Important new step toward producing stem cells for human treatment

September 25, 2008
Important new step toward producing stem cells for human treatment
Konrad Hochedlinger

( -- A team of Harvard Stem Cell Institute (HSCI) scientists has taken an important step toward producing induced pluripotent stem (iPS) cells that are safe to transplant into patients to treat diseases.

Excitement over the ability of researchers to create this form of stem cell by inserting four genes into adults cells has thus far been tempered by the fact that the genes have been inserted using retroviruses, which have the potential to turn on cancer genes and trigger tumor growth.

But today Konrad Hochedlinger and HSCI colleagues at Massachusetts General Hospital and Joslin Diabetes Center report having created mouse iPS cells using harmless adenoviruses that ultimately disappear from the new cells and therefore do not integrate into their DNA like the retroviruses.

“The adenoviruses infect the cells” carrying the genes needed for cellular reprogramming, “but are cleared by the cells after a few cell divisions,” said Hochedlinger, an assistant professor in Harvard’s new inter-school Department of Stem Cell and Regenerative Biology (SCRB). “This wouldn’t be harmful in any way because the DNA of the new cells remains unaffected,” he said.

The report by the Hochedlinger group appears in today’s on-line edition of the journal Science.

Harvard Stem Cell Institute co-director Doug Melton, who is also co-chair of SCRB, said “this paper by the Hochedlinger’s group is another in a series by one of the leading labs, whose work is aimed at making stem cells from patient samples. In this advance, the use of viruses that integrate into the host genome have been eliminated, making the process easier and the end product, the induced pluripotent stem cell, that much more safe.”

It has previously been believed that the viruses carrying the four essential transcription factors had to be integrated into the genome of the target cell in order for adult cells to be reprogrammed into pluripotent stem cells, “but we’ve shown that you don’t need integration of the virus into the genome to produce iPS cells,” Hochedlinger said.

Hochedlinger and colleagues Mathias Stadtfeld – the study’s lead author, Masaki Nagaya, Jochen Utikal, and Gordon Weir – head of HSCI’s Diabetes Program, have used the new technique to create iPS cells from mouse skin cell, and mouse fetal and adult liver cells.

“We get stem cell lines,” said Hochedlinger. “They are all pluripotent” – meaning that they can become any type of cell –“and they have no traces of the adenovirus.” Even more important, he said, thus far none of the mice carrying the new cells lines have shown any signs of developing tumors – and tumors were being frequently reported in mice carrying the cell lines created using retroviruses.

“The next step is to reproduce this work using human cells, and there’s no reason why it can’t work,” Hochedlinger said, adding that “this basically provides us with a system with which to test the question of whether iPS cells are the equivalent of human embryonic stem cells. That’s a question that, in my opinion, hasn’t been answered yet.”

As Hochedlinger and his colleagues have been working to find viral substitutes for the use of retroviruses in the production of iPS cells, some HSCI researchers are reported to be looking for chemicals that might be used in place of viruses, and some of those experiments are said to be quite promising.

The work reported today was supported by grants from the Harvard Stem Cell Institute, and by a National Institutes of Health New Innovator Award Hochedlinger received last year.

Provided by Harvard University

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not rated yet Sep 25, 2008
This is profound!
He has overcome perhaps the biggest obsticle in gene therapy. Konrad Hochedlinger needs to be given all the assistance and help possible irregardless of cost. This demonstration of Adenovirus gene therapy is pure genius. If successful the benefits to medicine are mind boggling.

"We are in the process already of trying to make integration-free iPS cells in human cells," Hochedlinger said.

"It is a little more tricky because human reprogramming takes a little while longer than mouse reprogramming."

If it works, some day doctors may be able to make tailor-made transplants to treat diseases in people by removing a few cells, transforming them in the lab and transplanting the new tissue or organs back in.

not rated yet Sep 25, 2008
Gee, now more people can work for twice as many years.
not rated yet Sep 26, 2008
This is profound!
He has overcome perhaps the biggest obsticle in gene therapy. Konrad Hochedlinger needs to be given all the assistance and help possible irregardless of cost. This demonstration of Adenovirus gene therapy is pure genius. If successful the benefits to medicine are mind boggling.

The real breakthrough was the one when scientists created iPS in the first place by transforming them with just 4 genes! That was genius and deserves a Nobel price.

Induced pluripotent stem cells were first generated by Shinya Yamanaka's team at Kyoto University, Japan in 2006. Yamanaka had identified genes that are particularly active in embryonic stem cells, and used retroviruses to transfect mouse fibroblasts with a selection of those genes. Eventually, four key pluripotency genes essential for the production of pluripotent stem cells were isolated; Oct-3/4, SOX2, c-Myc, and Klf4.

The work reported here OTOH is just a standard derivative scientific work with minimal new ideas involved. Adenoviruses are standard vectors. Since iPS were created it was obvious better ways of making them are needed so scientists took on to testing various routes, this one worked other didn't, nothing brilliant here, mostly luck.

Its sad when credit goes to the wrong people.
not rated yet Sep 26, 2008
you make a good point. These days new inventions are generally made on the shoulders of giants. Check out the series called Connections by James Burke.
Even Einsteins famous e=mc2 was postulated less completely many years earlier by other physicists. Their names are overshadowed.

One could argue that Yamanaka's work was on the shoulders of giants. Identifying genes is hardly new and might even be considered routine research. Using retroviruses to manipulate genes in 2006 was not an invention - nothing new either. No one else probably bothered doing his area of research because of the known cancer risk with using retroviruses.
IM(very)HO I would say that getting gene therapy working (i.e. cancer free) for the first time is something worthy of credit. The idea might have even been obvious to those in the field. However this guy actual got it working. Ideas are great however they are just words. It is the people who have ideas and physically apply them that society gives credit e.g. it is trivial to have the idea of man on the moon; actually travelling to the moon is a spectacular achievement.

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