WASHINGTON — Two weeks ago, Will Burlingham, a professor of transplantation at the University of Wisconsin School of Medicine and Public Health, got a surprise call from the National Institutes of Health: Would he like a little extra money to create more laboratory mice?

“It’s like Santa came early,” Burlingham told STAT. “We’ve been advised that we need to gear up and hire people.”

These aren’t just run-of-the-mill rodents. Burlingham’s mice are part-animal, part-person, implanted with a human-like immune system derived from tissue leftover when newborns undergo heart surgery. And the NIH is taking an interest in these mice because scientists might, in some cases, be able to use them instead of a more politically controversial research tool — mice implanted with fetal tissue that comes from abortions.

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But mice made with similar techniques simply aren’t as useful, scientifically, as their counterparts created with fetal tissue. They tend to die more quickly, and the human-like immune systems the scientists want to study are less complete.

Burlingham’s mice in particular are still highly experimental, too — he and his colleagues haven’t yet run tests to compare how the mice compare to their cousins made using fetal tissue. Their research was only just published, in April.

The same is true for other alternatives to fetal tissue: There are no alternatives that can, today, serve all the same purposes as the controversial technology.

“The consensus is that there are certain things about fetal tissue that make [it] unique,” said Paul Knoepfler, a professor at the University of California, Davis, School of Medicine. “Certain experiments can really only be done on actual fetal tissue.”

But as the NIH’s call to Burlingham shows, the agency is upping its efforts to find alternatives to fetal tissue, though a top agency official told STAT that some research projects might always require fetal tissue. The Trump administration announced last week that it intends to devote as much as $20 million to research into alternatives to fetal tissue, the latest step in an ongoing Trump administration audit of the way federally funded research uses fetal tissue. (It declined to comment on conversations with Burlingham.)

At an NIH meeting Thursday, Director Francis Collins said that research into alternatives is “scientifically, highly justified,” but also defended the value of fetal tissue research, saying, “There is strong evidence that scientific benefits can come from fetal tissue research, which can be done with an ethical framework.”

As part of the Trump administration audit, NIH in September froze the acquisition of new fetal tissue purchases. That has already upset research at an HIV lab in Montana and may soon hamper work in groups studying cancer and eye disease. Spokespeople for the Department of Health and Human Services, and the NIH, said that the audit was not intended to interrupt current research (but that has been the result) and that the NIH is working to get the labs the tissue they need.

The research is controversial because fetal tissue comes from abortions. For years, Republicans have argued that the organizations that collect this tissue and sell it to researchers are profiting off the enterprise, which is against federal law and which the organizations themselves dispute.

In some ways, alternatives have distinct advantages, scientists said. Some are easier or cheaper to manufacture. They are less politically controversial — in some states, it is illegal to do any research on fetal tissue, and using other kinds of tissue can make it easier for scientists to collaborate. Researchers have been working on developing tools that do not depend on fetal tissue for decades.

Below, STAT looks at several looming questions for the future of fetal tissue research — why it matters, what alternatives are out there, and which research areas will be hit hardest by the Trump administration’s changes.

Why do scientists use fetal tissue?

Some scientists use the tissue as an ingredient to build human-like models to test drugs and study diseases. Others do research on the tissue itself to learn more about the fetus. The work applies to a wide variety of diseases, from cancer to HIV to Zika to eye disorders.

“There’s a wide variety of human diseases that either are traceable to developmental problems, or we can learn more about them using fetal tissue,” Knoepfler said.

It’s difficult to quantify the number of scientists who are using fetal tissue in their research. Multiple scientists told STAT that their colleagues who use fetal tissue in their research would be loathe to discuss it because of the political controversy. And the oft-cited number of $103 million — the NIH’s estimate of how much research it funds that has anything to do with fetal tissue this year — isn’t a great estimate, since it includes money spent parts of the research project that don’t use fetal tissue.

Can an alternative deliver the same kind of science?

The feasibility of alternatives depends on what exactly the researchers are trying to do. Finding an alternative to mice created with fetal tissue is probably going to be easier than finding an alternative to using fetal tissue to study fetal tissue, said Carrie Wolinetz, associate director for science policy and acting chief of staff at the NIH.

“If you are studying human fetal development, or diseases specific to fetal development — Zika is a very good example of that  — there might not be ultimately an alternative that would really substitute,” Wolinetz said. If a woman is infected with ZIka virus while she is pregnant, the fetus can develop microcephaly, a disease that shrinks their brains.

She added, “Again, science is amazing and it goes in all sorts of directions, so you never say never, but this is an example where it’s sort of harder conceptually to imagine an alternative.”

What kinds of alternatives are out there?

In an announcement last week, the NIH put forward three general categories of alternatives — stem cells, organoids, and different kinds of humanized mice — while also keeping the door open for other scientific ideas.

Those are broad categories, and exactly how well each would work as an alternative — or how feasible the technology is — varies. Stem cells are a more fundamental technology than the other two in that list — more like a building block for future alternatives to fetal tissue. They could be used to create tissue samples that would remove the need to use actual tissue from a fetus.

Many scientists are already using other humanized mice and organoids to test drugs and study diseases. Some scientists gave brain organoids cancer; and others manufactured mini-hearts that can beat like the real ones.

Humanized mice

Burlingham isn’t the only researcher who’s found a way to create mice with a human-like immune system without using fetal tissue.

Scientists start by genetically engineering a mouse that does not have an immune system. Then they grow something that resembles a human immune system inside of that mouse — this time using stem cells or other tissue, rather than fetal tissue. All those mice will allow the scientists to study how certain disease affect the human immune system, like HIV, without experimenting on humans.

But mice created with fetal tissue tend to live longer, and their immune systems are more complete, which make them better, in certain cases, for studying the long-term effects of a drug or the progression of a disease.

It’s also difficult to actually make those mice, said Jerome Zack, a professor in the David Geffen School of Medicine at the University of California, Los Angeles, who recently founded a company based on technology that comes from humanized mice. Scientists need to do individual surgeries on the mice to insert the human immune system. And they need special facilities to house the animals.

Organoids

Another alternative the NIH put forth are “organoids,” which are little blobs of cells that resemble human organs. In order to make them, scientists take stem cells, or similar cells, and grow them in a dish so that they all develop into cells of the same organ. That means that the cellular blob mimics some of the organ’s properties.

Organoids, however, are also imperfect for researchers who are using fetal tissue. They aren’t miniature versions of the organ — a stomach organoid wouldn’t digest food, for example. They don’t have the same network of veins and arteries to deliver blood. And they don’t have the same physical structure as the real organs.

That all makes it hard to study a disease that affects the entire organ, Knoepfler said. There might be ways around the differences, such as building in blood vessels, he said, but “that’s still sort of in its infancy.”

Take microcephaly, he suggested. Using actual organs is pivotal to understanding the condition.

“The actual fetal brain is going to have features that are just not going to be present in an organoid,” Knoepfler said. “Like, in an organoid study, you might have predominantly the front part of the brain, but microcephaly affects the whole brain.”

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  • StatNews article

    Thank you Mr. Swetlitz for a good summary of the issues we researchers face when trying to work with fetal/developing tissue, and thank you StatNews for providing a forum for discussion.

    This article provides a great opportunity for us to get at what I believe are the central ethical questions for anyone conducting, authorizing, or protesting developmental biological research: When does a fetus or newborn become human and when is it ethically mandated to stop experimenting with human tissue?

    I believe the answer resides with the answer to the question of when does a human fetus/newborn become conscious?

    There is a significant amount of evidence to suggest a developing human does not become conscious until shortly before, or perhaps even shortly after birth, and I’ll be happy to state that evidence very soon, but I wanted to throw this out to your readers so we can discuss this. Do you agree at the moment or disagree? What evidence can we add that furthers the discussion? Thanks so much for your consideration, as I plan to develop organs for transplantation (which is still ~20 years down the road), but I believe it’s important to have these discussions now as I’d like to sway public opinions on these important questions. Thank you for your consideration.

    Sincerely,

    Robert Smith
    Virginia, USA

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