

Savatier and colleagues recently found that human naive PSCs stalled in the G1 phase of the cell cycle and therefore could not contribute to chimera formation when introduced into rabbit or macaque pre-implantation embryos (Aksoy et al., 2020), which is not observed in the present study.

Basically, as it looks today it’s just Izpisua Belmonte’s lab capable of doing interspecies chimera. Either that, or the others are not allowed to. The 2017 Cell paper didn’t have a COI statement, but the 2021 does: “The authors declare no competing interests“. Which is weird because Izpisua Belmonte and Jun Wu hold since 2017 a patent on “Mammalian chimeric complementation“:

In some embodiments, the first mammal is selected from the group consisting of mouse, rat, rabbit, guinea pig, cow, pig, horse, goat, and sheep. In some embodiments, the first mammal is a cow or a pig. In some embodiments, the second mammal is selected from the group consisting of mouse, rat, rabbit, guinea pig, human, cow, pig, horse, goat, and sheep. In some embodiments, the second mammal is a human. […] In some embodiments, the organ or tissue comprises at least one of the group consisting of liver, kidney, pancreas, hematopoietic stem cells, spleen, bone marrow, heart, lung, skin, cornea, eye, spinal cord, uterus, intestine, heart valve, bone, cartilage, tendon, ligament, lymphatic vessel, and blood vessel. In some embodiments, the organ or tissue is chimeric. […] In some embodiments, the organ or tissue has a percentage chimerism as a ratio between the second mammal and the first mammal of at least 90% to 99%. In some embodiments, the genetic modification disables organogenesis of an organ or tissue.

Rat-mouse

Maybe this is why Izpisua Belmonte’s is basically the only lab in the world able to create chimeric animal embryos? Remember the above cited press release, where other researchers are mentioned to have made a rat-mouse chimera already in 2010? Here is this other lab, described in a 2015 Science article decrying the cancellation of NIH funding for Izpisua Belmonte’s human chimera research:

“For Hiromitsu Nakauchi, a stem cell scientist at Stanford University, and the University of Tokyo, the debate is familiar. He showed in 2010 that by adding rat stem cells to mice embryos lacking a pancreas gene, he could grow a rat pancreas in a mouse. The technique also enabled his team to grow a pancreas from one pig species in the body of another. But the follow-up experiments he wanted to do with human stem cells in goat or pig embryos were forbidden in Japan. An ethics commission decided that the experiments should be allowed, but official regulations still aren’t in place, Nakauchi says. In part because of the restrictions in Japan, he accepted a position at Stanford University, where he received $6.2 million for the work from the California Institute for Regenerative Medicine (CIRM).”

Indeed, Hiromitsu Nakauchi in Stanford seems to be the only other scientist capable of generating interspecies chimeras. As it happens, he also has a patent on “Method of Producing Chimeric Animal“, issued in 2018 (interestingly, another holder of this patent is Irving Weissman in Stanford). Basically, California holds the monopoly on world’s interspecies chimera industry. This was confirmed to me by Christine Mummery, professor in Leiden, Netherlands, and President of the International Society for Stem Cell Research (ISSCR), whom I approached for information which other labs except of Izpisua Belmonte’s may have succeeded in generating chimeric embryos up to the organ-harvesting stage. Mummery wrote that it was indeed only Nakauchi:

This was the first paper in that area:

Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Kobayashi T, Yamaguchi T, Hamanaka S, Kato-Itoh M, Yamazaki Y, Ibata M, Sato H, Lee YS, Usui J, Knisely AS, Hirabayashi M, Nakauchi H. Cell. 2010 Sep 3;142(5):787-99. doi: 10.1016/j.cell.2010.07.039.

Hiro Nakauchi (now in California) has done a lot of work in this area. He wrote a review in 2018:

Interspecies chimeras. Suchy F, Nakauchi H. Curr Opin Genet Dev. 2018 Oct;52:36-41. doi: 10.1016/j.gde.2018.05.007. Epub 2018 May 30.

More of his articles:

Interspecies organogenesis generates autologous functional islets. Yamaguchi T, Sato H, Kato-Itoh M, Goto T, Hara H, Sanbo M, Mizuno N, Kobayashi T, Yanagida A, Umino A, Ota Y, Hamanaka S, Masaki H, Rashid ST, Hirabayashi M, Nakauchi H. Nature. 2017 Feb 9;542(7640):191-196. doi: 10.1038/nature21070. [rat-mouse chimera again]

Generation of functional lungs via conditional blastocyst complementation using pluripotent stem cells. Mori M, Furuhashi K, Danielsson JA, Hirata Y, Kakiuchi M, Lin CS, Ohta M, Riccio P, Takahashi Y, Xu X, Emala CW, Lu C, Nakauchi H, Cardoso WV. Nat Med. 2019 Nov;25(11):1691-1698. doi: 10.1038/s41591-019-0635-8. Epub 2019 Nov 7 [That Mori et al 2019 paper was actually about mouse-mouse chimera, not interspecies, -LS]

And another article from Izpisua Belmonte using pigs as chimeric emrbyo

Pig Chimeric Model with Human Pluripotent Stem Cells. Zhong C, Wu J, Izpisua Belmonte JC. Methods Mol Biol. 2019;2005:101-124. doi: 10.1007/978-1-4939-9524-0_8. PMID: 31175649

The monopoly

So the rat-mouse chimera technology is at least 11 years old and yet the only ones using it so far are its original developer Nakauchi and Izpisua Belmonte? The latter being the only lab in the world able to create all possible interspecies chimera (“early success with cows, too“), apparently EXCEPT the monkey-pig chimera NIH funded him for? Although, even Nakauchi is sceptical about his colleague’s claims, as quoted by STAT News:

The pig chimera, for example, contained so few human cells that Stanford stem cell researcher Hiromitsu Nakauchi said it seemed “like more a negative result.

So the human-biest chimera technology basically only works in Izpisua Belmonte’s hands (neither he nor Nakauchi replied to me to explain why). Is it because of the patents? Do you have to pay a huge tithe to the Californians if you wish to try interspecies chimera research, even academically? I shouldn’t think so, but what other explanations can we have for such exclusivity? I know, the professor’s genius! Learning the methods is not enough, you as a lab mentee need to be daily basked in the genius radiance of Izpisua Belmonte in order to get the chimera right! Tough assignment, to “science 25 hours a day“, this being the Master’s work ethos.

Or maybe the interspecies chimera research is a dead-end which others abandoned long ago, because the donor cells hardly or not at all integrate, the resulting embryos are inviable and never develop, certainly not anywhere interesting. The only way to get attention there is to do something media-savvy with human-animal chimera, but this is not allowed in USA, and by now probably not even in Spain, catholic or not. But China is open for business, and Cell doesn’t know how to spell “ethics”. And this is what makes Izpisua Belmonte truly a genius, if not of science, then of chutzpah.

There never will be any chimera-derived human organs, simply because there never will be any sufficiently viable foetuses, even if China implants them into thousands of pigs or macaques. That “organ shortage” is just the selling pitch to justify the research in the first place. Research which diverts millions of dollars from other areas and scientists. But yes, I agree, it makes the best headlines ever.

Original image: Salk

The game works. The Salk professor Izpisua Belmonte was even named one of TIME magazine’s50 Most Influential People in Health Care‘ in 2018:

Juan Carlos’ work is at the absolute forefront of an astounding number of biomedical areas with game-changing potential for people’s health,” says Salk President Rusty Gage. “He is very much a scientist and a humanitarian in the mold of all Salk faculty, and we are overjoyed to have his pioneering research acknowledged by a magazine as prominent as TIME.

Well, I don’t know about humanitarian values of Salk faculty, they were sued by their own female professors for sexist discrimination, and their former president Inder Verma was denounced as a sexual harasser. One of Salk’s top scientists, Tony Hunter, published many papers with manipulated data, the institute took zero action but was very angry about my reporting. And Gage’s own mentee Alysson Muotri is trolling the world with braindead minibrain research which would land in the trash if not for Cage’s mighty support. Male networks are what Salk is really about, these are their real humanitarian values.

Fountain of Youth

Thing is, human-pig or human-monkey chimera is not the only thing Izpisua Belmonte made news worldwide in the recent years. In 2015, he proposed to use his patented technology of mitochondrial gene editing (with TALEN) to fix fertilized human oocytes. That was also published in Cell. No conflict of interest was declared.

Pradeep Reddy, Alejandro Ocampo, Keiichiro Suzuki, Josep M. Campistol, Carlos T. Moraes, Juan Carlos Izpisua Belmonte Selective Elimination of Mitochondrial Mutations in the Germline by Genome Editing Cell (2015) DOI: 10.1016/j.cell.2015.03.051

The Californian stem cell researcher and blogger Paul Knoepfler was not convinced the approach made sense:

The idea that a gene editing approach to mitochondrial disease in humans could be superior to the so-called “3-person IVF” or “mitochondrial transfer” approach to mitochondrial disease is kind of provocative. […]

For many families facing mitochondrial disease and wanting to have a genetically related baby, a better and far safer approach is preimplantation genetic diagnosis (PGD), although admittedly that is not an option for 100% of families.

It is also notable that multiple groups and I myself on this blog have called for restrictions on clinical application of gene editing technology in humans.”

But Nature News mentioned:

Nevertheless, Ocampo and Izpisua Belmonte say that they are in the process of acquiring discarded human eggs and embryos from a fertility clinic, and waiting for approval from an ethics board. They plan to develop a line of stem cells from these modified cells, but say that they will not implant embryos into mothers or allow them to grow.

Unsurprisingly, this Izpisua Belmonte technology went nowhere. So the next year he also announced a discovery of an eternal youth, based on induced pluripotent reprogramming (originally discovered by Shinyo Yamanaka) in vivo. To suggest this genetic approach as a therapy for humans is simply irresponsible and bordering on insane. Even if you don’t mind some rich old gits dying of multiple cancers after buying the genetic cure of induced pluripotency (iPS), their families will sue you for billions in damage. But it sounded great as peer reviewed study, as the 2016 press release announced:

The team induced expression of Yamanaka factors in all cells of the organism using their partial reprogramming approach. Several organs improved. For instance, tissue from skin, spleen, kidney and stomach all had improved appearance when inspected under a microscope. The cardiovascular system, which often fails and causes early death in these prematurely aging mice, also showed improvements in structure and function.

Cartoon provided by Salk Institute with the press release

To be fair, those were not normal old mice, but progeria mice, Lamin A/C gene-deficient and very miserable animals who die very young. And this was the paper:

Alejandro Ocampo, Pradeep Reddy, Paloma Martinez-Redondo, Isabel Guillen, Pedro Guillen, Juan Carlos Izpisua Belmonte In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming Cell (2016) doi: 10.1016/j.cell.2016.11.052

The study was co-funded by Fundacion Pedro Guillen, the founding president (who owns a knee surgery clinic in Madrid) and his daughter Isabel Guillen are also listed as authors of the paper. There is however no conflicts of interest statement.

The Guardian was excited and quoted the genius discoverer of the rejuvenation therapy:

““Our study shows that ageing may not have to proceed in one single direction. With careful modulation, ageing might be reversed.” […] “We believe that this approach will not lead to immortality,” said Izpisua Belmonte. “There are probably still limits that we will face in terms of complete reversal of ageing. Our focus is not only extension of lifespan but most importantly health-span.

You would think after the initial press hype in 2016 everyone would have understood the dangerous insanity of using iPS transgene technology in living humans, but nope. In 2019 MIT Technology Review titled: Has this scientist finally found the fountain of youth?

Izpisúa Belmonte cautions that epigenetic tweaks won’t “make you live forever,” but they might delay your expiration date. As he sees it, there is no reason to think we cannot extend human life span by another 30 to 50 years, at least. “I think the kid that will be living to 130 is already with us,” Izpisúa Belmonte says. “He has already been born. I’m convinced.

As it happens, only 4 years later Izpisua-Belmonte published a paper on genetic therapy for knee osteoarthritis. Among its co-authors was the God-impersonator from Harvard, George Church, and again the entire Guillen family (who, you recall, own the clinic for knee surgeries). Among the authors, the patriarch and one of the corresponding authors Pedro Guillen Garcia, now accompanied by his two daughters Isabel and Marta Guillen-Vicente, and also Isabel Guillen-Guillen (daughter from another marriage?) who works as Izpisua Belmonte’s postdoc. The latter even shared the first authorship. All authors, even the knee surgery clinic owners, declare “no conflicts of interest”.

Martinez-Redondo, P., Guillen-Guillen, I., Davidsohn, N. et al. αKLOTHO and sTGFβR2 treatment counteract the osteoarthritic phenotype developed in a rat model. Protein Cell (2020) doi: 10.1007/s13238-019-00685-7

The press release proclaimed:

“”What’s really exciting is that this is potentially a therapy that can be translated to the clinic quite easily,” says Juan Carlos Izpisua Belmonte, lead author and a professor in Salk’s Gene Expression Laboratory. “We are excited to continue refining this promising combination therapy for human use.”

I know a Madrid clinic which might be interested to collaborate! Knee joint rejuvenation is a huge market worldwide, Unity Technology just landed on its face with their senolytics approach against knee osteoarthritis. Izpisua Belmote, like all his coauthors, declared no conflict of interest for this osteoarthritis therapy study, but as it happens his former lab manager Ilir Dubova owns a company, GenuCure, which seeks to treat exactly this disease, and referenced his former boss’ research in the above mentioned MIT Technology Review article. I wonder if this is another financial entanglement, there is no information about that company available online.

Spanish friends

Spain always adored its scientists abroad, and the Salk researcher Izpisua Belmonte is one of the country’s most famous scientists. Over a decade ago, he was lured back home to set up the Barcelona Centre for Regenerative Medicine (CMRB), where only after a few years he had to resign in 2014 as the institute’s head and retreat back to Salk. According to local media:

Izpisúa assumed the direction of the CMRB without renouncing to continue directing his laboratory at the Salk Institute in California. In addition, instead of hiring good researchers for the CMRB to develop their own lines of research and turn Barcelona into one of the European capitals of regenerative medicine, which was the initial objective, he preferred that the researchers from the center work on the lines research that he directed from California. […] the CMRB continued to function, not as a Catalan research center, but as a satellite center of the Izpisúa laboratory at the Salk Institute in California.

After ten years of operation and some 30 million euros of public investment, the results have not met the initial expectations of the center. In these ten years, the European Research Council (or ERC, which invests in research projects based only on criteria of excellence) has not financed a single project. And he has had only one investigator, Icrea (Ángel Raya, who had to leave because Izpisúa would not let him grow as a researcher and who is now returning to the CMRB as director).

Now Izpisua Belmonte may sound as a mean guy here, but he can be very nice.

In 2019, he published a study about a gene editing method which he developed in collaboration with… Carlos Lopez-Otin. That was done soon after Lopez-Otin was slapped with 9 retractions, having been exposed as research forger (read here).

Keiichiro Suzuki, Mako Yamamoto, Reyna Hernandez-Benitez, Zhe Li, Christopher Wei, Rupa Devi Soligalla, Emi Aizawa, Fumiyuki Hatanaka, Masakazu Kurita, Pradeep Reddy, Alejandro Ocampo, Tomoaki Hishida, Masahiro Sakurai, Amy N. Nemeth, Estrella Nuñez Delicado, Josep M. Campistol, Pierre Magistretti, Pedro Guillen, Concepcion Rodriguez Esteban, Jianhui Gong, Yilin Yuan, Ying Gu, Guang-Hui Liu, Carlos López-Otín, Jun Wu, Kun Zhang, and Juan Carlos Izpisua Belmonte Precise in vivo genome editing via single homology arm donor mediated intron-targeting gene integration for genetic disease correction Cell Research (2019) doi: 10.1038/s41422-019-0213-0

Pedro Guillen is on board again, without his daughters this time. As usual, all authors declared to have no conflicts of interests, while both the first and last author hold a joint patent on apparently just this gene editing method, filed already 2017.

It is likely that Izpisua Belmonte helped to save the sinking career of Lopez-Otin in another case. After all, both these Spanish men work on progeria and rejuvenation. Two papers were published back to back in 2019 in Nature Medicine, which is seen as an elite journal. Lopez-Otin’s study Santiago-Fernandez et al 2019 was shoehorned as “Brief Communication”, just as the other one:

Ergin Beyret, Hsin-Kai Liao, Mako Yamamoto, Reyna Hernandez-Benitez, Yunpeng Fu, Galina Erikson, Pradeep Reddy & Juan Carlos Izpisua Belmonte Single-dose CRISPR–Cas9 therapy extends lifespan of mice with Hutchinson–Gilford progeria syndrome Nature Medicine (2019) doi: 10.1038/s41591-019-0343-4

I wonder if Lopez-Otin, who back then just retracted a paper at another Nature family journal for data manipulation, would have gotten that manuscript in if not for his friend at Salk. And look, the association was even celebrated in local media denouncing a sinister terror conspiracy against Lopez-Otin:

Otín has made news again recently, when he published a new scientific article in the journal Nature Medicine, concerning a gene-based therapy for the treatment of the accelerated aging syndrome of Hutchinson-Gilford. The magazine also publishes an article that designs another similar therapy carried out by the team of Juan Carlos Izpisúa-Belmonte, of the Salk“.

Finally, a quote from a perspective paper by Izpisua Belmonte back when he ran the Barcelona institute:

Angel Raya, Juan Carlos Izpisúa Belmonte Stem Cell Research in Spain: If Only They Were Windmills … Cell Stem Cell (2009) doi: 10.1016/j.stem.2009.05.016

“A recent example of the accomplishments of translational research in Spain, particularly relevant for regenerative medicine, was the successful transplantation of a tissue-engineered trachea performed at the Hospital Clinic in Barcelona (Macchiarini et al., 2008).”

I wonder if Izpisua Belmonte and his CMRB successor still admire that Lancet paper by Paolo Macchiarini.


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3 comments on “The Island of Dr Izpisua Belmonte

  1. Pingback: I miei raccomandati – ocasapiens

  2. Lee Rudolph

    Forget it, Jake, it’s Chimeratown.

    Liked by 1 person

  3. NMH, the failed scientist and incel

    Lets see, no one can reproduce your patented work: sounds like someone wants to sell to big pharma and live big (off the wake of pfizered scientists) like David Sinclair. He is such an inspiration to us!

    Like

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