‘We don’t want to freak people out’: about that Jacob Hanna human embryo model startup

Stem cell biologist Jacob Hanna has a new startup called Renewal Bio.

Its goal is to harvest cells or tissues from human embryo or fetus models for clinical use.

I believe that their commercial ambitions have so far outstripped careful thought and discussion in the broader community of researchers. There are major risks here for the stem cell field as a whole as the company pushes forward.

Jacob Hanna firm Renewal Bio

The startup plans to generate tiny embryo-like versions of people, called embryo models, using the same people’s stem cells. Then Renewal Bio would collect specific cells or mini-organs from the lab-grown models. If all goes well, the same people could get the embryo model material as a therapy. It would be an autologous transplant.

Two relatively new core technologies come together here to potentially make this possible. Extended growth of mouse embryos in the lab and the relatively new methodologies to make realistic mouse and human embryo models from stem cells.

If you bring these methods together with human pluripotent stem cells instead of mouse cells then you might, in theory, be able to make older models of human embryos grown for extended periods in the lab. It would likely require some tricky human-specific customization of the long-term in vitro mouse embryo growth protocol. It might not be workable.

But if it does work, this planned effort by Renewal Bio has some novel clinical potential. At the same time, it raises daunting ethical complexities and risks.

There are also existing powerful alternatives that aren’t so controversial and ethically dicey.

Note that Hanna’s group is not the only one working on stem cell-based mouse embryo models. In fact, Magdalena Zernicka-Goetz was a much earlier pioneer in this field. Her team has two new important preprints showing advances with embryo model methods in this area: here and here.

Also, see this 2017 post I did on her early work with mouse embryo models.

Human embryo models

Before we go much further, what exactly are synthetic human embryos or embryo models?

They are embryo-like structures made from human pluripotent stem cells. Under the right growth conditions, these stem cells will start spontaneously forming embryo-like structures. It’s fascinating.

The general goal in the field of making embryo models, sometimes called blastoids or iblastoids, has been to gain a better understanding of human development and disease. So far such models have been grown for only days or at most about two weeks or a little more.

I support that kind of short-term human embryo modeling research if it’s done in a careful, thoughtful way with a good rationale and ethics approval. It could teach us a great deal about early human development and what can go wrong related to human disease.

Embryo modeling technology has been rapidly advancing such that in some ways the models have striking similarities to the real thing, meaning actual human embryos.

At a basic level, the goal for Renewal Bio is very different than the human embryo modeling research that has already been reported. First, the firm wants to grow the embryo models far longer than anyone before. Also, they seem to have less interest in studying the models per se.

They’d be growing the models as production units in a sense in order to take their mini-organs, tissues, or cells as clinical tools.

Not Mini-Me medicine?

The fact that each embryo model would be genetically identical to the person who donated the cells that were made into stem cells (iPS cells) to start the process would be helpful. The materials would be unlikely to be rejected after transplantation.

Antonio Regalado at MIT Tech Review, digs into Renewal Bio in a new article and covers some of its anticipated areas of controversy. I recommend reading his article.

At one point Antonio refers to the Hanna/Renewal Bio effort with the term “Mini-Me”, which Hanna disputes in a quote.

But I think the mini-me term fits to some extent because of the matched genetic identity of the donor and the embryo model. This would be a cell/tissue cloning effort. In addition, oddly one of the first types of “cloned” embryo models the company will make is reportedly from Hanna himself:

“In a next set of experiments, Hanna is using his own blood or skin cells (and those of a few other volunteers) as the starting point for making synthetic human embryos. It means his lab could soon be swimming in hundreds or thousands of tiny mini-mes—all genetic clones of himself.”

Doesn’t that seem like something out of a Bond or Austin Powers movie?

Existing alternatives such as iPS cell-derived cells/tissues

There are quite a few potential issues with Renewal Bio and its plans.

For instance, in thinking about making regenerative therapies from stem cells, is the proposed embryo model phase even necessary? We can already readily differentiate iPS cells or ES cells into specialized cells and tissues in a lab in a dish for subsequent clinical use.

This can be done in various ways with the goal to make many kinds of cells and tissues. As just one example, researchers can differentiate human pluripotent cells into human neural cells. Those cells could then be used as a therapy. Such stem cell-derived brain cells could be precursors or neurons, glia, or oligodendrocytes.

Lung, kidney, muscle, eye, and other kinds of cells and tissues are regularly made. This kind of approach is already going on all around the world in pre-clinical and clinical research. Think of the pluripotent stem cell-based macular degeneration work including in Japan where retinal cells and cellular sheets made of them have been generated from iPS cells for clinical trials. There are loads of similar examples of tissue engineering using various kinds of stem cells, including adult stem cells.

Some of the products like organoids are 3D tissues or mini-organs too.

None of these require making anything like the new generation of human embryo or fetus models.

The possible clinical potential here

In that context, how could Renewal Bio’s approach be better than these current approaches, some already in clinical trials?

The rationale here seems to be that growing tissues in the more native context of a human embryo model might yield far better results.

For example, the cells and tissues from embryo models might be more fully differentiated and hence more functional than differentiated cells made from iPS cells more traditionally in a lab dish, flask, or bioreactor. Entire mini organs might someday be transplantable as well from later stage models.

There is real potential here for new therapies.

Human fetus models?

But there are complexities here too.

The planned extended culturing is central to much of what Renewal Bio wants to achieve. This is where the Mini-Me push is most likely to lead to a mega mess.

From Antonio’s piece, Hanna is going to build on mouse embryo work to grow up human models mimicking 6-7-week human embryos or even later-stage embryos.

There are currently no limits on the length of the growth period for human embryo models:

“Hanna tells MIT Technology Review he is already working to replicate the technology starting with human cells and hopes to eventually produce artificial models of human embryos that are the equivalent of a 40- to 50-day-old pregnancy. At that stage basic organs are formed, as well as tiny limbs and fingers.”

That’s a very long time to grow human embryo-like structures in a lab.

At some point, it’s probably going to be more accurate to call them human fetus models, which sounds a lot more controversial. Note that at roughly eight weeks of normal gestation, human embryos generally are considered fetuses instead.

Big risks, need for transparency

Things get much riskier on that path of long-term embryo/fetus model growth.

If the firm is successful in producing the long-term-grown human embryo/fetal models and they are transparent about it, then pictures of their models will likely get into the public domain from research articles or press on the firm. That could stir major controversy and negative outcomes for the firm and the broader stem cell field.

Just the possibility of such negative press might make Renewal Bio highly secretive about its work.   From Antonio’s article, we already see possible hints of a lack of transparency and it’s clear the leaders are worried about likely negative reactions (emphasis mine):

“Renewal Bio’s precise technical plan remains under wraps, and the company’s website is just a calling card. “It’s very low on details for a reason. We don’t want to overpromise, and we don’t want to freak people out,” says Omri Amirav-Drory, a partner at NFX who is acting as CEO of the new company. “The imagery is sensitive here.”

So they may never release or publish work containing images of the long-term grown human embryo/fetus models. That possible lack of transparency would be a major problem of its own.

How can anybody outside Renewal Bio know what’s actually going on?

Past issues with many of Jacob Hanna’s research articles raise the need for a high level of transparency here.

Ethically thorny questions

Beyond the practical issues and risks, is making lab-grown human fetus models even ethically permissible? I don’t know.

What do you think?

Also, the answer for some people could depend on whether the fetus models are just studied or are used for tissue harvesting.

I asked Stanford Law Professor Hank Greely for his thoughts on Renewal Bio and here’s what he said:

“Jacob Hanna is certainly not timid.  His work on mouse embryo models (similar to that published three days later by Magdalena Zernicka-Goetz) is fascinating, groundbreaking, and (“just says in mice”). But he is quickly jumping into the idea of commercializing human embryo models similarly derived, possibly as sources for human cells, tissues, and organs for transplanting into living people. He seems to want these embryo models to straddle a line between “definitely not human embryos” and “human enough to be organ donors”.  The good news is that the technical steps between an 8 1/2 day mouse embryo and a 6 week human embryo are vast and may not be surmountable. We have time to think through the ethical issues. But Hanna’s work, and his ambitions, are good reasons for us for us to start thinking about them, now!”

Where I tend to disagree with Hank is on the amount of time we likely have to discuss all of this.

Possible negative public reaction, rogue actors

I can see the potential here with Renewal Bio-type efforts for helping patients with illnesses such as diabetes, but on the other hand pluripotent stem cell-based work using no embryo models at all is already in clinical trials for diabetes.

Infertility has also come up as a possible target condition for Renewal Bio, but here again, other work trying to produce germ cells is looking promising.

Much of the reaction to Renewal Bio is likely going to depend on whom you ask.

The firm is an Israeli company and you might get one set of views there and possibly a different one in the US or elsewhere.

Notably, the company only mentions the U.S. on its website, suggesting the U.S. could be the main target market. I can see how a large part of the U.S. could be strongly opposed to this whole thing. The efforts could lead to broader restrictions on stem cell research that are harmful.

Another worry is that someone may go rogue building off of these technologies.

They may go ahead to make and implant human embryo/fetus models (using Renewal Bio’s methods) into surrogate mothers in an attempt at human cloning or with some other misguided goal.

Do you think no one would ever do that?

Some of us predicted starting back in 2015-20216 that CRISPR babies would be made, and a few years later along came He Jiankui. See my late 2015 TED talk below.

Can Renewal Bio do it?

A major, more practical question is whether Renewal Bio can even successfully grow largely normal human embryo models for 7 weeks or longer any time soon.

I kind of hope they can’t.

However, even the failures along the way might be problematic. Again from the MIT Tech Review article:

“Even so, techniques for growing synthetic embryos remain inefficient. Fewer than 1 in 100 attempts to mimic a mouse embryo was successful, and even the model embryos that developed for the longest time eventually suffered abnormalities, including heart problems, perhaps because they couldn’t grow any further without a proper blood supply.”

If anything, the human models are likely to be even more difficult to make than the mouse ones. This could lead to hundreds of “unsuccessful” human embryo/fetus models. Would those remain hidden?

Looking ahead

With all of this in mind, overall, where should we go from here?

I believe it’s too early for tissue harvesting-focused commercialization of human embryo/fetus modeling in the lab. I’m not sure I’d ever be okay with that. Other folks would likely be enthusiastic about it.

What we really need is more open dialogue before commercialization rushes ahead. It may be that Renewal Bio is just trying to stake a claim to a future lucrative position and IP in this space, but they’re not going to get much successfully done any time soon. I wouldn’t count on that though.

Transparency will also be crucial. Can we count on Renewal Bio to be totally transparent about their efforts and results? Even with uncomfortable imagery?