The Mouse and the Rat

The Organ Factory

The Mouse and the Rat
Science, technology, and life.
July 29 2005 5:19 PM

The Organ Factory


Mice are for babies...
Click image to expand.
Mice are for babies...

This is the conclusion of a five-part series. To read the first part, click here. To read the second, click here. For the third, click here. For the fourth, click here.

William Saletan William Saletan


Three days ago, we looked at a study in which Japanese scientists extracted rat embryos from wombs, cultured them in lab dishes, and used them as hosts to grow transplantable kidney tissue from human stem cells. The scientists called this an "in vitro organ factory" based on "whole-embryo culture."


Yesterday I talked to Dr. Helen Liu, a researcher at Cornell University's Center for Reproductive Medicine and Infertility. She has grown womb tissue in the lab, put mouse embryos on it, and watched them implant and develop. After a week, she moved some of them to the abdominal cavities of adult mice. At 17 days—four days shy of full term—she took them all out. The embryos in vitro had died, but not before developing functional hearts. The embryos in vivo, which had spent nearly half their gestation in vitro—and none of it in a womb—seemed small but otherwise normal. They looked, says Dr. Liu, like "a well-formed, healthy mouse with eyes, with legs, with a tail."

The purposes of the two experiments couldn't have been more different. Dr. Liu helps women with fertility problems. She's trying to grow babies, not organs. But her methods fit the rat study like a key in a lock. The rat embryos had to be grown halfway to term in the womb, and they died soon after being removed. The mouse embryos grew to the same stage—and in many cases beyond it—outside the womb. Put the two technologies together, and you could grow organs in embryos without ever implanting them in a womb.

The rat study shredded the distinction between in vivo and in vitro. The human cells were inside an organ inside an embryo inside a dish. But the mouse study added a third, crucial in vivo layer: a blanket of womb tissue (endometrium) between the embryo and the dish. That's why Dr. Liu's mouse embryos, unlike mouse embryos in previous experiments, kept growing. Other researchers "only culture them in vitro, without any of the endometrium," she says. "Mine is with engineered endometrium tissue. This tissue is sort of like in vivo. … The embryo and the endometrium must interact with each other, and the endometrium must produce a lot of factors to support embryo growth."

Rats are for organs.
Click image to expand.
Rats are for organs

Why did she engineer the womb tissue? Because medicine demanded it. Some infertility patients have physical difficulty with implantation or pregnancy. If the embryo won't come to the womb, maybe the womb can come to the embryo.

But soon medicine may demand something else. The science we examined Monday and Tuesday suggests that to save patients suffering from some diseases, we might need to grow transplantable tissues in embryos. The ethics we studied Wednesday and Thursday indicate that we could grow embryos for several weeks based on many of the same principles—organization, neural development, utility—that already justify research up to 14 days. But we left out one principle and one problem: implantation.

Ethics committees have generally forbidden implantation of embryos used in research. They've done this to draw a bright line between embryos for procreation and embryos for research. The line assured us that research embryos weren't really potential people, since they lacked the womb necessary for development. It also spared us the trouble of figuring out how many days or weeks we should let them grow. As Canada's national ethics report put it 11 years ago, "Researchers have not to date been able to keep human zygotes developing normally in vitro beyond 7 days, so there is no realistic possibility, for the foreseeable future, of experimenting on zygotes that have reached the stage of individuation."

Well, now there's a realistic possibility. Dr. Liu says she has grown human embryos to 10 days in artificial wombs, and the only reason she stopped at that point was to comply with the 14-day rule. That was four years ago, before she grew mice nearly to term. The technology is always improving, and as we saw yesterday, it's easy to relax the 14-day rule. We gained some control of the implantation line three decades ago when we invented in vitro fertilization. Now we can push the line forward, and maybe get rid of it.

You could argue that implantation in a dish is still implantation. But it shatters our moral understanding of the word. Two months ago, when the House passed legislation to expand funding of embryonic stem cell research, Rep. Dana Rohrabacher, R-Calif., explained, "Those leftover eggs will have no potential ever of becoming a human being unless they are implanted in a woman's body." Sen. Orrin Hatch, R-Utah, declared, "I do not believe that life begins in a Petri dish." Really? Were the mice with beating hearts in Dr. Liu's lab not alive? How about the human embryos? Are they fair game for research—not Dr. Liu's kind, but the kind we saw in the rat study—until they're transferred to a woman's body? How many weeks of in-vivo-in-vitro tissue differentiation will that buy us?

Our legal system is completely unprepared for this. Massachusetts used to define an "unborn child" as "the individual human life in existence and developing from fertilization until birth." This year, as part of a stem-cell research bill, it changed that definition to "the individual human life in existence and developing from implantation of the embryo in the uterus until birth." New Hampshire law says, "No preembryo that has been donated for use in research shall be transferred to a uterine cavity." But what if there's no cavity? What if there's no transfer? What if the embryo never implants "in the uterus"?

Ethics reports are blind, too. The latest one, issued last year by President Bush's bioethics council, calls for a ban on 1) "the transfer of a human embryo (produced ex vivo) to a woman's uterus for any purpose other than to attempt to produce a live-born child" and 2) "the transfer, for any purpose, of any human embryo into the body of any member of a nonhuman species." Neither provision bars a combination of the rat and mouse experiments—whole-embryo organ culture in an artificial womb—using human embryos.

Step by step, science is erasing the moral distinctions that kept us safe and sane. Artificial wombs erase the line between in vitro embryos and implanted embryos. Whole-embryo organ culture erases the line between therapeutic and reproductive cloning. Alternative stem-cell proposals, now before the Senate, erase the line between adult and embryonic stem cells. Adult can become embryonic. Implantation can be in vitro. Reproduction, at least through the early weeks of development, can be therapeutic.

Even the definition of the embryo is blurring. Under a proposal by William Hurlbut, a member of Bush's bioethics council, a single genetic tweak could turn a would-be embryo into a "clonal artifact" that "might legitimately be developed within artificial microenvironments beyond 14 days. This would allow the production of more advanced cell types, the study of tissue interactions and the formation of primordial organismal parts." Why has Hurlbut, a pro-lifer, invited scientists to grow and exploit near-embryos in artificial environments beyond 14 days? Because he knows that the demand for parts and tissues, combined with the difficulty of making them from stem cells, will build pressure to lift the 14-day limit on the real thing.

None of this is what Dr. Liu had in mind. She wants to transplant embryos back into the womb once they've developed far enough. Trying to replicate later stages of pregnancy in the lab is "too complicated," she says. That's a big problem if, like her, you want a baby. But if all you want is tissue, who cares? You can tell yourself what we already tell ourselves about unwanted in vitro embryos: They're doomed anyway. Patients' lives are at stake. We can't let personal morality get in the way of science. We can't wait.

But that's the funny thing: We are waiting. Every day that we don't grow embryos beyond two weeks for their tissue, we're waiting. I wonder why.

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