The Niche

Ian Wilmut’s move from cloning: getting practical with iPS

The scientist that helped clone Dolly the sheep has moved away from cloning and toward making embryonic-like stem cells without eggs. The shift is described in an article and interview in Scientific American. Wilmut (and others) think that iPS cells might one day replace ES cells for clinical applications and drug-testing applications, but no one thinks that day is now here. Bits of the SciAm articles are floating around the blogosphere, but these (willfully?) strip away some of the nuances, so it’s worth reading the full articles from the source. I also think that the article conflated and neglected a few ideas, which I’ll outline below.

iPS versus ES versus cloning

To me, the article muddled risks from cloning and risks from the incredible flexibility of any sort of embryonic stem cells when it describes the FDA’s decision earlier this year to place a hold on its clinical trial. (See NatureNews ) The cells that Geron wants to test in patients with spinal cord injury come from human embryonic stem cells made from embryos supplied by fertility clinics, not from embryonic stem cells made from cloned human embryos. At an advisory meeting this April, the FDA was trying to figure out what evidence it needed to see to know that embryonic-stem-cell products were safe. (See FDA to vet embryonic stem cells’ safety ports/theniche/2008/04/gearing_for_nittygritty_questi.html” > blog coverage.)

The FDA’s concerns apply not to cloned cells but to pluripotent cells, and right now the only type of pluripotent cell that has been characterized sufficiently to even be close to being tested in patients is embryonic stem cells. When I attended the FDA’s meeting in April, work with iPS cells had already shown that the cells could cure sickle cell anemia in mice and alleviate Parkinson’s symptoms in rats. I couldn’t believe that none of the iPS pioneers attended, and that iPS cells were hardly mentioned.

(An aside: I know I have several readers convinced that the FDA’s decision to halt Geron’s clinical trial came from political pressure from the Bush White House. This would be counterevidence to that view. Also, see my previous blog.)

Since it’s my job to ask the obvious questions, I asked where the iPS people were. Expert attendees smiled at my naïveté. Human iPS cells are less than a year old, they reminded me. No one has yet been able to make any sort of iPS cell without permanent genetic alteration. The reprogramming in iPS cells is different than in ES cells. It’s still unclear what those differences are and whether they matter. To those trying to move cell therapy into patients, telling researchers to give up on ES cells and shift focus to iPS cells is like telling office workers to turn off their computers and not turn them back on until Microsoft’s Longhorn or Vista o rwhatever the next operating system is is bugfree. iPS cells might be just the thing for cell therapy, but not until techniques to make and assess them improve, and certainly not yet.

Easy iPS

So why is Ian Wilmut turning toward iPS? After all, it was just last June that he wrote a commentary in Nature Reports Stem Cells calling for people to work on trying to clone embryonic stem cells using cow eggs and human nuclei.

Wilmut wants to use the cells for drug screening; he’s not trying to turn the cells into therapies themselves. For that, you need as many different lines as possible, not a few highly, highly characterized lines. To turn a molecule into medicine, scientists run it through a gamut of tests, many of which involve killing rodents. Using human cells could make tests cheaper, faster, and more accurate; plus they would require fewer furry corpses. (See our article on drug screening and blog entry.)

More scientists than Ian Wilmut are excited about iPS cells for this and other reasons: Several of these scientists are at drug companies, BTW; I met them at the big stem cell meeting in June. (See our account of that meeting.)

For drug screening, and for answering some basic questions about how one cell type turns into another; it’s useful to have several different stem cell lines with greater genetic diversity. iPS cells promise to be a more efficient way to get these lines quickly than nuclear transfer, but to address mechanisms of how reprogramming works, many scientists want to study egg-assisted reprogramming (i.e. nuclear transfer or therapeutic cloning) as well as making iPS cells (a technique that generally requires inserting four genes into differentiated cells). As Wilmut told reporters at the annual stem cell meeting, “What the egg does is fundamentally different from what the four factors do.”

The backstory in the shift from cloning

Cloning embryonic stem cells is much, much more difficult than the very new technique of inducing pluripotency in differentiated cells. In fact, though monkey cells were cloned last year, no one has been able to clone human embryonic stem cells yet. Most believe it is possible: to succeed, a scientist will most likely need

1) a large number of fresh human eggs

2) incredibly adept hands to swap out the egg’s original nucleus with that from another person and to stimulate the “reconstituted embryo” to grow into the hollow-ball, or blastocyst stage

3) high levels of patience, because most of the attempts from step #2 won’t work

4) reasonably adept hands to remove the inner cells from the blastocyst (all conventional techniques destroy the embryo, but see our blog ) and place them in culture where some attempts will grow into embryonic stem cells

To make induced pluripotent stem cells, a scientist needs a simple skin biopsy, a suite of accessible viruses, and a technique to identify the reprogrammed cells. Many laboratories have already succeeded in making these. The month that the creation of human iPS cells were announced, Ian Wilmut was quoted in the Telegraph saying he would be giving up on cloning and start using iPS cells for drug screening. The Scientific American articles reiterate this attitude and describe it more fully.

Sidenote: a rbbbt quibble

Adult frogs have been created from cloning, but only if the nucleus came from a tadpole or a frog embryo. Attempts to use adult nuclei to clone frogs resulted in tadpoles that grew abnormally.

A short account from Nature Milestones describing Molly, the first cloned tadpole, and Dolly, the first cloned mammal.


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