The Organ Factory
This is the second part of a five-part series. To read the first part, click here.
Yesterday we learned that cloned tissue can be transplanted into animals without rejection, can rebuild organs, and can fix genetic flaws. But we haven't proved we can grow all this tissue in vitro. Why not? Will we have to grow it in vivo—in an embryo?
Here are three possible answers. The first is that tissue production in the lab just needs time. If you look at the latest studies, you'll see progress in differentiation—growing human embryonic stem (or hES) cells into blood, heart tissue, and dopamine neurons. Scientists are trying hard. They're learning to make tissues more efficiently and with higher quality.
But you'll also see them struggling. They confess their inability to make hES cells become exactly what we want. They lament how long it takes. They concede that the resulting cells are immature and incompletely specialized. They regret their ignorance about which recipes produce which tissues. They apologize for the low volume of output and blame this for the lack of studies testing whether lab-grown tissues are safe and effective in transplants. They worry that the tissues might flunk that test.
Look at the recent cardiac and neural studies. It takes eight weeks to make midbrain dopamine neurons—the same time required in vivo—and only 10 to 20 percent of the resulting cells have even immature versions of the synaptic contacts that define neurons. It takes eight weeks to make hES cells functionally equivalent to some adult heart cells, and they still don't replicate the variety of adult cells. This is progress, but it's chasing a standard set by nature. The authors admit they're trying to "mimic" and "recapitulate" embryonic development.
Maybe there's something about embryonic development that cloning can't recapitulate. That's a second possibility. Last year, in a review of recent studies, Czech and Japanese researchers theorized that nature corrects some gene-related errors during embryonic production of germ cells, which form the next generation. Cloned embryos skip this editing process, since they come from regular body cells, not germ cells. Consequently, the researchers argued, these embryos might have fatal errors that could be corrected if they were allowed to "pass through the germ-cell formation processes." But as we saw yesterday, that would mean growing embryos for at least five weeks.
Even if we did that, it wouldn't address the original problem: Why have transplant scientists succeeded with tissue grown in vivo but not in vitro? The cardiac study offers a clue: Each part of the cell cluster the researchers grew from hES cells became a distinct type of tissue, depending on "its unique microenvironment." To grow a particular tissue from hES cells, you have to put them in a particular place, and that place has to be dynamic. As Nature explained two months ago:
Some researchers argue that providing an appropriate three-dimensional environment in which signals come from the right direction will matter as much as using the right biochemicals. The same may go for getting stem cells to give rise to the appropriate tissues. … [M]ost researchers working with embryonic stem cells are trying to get them to differentiate into specific cell types in the lab. But to unlock the cells' potential fully, biologists may need to find ways to recapitulate the changing microenvironments that characterize the long journey from embryonic stem cell to adult tissue.
This points to a third possibility: We can't produce some tissues precisely or efficiently outside the embryo, because the embryo is what produces them. Maybe that's why the 2002 study of cloning and gene therapy, which we looked at yesterday, succeeded with cells differentiated in vivo but failed with genetically identical cells differentiated in vitro. At the time, pro-lifers pounced on the study, arguing that it proved the superiority of "adult" stem cells. The war between adult and embryonic stem cells drowned out the deeper issue of in vivo differentiation.
And maybe that's why pro-lifers missed the biggest in vivo differentiation story since then, which involved neither hES cells nor adult stem-cell therapy. Four months ago, Japanese researchers reported, "Anatomically complicatedorgans such as the kidney and lung, which are comprised of severaldifferent cell types and have a sophisticated 3-dimensionalorganization and cellular communication, have proven more refractoryto stem cell-based regenerative techniques." But the researchers brought good news: They had figured out how to beat the problem. They had demonstrated a way to grow human adult bone marrow stem cells into kidney tissue: by putting the cells in embryonic rats.
The embryos had gestated for nine to 10 days—in human terms, about four months. The researchers extracted them from their mothers, injected the human cells into regions of the embryos where kidneys were forming, and cultured the embryos in vitro for two days. The researchers called this process "whole-embryo culture." While it was going on, the embryos somehow caused the human bone-marrow stem cells to become capable of producing kidney tissue. The embryos died, but the researchers removed the developing kidneys and cultured them separately for another six days. They reported that "kidney rudimentscontinued to grow."
The authors concluded that putting marrow stem cells "in a specificorgan location in whole-embryo culture can commit them to thefate of that organ." The cells "could be reprogrammed for other fates and organstructures, depending on the embryonic environment," they added. This validated the microenvironment theory subsequently outlined in Nature. But it also validated something larger. Nature pointed out that stem-cell researchers were trying to reproduce "changing" microenvironments. The Japanese study showed that the easiest way to reproduce these changing microenvironments was to reproduce the macroenvironment that changed them: the embryo. As the authors noted, "Only the [marrow cells] differentiated in the whole embryo are able to express kidney-specific gene[s] after organ culture."
The authors called this "an in vitro organ factory." Technically, that was correct, since the factory was in a lab dish. But the factory itself was a rat. The human cells were inside a living organ inside a living being inside a dish. The distinction between in vivo and in vitro had collapsed. So had the barrier to making transplantable tissue. The report's final sentence said it all: "Here, we have demonstrateda system that might provide the means to generate self-organs… by using the inherent developmental systemof an immunocompromised xenogeneic host."
Inherent developmental system. That's the key: a 9-day rat, a 4-week pig, a 6-week calf. But those are all foreign species—"xenogeneic," in the language of the Japanese study. They have to be "immunocompromised"—deprived of the ability to reject your cells—because their DNA doesn't match yours. The only developmental system that doesn't have to be immunocompromised is your clone.
Don't be scared. We don't have to grow a whole new you. Judging from the studies we looked at yesterday, an embryo cloned from one of your cells would need just six or seven weeks to grow many of the tissues you need. We already condone harvesting of cells from cloned human embryos for the first two weeks. Why stop there? We'll tackle that question tomorrow.
Will Saletan covers science, technology, and politics for Slate and says a lot of things that get him in trouble.