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.