October 17, 2005
New Methods To Create Embryonic Stem Cells Sidestep Some Ethical Objections

Scientists at the MIT Whitehead Institute demonstrated on mouse murine cells that altered nuclear transfer (ANT) where genes are deactivated in the donor nucleus will allow creation of embryonic stem cells from embryos that could never develop into a full organism.

Some senators unhappy with those proposals have suggested that 'alternative' methods of deriving the cells, which don't require the destruction of viable embryos, could help to bridge the ethical divide (see Nature 436, 309; 2005).

Until now, such methods have been purely theoretical, but in work published online by Nature this week, two teams report their successful use in mice. Rudolf Jaenisch and Alexander Meissner of the Massachusetts Institute of Technology describe a variant of therapeutic cloning called altered nuclear transfer (ANT), in which a gene in the patient's donated cell is switched off before the nucleus is transferred into a fertilized egg. The resulting egg grows into a normal ball of cells called a blastocyst from which ES cells can be derived, but the deactivated gene means that the ball lacks the ability to implant in a uterus and so develop into a baby (A. Meissner and R. Jaenisch Nature doi:10.1038/nature04257; 2005).

The deactivation of a single gene prevents a pregnancy from being possible to initiate.

Jaenisch and Alexander Meissner, a graduate student in his lab, focused on a gene called Cdx2, which enables an embryo to grow a placenta. In order to create a blastocyst that cannot implant in a uterus, the researchers disabled Cdx2 in mouse cells.

They accomplished this with a technique called RNA interference, or RNAi. Here, short interfering RNA (siRNA) molecules are designed to target an individual gene and disrupt its ability to produce protein. In effect, the gene is shut off. Jaenisch and Meissner designed a particular form of siRNA that shut off this gene in the donor nucleus and then incorporated itself into all the cells comprising the blastocyst. As a result, all of the resulting mouse blastocysts were incapable of implantation.

However, once the stem cells had been extracted from the blastocysts, Cdx2 was still disabled in each of these new cells, something that needed to be repaired in order for these cells to be useful. To correct this, Meissner deleted the siRNA molecule by transferring a plasmid into each cell. (A plasmid is a unit of DNA that can replicate in a cell apart from the nucleus. Plasmids are usually found in bacteria, and they are a staple for recombinant DNA techniques.) The stem cells resulting from this procedure proved to be just as robust and versatile as stem cells procured in the more traditional fashion.

"The success of this procedure in no way precludes the need to pursue all forms of human embryonic stem cell research," says Jaenisch, who is also a professor of biology at MIT. "Human embryonic stem cells are extraordinarily complicated. If we are ever to realize their therapeutic potential, we must use all known tools and techniques in order to explore the mechanisms that give these cells such startling characteristics."

ANT, Jaenisch emphasizes, is a modification, but not an alternative, to nuclear transfer, since the approach requires additional manipulations of the donor cells. He hopes that this modification may help resolve some of the issues surrounding work with embryonic stem cells and allow federal funding.

I like Jaenisch's approach because it will work with any donor nucleus. So a person have their own nuclear DNA used to create a cell line to create stem cell therapies and replacement organs made from their own DNA.

Some will object to Jaenisch's approach as essentially consigning a potential human to death. But as knowledge of more genes involved in development become identified more genes could get turned off in an extended version of this approach where the resulting embryo looked ever less like something that would develop into a human. Imagine, for example, that if one wanted to grow kidneys one turned off all the developmental genes for a head so that the embryo would only have potential to grow into a few chest organs.

Robert Lanza of Advanced Cell Technology in Worcester Massachusetts and colleagues took a different but very straightforward approach where they removed single cell from an early stage 8 cell embryo called a morula and then expose that cell to existing embryonic stem cells to stabilize it as an embryonic stem cell.

The procedure involves removing a blastomere, one of eight cells that make up an early embryo before implantation in the uterus, and putting it in a culture with other stem cells to encourage it to form into independent stem cells.

The technique, used in pre-implantation genetic diagnosis (PGD) by couples with a family history of hereditary conditions such as muscular dystrophy to screen out affected embryos, allows the embryo to continue to grow normally despite the removal of the cell.

To meet the objections of ethical opponents Lanza's technique still requires treating the other 7 cells as being destined to make a new baby. That is problematic. Suppose you want to make a stem cell line from your own DNA to, for example, grow a replacement kidney for yourself. Chances are most people won't be keen on creating a baby as a side effect. Also, in order for the stem cell line to perfectly match your DNA then embryo has to be a clone and so you have to clone yourself if you go down this path.

The other 7 cells remain in the embryo and get implanted in a womb.

But the key benefit of this technique may be that the remaining 7-cell embryos, when implanted into the wombs of female mice, developed into completely normal baby mice. Of the 47 implanted, 23 came to term, exactly the same rate as for “control” 8-cell morulas that had not had a blastomere removed.

“It means we overcome the key pro-life objection, that you must destroy life to save life,” says Lanza. Also, he says that the technique used to extract the blastomere is identical to that used routinely in pre-implantation diagnosis during IVF to screen out embryos which are defective and have no chance of surviving. “This procedure has been done hundreds of thousands of times, so we know it has a minimal or negligible effect on the embryo,” he says.

This works okay as a way to get a cell from IVF procedures that are going to get done anyway. So this technique can be utilized to generate new embryonic stem cell (ESC) lines for research and potentially for therapy as well.

Some people reject these approaches.

Much of the debate centers on the precise definition of "embryo," because it is considered by some people to have the same moral status as a human being. In one of the new sets of experiments, researchers crafted stem cell lines from lab creations characterized as "nonviable" entities.

Others dismissed such arguments as semantic quibbling.

"This is an attempt to solve an ethical issue through a scientific redefinition that really doesn't solve the issue," said Jaydee Hanson, director of human genetics at the International Center for Technology Assessment, a Washington, D.C., nonprofit organization that opposes some kinds of cloning and stem cell research on moral grounds.

My guess is that not all moral objectors have to be satisfied by new methods of making ESCs. The approaches just have to win over enough of the objectors that the remaining opponents can not form political coalitions big enough to stop which is done using human ESCs with one of these approaches.

Scientists will keep on developing more improved techniques for making pluripotent stem cells in ways that satisfy an increasing number of the objectors to existing methods for making stem cells from embryos. As more genes involved in development are identified and as more techniques for manipulating genetic regulatory state are discovered stem cell researchers will find all sorts of additional ways to skate around ethical objections. In the process they will also develop useful toolboxes for manipulating stem cells for other goals as well..

Share |      Randall Parker, 2005 October 17 03:16 PM  Bioethics Debate

Marvin said at October 18, 2005 8:58 AM:

In the US, embryonic stem cell research is completely legal. There is no reason why the top scientists in the US cannot get funding, given the promise of ESCs. Will every scientist who wants funding for ESC research get the funding? Not likely.
The problem of lack of federal funding to develop new lines of ESCs, will be solved at the next presidential election.

Under Clinton it was much harder to proceed with ESC research than under Bush. Bush partially opened the door. It is up to the next president to open it further.

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