First 3-person IVF baby born via “rogue” experiment at Mexico clinic?

Today we got the first report of a baby being born via so-called “3-person IVF”, sometimes called 3-parent IVF, in which the DNA of three people contribute to an offspring.

Before discussing this further I have to emphasize that we need proof that this is indeed really a 3-person IVF baby via genetic testing. Until that data is released publicly we should all be cautious on this news. Apparently the clinic plans to present such data later.

Assuming it is a 3-person IVF baby, which seems most likely, I discuss the key issues below.

For the 3-person IVF baby, it is hoped to be free of mitochondrial disease (the whole point of doing the procedure), but there are serious risks here. The doctor doing this experiment was John Zhang of New York University and New Hope Fertility Center, but he did it in Mexico.

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John Zhang holds the baby; New Scientist picture

I’m deeply concerned by this news.

The fact that Zhang went to a place where he reportedly himself said, “there are no rules”, to do this illustrates that this 3-person IVF procedure was not given proper regulatory and ethical oversight. It feels more like it was done in secret.

Marcy Darnovsky, Executive Director of The Center for Genetics and Society referred to this kind of thing as “rogue experimentation” in a press release. In a sense she’s right about this, in particular because the world’s experts are really still trying to sort out the core issues surrounding this kind of technology. It is an understatement to say this was jumping the gun. 3-person IVF is not permitted in the US due to safety concerns.

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Interview with Fredrik Lanner who is CRISPR’ing healthy human embryos

In the past year there has been a great deal of attention given to the potential use of CRISPR-Cas9 for gene editing in human embryos. An important recent development, described in a new NPR article by Rob Stein, is the use of CRISPR-Cas9 in healthy human embryos for developmental biology research by assistant professor Fredrik Lanner of The Karolinska Institute. Dr. Lanner, who invited Stein into his lab to observe the work, kindly agreed to do a Q&A interview with me (below) on his team’s use of CRISPR-Cas9 gene editing for research in healthy human embryos.
ssistant Professor Fredrik Lanner

Assistant Professor Fredrik Lanner. Picture by Rob Stein

PK: What got you interested in doing gene editing in healthy human embryos?

FL: I studied mouse preimplantation development during my postdoc in Janet Rossant’s lab and one of the discoveries we made was the importance of fgf-erk signaling in EPI-PE segregation (Yamanaka, Lanner and Rossant Development 2010). A couple of years later two papers showed that the same mechanism is not controlling the same segregation in human embryos. Since then it has become widely appreciated that the mouse probably is not such a great model system for the human and we really need to start studying human embryos to understand human preimplantation development. I therefore moved back to Sweden, Karolinska Institutet to start my own lab with that specific focus. As a first start we have built a transcriptional single cell roadmap of how the first cell types emerge during the first week of human development (Petropoulos et al Cell 2016). We now want to move from descriptive to functional studies. For this we are of course using pharmacological inhibitors for various signaling pathways but to be able to elucidate which transcription factors are important for how the first cell types are established and how pluripotency is controlled we need other approaches. CRISPR is therefore an obvious next step to evaluate.

PK: Did you have to get some kind of official approvals from your own Karolinska Institute? Did you also need some kind of approval from the Swedish government?

FL: We applied for and got ethical permits from the Swedish regional ethics board (EPN.SE) last spring, 2015. We have also lifted these experiments in KI’s internal ethics board, to inform the KI leadership of our plans and to make sure we had their support.

The Swedish law is clear that genome editing is only allowed within the first 14 day as long as the embryo is not transferred back for a continued pregnancy. This means that heritable genome editing for clinical purposes would not be allowed in Sweden. The clear legislation has been key in us moving ahead with these plans.

PK: What is the source of funding for this work?

FL: Towards the functional gene studies I have internal funding from KI and external funding from the Knut and Alice Wallenberg foundation and through Lau fellowship. For our embryo research I also have funding from the Swedish Research Council, Ragnar Söderberg fellowship and the Swedish Strategic Research Foundation.

PK: Did you receive any kind of bioethics training related to CRISPR’ing human embryos or discuss it with a bioethicist before beginning?

FL:  We have discussed it within the KI ethics council consisting of people with legal, ethics and research expertise. I have further presented and discussed at the symposium organized by National Academies of Sciences in Paris http://www.nationalacademies.org/gene-editing, and a Scandinavian meeting organized by The Norwegian Biotechnology Advisory Board. Early October I will discuss this further with The Swedish Gene Technology Advisory Board. We have followed these discussions closely during the last two years.

PK: I realize you declined to say to Rob Stein what gene(s) you are targeting, but can you name them now? My own view is that with gene editing of human embryos that transparency is needed combined with a strong base rationale, which together make for good reasons to be open publicly about the genes being targeted. If you can’t say the genes is it because you’re concerned about competition from other researchers?

FL:  We are targeting genes that we think will be involved in lineage specification and establishing pluripotency. We want to be open but I’m still not ready to disclose exactly which genes we will focus on.

PK: Are you aware of other teams in your own or other countries doing gene editing in healthy human embryos? I’m trying to get a sense of how much of this kind of work is ongoing around the world.

FL:  No I only know of Kathy Niakans’ plans to look at similar questions.

PK: Is one of your ultimate goals to aid in fertility treatments? Would this involve in the future germline gene editing of human embryos then used to make people if all went well? Or would it rather be based on the knowledge you gain, but applied in a non-gene editing approach during reproduction? How are you seeing this play out in the future?

FL:  We are trying to generate fundamental knowledge and we don’t have any ambition to move in that direction. I’m actually pretty skeptical that the technology will be used for genome editing in the early embryo anytime soon. My questions concerns efficiency, safety and competitiveness compared to preimplantation genetic diagnosis. Targeting somatic cells is already leading the development of this technology.

PK: What is the source of the human embryos being used in your research?

FL:  The embryos are from infertility treatments where the couples mostly have gotten their children. In Sweden you can only store the embryos frozen up to 5 years after which they will be destroyed. At that point they can instead donate the embryos to research. These embryos are frozen at embryonic day 2 at which time the embryo consists of 4 cells.

PK: How did you decide to invite a journalist into you lab to observe the work?

FL:  Since NPR has a good reputation I did not hesitate to let Rob Stein come and visit if he could come the date we were planning to perform the experiment and as long as it did not impact on the practical work.  However, it is clear that we can not have reporters in the lab while we perform experiments on a regular basis.

PK: Anything else you feel is important to know?

FL: I would like to emphasize that we have not rushed into this but spent extensive time evaluating targeting strategy in human ES cells. We got the ethical permit during the spring of 2015 after which we have followed and participated in national and international discussions surrounding this technology over a year. This discussion has led to several organizations recommending that the fundamental research in cultured embryos is acceptable and important whereas the clinical translation of the technology with intention to generate a person is not. This in accordance to our Swedish legislation and has encouraged us to initiate these studies to evaluate the feasibility to study gene function in early human embryos using CRISPR-Cas9. I would also like to emphasize that I strongly think these experiments should be performed in genetically normal embryos if we are to learn anything about normal human preimplantation development.

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Cynata approval for 1st ever allo trial of IPSC-derived MSCs for GVHD

cynataCynata Therapeutics Limited has received approval from UK regulators to start a first-of-its-kind allogeneic IPSC-based trial of MSCs for graft versus host disease (GVHD). Cynata also had some big news a couple weeks back with a deal with Fujifilm.

The company is aiming to recruit 16 patients to test whether the MSCs (a type of adult stem cell) made from pluripotent stem cells created in the lab is safe and eventually whether it can aid patients facing GVHD, a potentially life threatening consequence of bone marrow/hematopoietic stem cell transplantation. There are 4 key bullet points the company released on the study:

  • “UK regulatory authority MHRA approves Phase 1 trial with Cymerus(TM) MSCs
  • World first clinical trial with allogeneic iPSC-derived product
  • Major milestone for stem cell therapeutics and regenerative medicine
  • Cements Cynata’s global leadership in second generation MSC therapeutics”

Another allogeneic IPSC study, this one in Japan and led by Masayo Takahashi, appears to be on the cusp of beginning using IPSC-derived retinal pigmented epithelial cells (RPEs) to treat macular degeneration. An earlier related autologous clinical study began with one patient receiving autologous IPSC-derived RPEs, but was halted due to regulatory changes in Japan. Also, IPSC-derived RPEs from a different patient were found to have a few mutations, which I’m still unclear as to whether had any significance.

Takahashi’s team just published a couple important papers on the allogeneic therapy reporting encouraging pre-clinical data in non-human primates where there wasn’t rejection. My sense is that their human clinical study is likely to start early in 2017.

I expect between these trials and other coming new ones we could see a half-dozen or so IPSC-based trials in the works by the end of 2017. Exciting times in the pluripotent stem cell-based clinical translation arena.

One question here with Cynata’s approach that first comes to mind relates to the question or autologous versus allogeneic therapies.

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KPBS piece sheds new light on Jim Gass stem cell case, ties to San Diego firms

KPBS reporter David Wagner has an important new piece out today on for-profit investigational stem cell treatments and he focuses to a large extent on a stem cell business in San Diego called Stemedica. If you’ve heard of this company it might be in part because they were involved in the Gordie Howe stem cells for stroke story that got so much buzz.

At a personal level the KPBS story is about the experience of patient Jim Gass, who received a number of non-FDA approved stem cell treatments outside the U.S. and ultimately ended up with a tumor on his spine. 

To be clear, Gass was not directly treated by Stemedica, but Wagner’s article makes the case that there are two relevant links with the stem cell business: a referral of Gass by a Stemedica director to a doctor in Mexico who did a treatment and the use of an MSC product made by Stemedica in that treatment.

Gass was brave enough to go public with his overall stem cell story a few months back. As part of her New York Times piece on Gass earlier this summer, Gina Kolata just briefly mentioned a possible indirect tie to Stemedica:

“I began doing research on the internet,” Mr. Gass said. He was particularly struck by the tale of the former football star and professional golfer John Brodie who had a stroke, received stem cell therapy in Russia and returned to playing golf again.

So Mr. Gass contacted a company, Stemedica, that had been involved with the clinic, and learned about a program in Kazakhstan. When Mr. Gass balked at going there, the Russian clinic referred him to a clinic in Mexico. That was the start of his odyssey.”

In the new piece on Jim Gass’ experience, Wagner provides additional concrete material on this situation in the form of emails to/from Gass, new information in the written part of the article, and via a startling video interview with Stemedica spokesman Dave McGuigan (below).

Wagner writes about how Gass’ treatment took shape:

“Gass traveled to Hospital Angeles in Tijuana, Mexico with the hope of recovering from a debilitating stroke. He received stem cells from Dr. Cesar Amescua based on a referral from Stemedica Cell Technologies, Inc., a San Diego company known for reportedly helping famous former athletes like hockey legend Gordie Howe make “miraculous” recoveries from strokes.”

What is the evidence for that referral that is mentioned?

The email documentation included with the article indicates that Marcie Frank of Stemedica referred Gass to Amescua (see image of part of the email below) in the form of saying, “Please contact Dr. Cesar Amescua”.

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Screenshot of part of Jim Gass email with Stemedica’s Marcie Frank

There are also Jim Gass’ own recollections of his experiences and his photo/video of being injected.

What happened next?

Gass went forward with the treatment, writes Wagner, which involved two kinds of stem cells:

cesar-anescua-jim-gass

Image from KPBS and Jim Gass

“Gass said he followed Stemedica’s referral and got in touch with Dr. Amescua. He said further down the line, he was told that for $30,000, he could receive a round of treatment involving two different types of stem cells.

The first type, Gass said he was told, would be mesenchymal stem cells. He said he was informed that they would be manufactured by Stemedica, and would be injected into a vein in his arm. Stemedica said its mesenchymal stem cells are derived from adult bone marrow.

Gass said he was told that the other type of stem cell would be fetal in origin, and would be injected directly into his cerebrospinal fluid. These fetal neural stem cells, Gass recalled being told, would be procured from Russia not by Stemedica, but by a different company, Global Stem Cell Health (GSCH).”

It’s not at all clear how Gass developed a spinal tumor nor for sure which of the several stem cell treatments he got around the world over the years might have contributed to the tumor.

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What happens next with FDA & stem cells: lower your expectations?

FDA stem cell meetingIn the total the FDA has held 3 days of public meetings on stem cells in the last few weeks ranging from science to policy and hearing from many parties including patients and even stem cell clinics so the big question now is, “what happens next?”

The FDA has 4 draft guidances pertaining to investigational stem cell clinical procedures and these were the subject of the second meeting that last a couple of days. Soon the FDA’s online commenting period related to these issues will close (you can still make comments here, but don’t expect the comment to appear quickly as I submitted mine 4-5 days ago and it’s still not up).

Once that is done, can we expect the FDA to finalize those guidances? And if it does, will the guidances change at all due to the meetings or online comments on the docket? My sense is that the FDA will take at a minimum months to consider the comments at the meeting and those submitted online so it’ll be 2017 most likely before they are even close to taking a next step at all.

I do not expect the guidances to change substantially. As a stem cell biologist, I didn’t hear anything at the meetings in terms of science or data that provided a compelling rationale to change the guidances. The FDA should base its decisions on the biomedical science.

There were a variety of ideas presented at the meeting for changes or new elements to the stem cell clinical arena including a “middle ground” that would get stem cell therapies to patients more quickly, but the trade-off there is that there would be far less data to support the potential safety and effectiveness of those stem cell products. On the whole this would simply put more patients at risk in my view.

Several speakers mentioned starting a registry for stem cell clinics, but I don’t see that as having a major positive impact as there are too many unknowns and complexities. Who would run the registry and pay for it? Who would oversee it (the FDA?) and what would happen if commercial entities were noncompliant with participating in the registry? What about the already existing clinicaltrials.gov?

A big meme at the FDA meeting was the idea of very widespread functional homology of fat stem cells throughout the body via paracrine signaling. Yes, the heterogeneous cells within “fat stem cell” products do make many growth factors that could act in a paracrine manner, but I don’t buy the idea that this makes them homologous to many diverse tissues in the body and I don’t expect the FDA will either.

The future

The FDA could never finalize the guidances, resulting in either the status quo continuing of thorough oversight of the good citizens of the field and little-to-no action on the stem cell clinics. Or even without finalizing the guidances, the FDA could step up its oversight of stem cell clinics, which would be helpful given that there are around 600 of them in the U.S. operating without FDA approval and the FDA has been issuing <=1 warning letter per year lately.

If the guidances remain (finalized or not) and are the basis for the FDA’s current thinking moving forward, then most adipose stem cell clinics should be subject to FDA action given that they are using more than minimally manipulated cells and hence drugs in an unapproved manner and they are almost always using the cells in a non-homologous manner.

Perhaps in the short run the most likely thing is that nothing will happen. As my state’s governor Jerry Brown once famously said to voters, “lower your expectations” and perhaps that can be applied to the FDA on stem cells. However, I’m not going to do it. I’m going to keep my expectations high on this.