Human-Animal Hybrids Find Their Place in Medicine

IRA FLATOW: This is Science Friday. I’m Ira Flatow. Human stem cell research is often in the crosshairs of Washington politics. It’s characterized by its detractors as monstrous and unethical or considered too polarizing to deal with. But two groundbreaking studies published this last week highlighted the promise and importance of stem cell research to human medicine. At Stanford University, scientists were able to grow a mouse pancreas inside of a rat, creating sort of a rat-mouse hybrid known in mythology as chimera.

The researchers were able to show for the first time ever that human cells could live inside a pig embryo. Sounds like science fiction, right? But it is not some Frankenstein’s monster. There’s a surprising real-world application here, to grow replacement organs in animals, organs to give to transplant patients who need them.

Joining me now to discuss this are my next two guests. Qiao Zhou is associate professor in the Department of Stem Cell and Regenerative Biology at Harvard, and Jun Wu is staff scientist at the Salk Institute for Biological Studies. Doctor Wu, Dr. Zhou, welcome to Science Friday.

QIAO ZHOU: Hello.

JUN WU: My pleasure.

QIAO ZHOU: Thank you.

IRA FLATOW: Thank you. Dr. Wu, when someone hears that researchers are creating chimeras in the lab, it sounds like science fiction. Explain to me why researchers are doing this work.

JUN WU: So the ultimate goal and the motivation behind this research is that there is a worldwide shortage of organ donors. And in United States alone, there is over 100,000 people on the waiting list for available donor organs. We scientists, especially stem cell scientists, are trying to use a very unique cell type called pluripotent stem cells that has the potential to generate all the cells in our body.

And in theory, it can also generate three-dimensional tissues and organs. But that potential hasn’t been realized in a culture dish, which we normally culture the cells. And we thought that the animals and humans are generating organs and tissues every day in a very precise manner. For example, a mouse, from one single cell to a born organism, it takes only 19 days.

And cells know exactly where to go and what to become in the specific organs or tissues. So we’re thinking, why not use the animal, a developing animal, to guide the human stem cells to generate the specific tissues and organs that we can use in the future for transplants.

IRA FLATOW: So you were able to get human cells to grow inside of a pig and a pig embryo at that point. How far did you let it go to development?

JUN WU: So in the current study, we stopped the experiment between three weeks to four weeks into pig’s gestation, which is about 1/3 of the entire gestation of the pig, around 112 or 114 days. So during this period of time, we think it’s enough to gather some information to know which type of human pluripotent stem cell can survive and contribute to early developing pig embryos so that they can become early progenitors that later on can generate the organs and tissues.

IRA FLATOW: Do you know how to direct the stem cells yet to generate the organ and tissues that you want?

JUN WU: Not with the human pig study at this stage. But with the rat and mice study, also included in this paper, we demonstrated that with the strategy that originally developed in 2010 by Hiro Nakauchi’s group, which we call it interspecies process [INAUDIBLE] which we can disable a particular organ or tissue development in a host animal, for example a mouse, so the mouse doesn’t generate the pancreas or heart, et cetera. And we can use the rat’s stem cells to populate that niche, basically can enrich the rat stem cell unit-specific organs so that we can have more or less the rat-cell enriched organs for transplantation.

IRA FLATOW: And Dr. Zhou–

JUN WU: But with a human we have–

IRA FLATOW: I’m sorry, go ahead.

JUN WU: But with a human, this is our very first study. We just want to know whether human cells can survive in there. And for the next step, we’d like to use the same strategy to disable the development of a particular organ in the pig so that we can see whether human cells can be enriched in that organ.

IRA FLATOW: Dr. Zhou, following up on Dr. Wu’s talking about the mouse-rat study, you wrote a companion piece in Nature about that study. What is the important part of that study, were they– just to repeat– that they were able to get mouse cells to grow inside the rat.

QIAO ZHOU: Yes indeed, so I wrote a commentary about the article published in Nature from Dr. Nakauchi’s lab at Stanford and also in Japan. So that study basically demonstrated you can grow a mouse pancreas inside a rat. And now you can subsequently harvest the mouse pancreas that is growing in the rat and isolate the pancreatic islets that contains insulin-secreting cells.

You can isolate that part of the pancreas, now transplant into a diabetic mouse and be able to cure the diabetes of the mouse. So I think this is a very interesting demonstration of how this interspecies organ growth can be used to treat disease.

IRA FLATOW: Were those pancreatic cells actually tested out in a diabetic mouse? Were they transplanted?

QIAO ZHOU: Exactly, I think that’s the main breakthrough, I would say a major step forward, because the same research group from Stanford and Japan, Nakauchi’s group, have demonstrated some years ago that you can generate an interspecies pancreas between these two different rodent species, but they didn’t do the transplantation in diabetes rats [INAUDIBLE]. So in this particular study, they now demonstrated that this is feasible.

IRA FLATOW: Diabetes, if I’m correct, is an autoimmune disease, which means the body attacks itself, right? I mean, how do you– even if you get new islets from the pancreas, how do you stop the process of the body, again, attacking those new cells?

QIAO ZHOU: Right, so this particular form of diabetes that the authors have treated the mouse model of diabetes is Type 1 diabetes. This is autoimmune disease. But Type 1 diabetes represent only a relatively minor subpopulation of the total diabetes patient population out there. So the majority of people diabetic patients are so-called Type 2 diabetes. And Type 2 diabetes is not an autoimmune attack.

But coming back to your question, now, in Type 1 diabetes patients, now we have new– let’s see if we can get new beta cells. But if you transplant the new beta cells into this autoimmune environment, these new beta cells will again be subjected to autoimmune attack. So people have to figure out ways how to protect them, for example using immunosuppressive drugs that’s currently used clinically to do this.

IRA FLATOW: So have they done that, successfully protected the cells?

QIAO ZHOU: They have, in fact. Yes, in fact for many years, for decades, pancreatic insulin-secreting beta cells and islets have been harvested from deceased donors and transplanted to people that are suffering from Type 1 diabetes. And then using immunosuppressants, these transplant recipients have been able to basically lead a pretty normal life for decades, years and decades. So it works. That we know.

But there are basically very little source of these transplantable islets available. So now the idea is, how can we get these islets? Perhaps through interspecies organ production, as Dr. Wu has just talked about.

IRA FLATOW: Dr. Wu, how far can you go now? How further along can you allow the embryo to try to develop further and actually create a human body part?

JUN WU: This is the very first step toward that goal and toward the dream to generate the human organs inside the pig. And in this study, we stopped very early due to several reasons. One of them is that in California, our protocol only allow us to go to no more than four weeks into the pig gestation.

And in Spain, we also have approval to actually go right before birth. But we choose not to. The reason why is at the very early stages, we can study how the human cells migrate or integrate and what type of tissues they can contribute so that we can develop a better strategy and an even safer strategy for the organ production in the future.

As you’re probably aware, there are some ethical concerns related to this topic. And one of the tissues we don’t want human cells to contribute, for example, is a brain and germ line tissue. And by studying these very early stages, we can develop strategies to prevent the human cells from going to the brain, from going to the germ line, and specifically guide them into a particular tissues and organs they want them to be.

IRA FLATOW: Yeah, well, what would be a first choice in the kind of tissue and organ you’d like to produce first? What would be the best candidate? I imagine the most simple one would be–

JUN WU: I think the pancreas is a good candidate. The reason for that is we don’t necessarily need a whole organ. We can isolate the beta cells and islets. And even if we can’t isolate those cells at the fetal stage, they probably perform better than adult cell type. So I would go for the pancreas as a first proof of concept.

IRA FLATOW: And you say you’re going to probably go, because of ethical considerations in this country and limits on research, you’ll probably work further in Spain on this?

JUN WU: After we gather more information. And at this stage of this study, seeing the contribution of the human cell is still too low, lower than we expected. The next step would be to develop a strategy to enhance the human cells a better percentage in terms of chimerism in the developing pig embryos, but at the same time control the human cells not to go to tissues that we don’t want to be.

IRA FLATOW: How do you do that? How do you prevent it from turning into brain tissue?

JUN WU: So there are several strategies. You can do this by genetically or epigenetically. For example, you can disable the master regulator for the brain development in the donor human cells. You can take out the gene. You can activate a particular gene so the human cells don’t have the ability to go to the brain.

The other strategy is to implement what we call a safety switch. Basically if the human cells contribute to the brain development, then the brain cells from the human donor cell will self-destruct, will not go further. And most recently, in our lab, we are developing a strategy that we can epigenetically basically change the denaturation status of some of the brain master regulators so that the donor human cells doesn’t have the ability to develop into the brain tissue.

IRA FLATOW: Let me ask Dr. Wu, what can your work or the work that you’re reporting about in the journal, commenting about, what can that contribute to what Dr. Wu is doing with the pigs and the human development.

QIAO ZHOU: So I think there is some important information we can get from these type of studies. For example, what Dr. Wu is doing at the Salk Institute is, as he mentioned, is actually, in fact, subject to quite a bit of constraints because of the ethical and potentially legal concerns. So these type of studies also can not use federal funding. You have to get resources to carry out this type of research, whereas in animal studies, I think you can ask different types of questions, more in-depth questions.

For example, one thing that has come up from generating Dr. Wu’s work, basically trying to make the human cells contribute to pig embryos, what has been observed and reported is that the contribution is relatively poor. That is, there is some type of unknown species barriers that prevents the human cells to contribute robustly to the pig embryos.

The same type of species barriers can also be seen between rat and mouse. So if we understand these species barriers and be able to identify them, study them, we might be able to, for example, lower these species barriers so that the human cells can better contribute to an animal embryo as a step towards the eventual goal of getting transplantable human organs.

IRA FLATOW: I’m Ira Flatow. This is Science Friday from PRI, Public Radio International. Talking with Jun Wu, staff scientist at the Salk Institute, and also talking to Qiao Zhou, associate professor in the Department of Stem Cell and Regenerative Biology at Harvard. How does the atmosphere, the sense of research and science in America these days, affect the research going forward? Are either of you concerned about whether funds for this type of research will be cut off in the new administration?

JUN WU: So for this study, we didn’t use any funds from the federal government. All the funding are provided by private source. And we’re hopeful that our published work can help the policymakers to evaluate whether this is a valuable research direction to go forward. And I think it’s important to come up with a step-by- approach and to evaluate the ethical, technical, and scientific challenges that we need to overcome before we go further.

I’m hopeful that after our published results that provides some new information regarding how the interspecies chimeric formation using the human cells, how low the contribution is. And at this stage, I believe that the ethical concern is not a big issue. But if we go forward, this type of research will for sure generate some of the concerns. But we can stop, and we can develop the strategy to prevent that from happening at this stage.

IRA FLATOW: Well, it all sounds very exciting, very interesting. This must be a fertile ground for research. And we always hear of new things happening in this kind of work. So I want to thank both of you and wish you good luck. And please, don’t be afraid to come back and tell us when you have something new to report.

QIAO ZHOU: Thank you.

JUN WU: Thank you. It’s my pleasure.

IRA FLATOW: You’re welcome. Qiao Zhou is associate professor in the Department of Stem Cell and Regenerative Biology at Harvard University, and Jun Wu is staff scientist at the famous Salk Institute for Biological Studies.

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