Researchers make major progress toward cell reprogramming

Two Harvard Stem Cell Institute  researchers, along with scientists at the  Whitehead Institute for Biomedical  Research and Japan’s Kyoto University,  have independently made major strides  toward discovering ways to reprogram cells in order  to direct their development—a key goal in regenerative  medicine. 

Three of the scientists’ papers describing these  discoveries confirmed initial findings reported last  year by one of the authors about reprogramming adult  cells, while a fourth has disproved a long-held view of  developmental biologists about the use of fertilized  eggs for nuclear transfer. 

In questioning some common assumptions in the  field, HSCI Principal Faculty member Kevin Eggan,  PhD, and his team demonstrated in mice that it is  possible to use previously fertilized eggs to produce  disease-specific stem cell lines using somatic cell  nuclear transfer (SCNT), a technique commonly  referred to as therapeutic cloning. This study is  featured on the cover of the latest issue of the  journal Nature. 

It has long been a given in developmental biology  that only unfertilized ova, or eggs, could be used to  perform SCNT, and difficulty in obtaining fresh ova  has brought that work to a standstill. “Now we’re able  to do an experiment a week, where we hadn’t been  able to do a single experiment for a year,” says Eggan. 

Eggan’s report came out simultaneously with the  exciting news that research groups led by HSCI  Principal Faculty member Konrad Hochedlinger, PhD,  of Massachusetts General Hospital; Kyoto University’s  Shinya Yamanaka, MD, PhD, and Rudolph Jaenisch,  MD, of the Whitehead Institute each independently  used four genes to transform adult cells into cells with  the properties of an embryonic stem cell, replicating  and expanding upon seminal work published last year  by Yamanaka. The Jaenisch and Yamanaka papers were  published in Nature; Hochedlinger’s appeared in the  inaugural issue of Cell Stem Cell. 

HSCI Scientific Co-Director Douglas A. Melton,  PhD, calls the new work exciting, addressing “an  important issue in developmental biology,  namely how can we change, or  reprogram, a cell, turning it ‘back’ to a  more embryonic state with a greater  potential. The promise of both  approaches is the possibility that we  will be able to create embryonic stem  cells from patients, and use those cells  to study the root causes of degenerative  diseases.” 

While all four reports have caused  enormous excitement in the scientific  and patient-advocacy worlds, the  researchers caution that, thus far, their  studies have been conducted using mice, and there is  no way to know if they will translate precisely, if at all,  to humans. 

“You can really turn back the clock from adult to embryonic” cells, says HSCI’s Hochedlinger, at the  same time warning that “the limitations are that we  don’t know whether this reprogramming would work  in humans.” Success in humans, he notes, would be “much more difficult to achieve than in mice.” 

Further, all three teams followed Yamanaka’s finding  by using retroviruses, which are known to randomly  turn on cancer genes, to introduce the necessary  genetic factors into the target cells. Thus not only  will scientists have to identify the factors that can  re-set the developmental clock in human cells—if,  indeed, there are such factors—but they will also need  to find a different way to get them into cells, which  may prove to be a daunting task. 

Although Eggan and Melton received Harvard  approvals a year ago to proceed with experiments  using SCNT to produce stem cell lines containing the  chromosomes of patients with diabetes and Parkinson’s  disease, they were stymied for an entire year from  conducting any experiments because of a lack of ova donors. If these results transfer to human cells, as  expected, the ability to produce disease-specific cell lines will be greatly accelerated.