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The Promise of Regenerative Medicine
Research on iPS Cells Continues, a Decade Since Groundbreaking Paper

Tsukasaki Asako [Profile]


In August 2006 Professor Yamanaka Shin’ya of Kyoto University published a paper reporting his success in producing induced pluripotent stem cells, and in a 2014 clinical study, tissue derived from iPS cells was transplanted to a patient for the first time. While a host of challenges must be overcome, the promise of regenerative therapies appears to be coming within reach.

Regenerative medicine has been a dream of researchers for years. The ultimate goal of this field is to restore the functions of failing body parts: eyes that have lost sight, limbs that no longer move, hearts on the verge of stopping. Replacing lost or diminished functions with eyeglasses, prosthetic limbs, and artificial organs may be considered regenerative medicine in a broad sense. A breakthrough loomed on the horizon 35 years ago, when scientists succeeded in producing embryonic stem cells from the embryos of mice in 1981. And in 1998 they were able to produce human ES cells.

The adult human body consists of roughly 60 trillion cells, all of which were generated from a single fertilized egg through repeated cell division. Stem cells are capable of replicating themselves through division and differentiating into a variety of cells—an ability called pluripotency. The fertilized egg, in particular, can produce every kind of adult cell.

ES cells are made from early embryos that have undergone only six or seven cell divisions after fertilization. In essence, they are stem cells that can proliferate almost indefinitely without losing their pluripotency. While offering hope in regenerative therapy, ES cells also faced a number of issues, such as the need for technologies to safely induce differentiation in targeted cells and to prevent rejection following transplantation. The biggest barrier, though, was ethical, as stem cells had to be made from human embryos.

As researchers around the world struggled to induce the differentiation of ES cells into various somatic cells, Yamanaka Shin’ya, a professor at Kyoto University, succeeded in producing pluripotent cells by taking an inverse approach.

Winning the Nobel Prize

Examining the 24 genes that are highly expressed in ES cells, Yamanaka ascertained 4 that later came to be known as the Yamanaka factors: Oct3/4, Sox2, Klf4, and c-Myc. Incorporating them into the skin cells of mice using retroviruses as carriers (vectors) resulted in pluripotent stem cells similar to ES cells. Yamanaka named these cells “induced pluripotent stem cells,” or iPS cells. The “i” was lowercased in the hope of repeating the global success of the iPod, Apple’s portable music player.

The details of the production process and the identity of these four genes were revealed in the August 25, 2006, issue of the US scientific journal Cell. Before iPS cells could be used in treating human patients, however, Yamanaka needed to prove that they could be produced with human rather than mouse cells. While the leap from mouse-derived to human-derived ES cells took 17 years, he succeeded in producing human iPS cells the following year.

A colony of human iPS cells established from fibroblasts. The width of the colony is about 0.5 mm. (Photo courtesy of Yamanaka Shin’ya)

Professor Yamanaka Shin’ya of Kyoto University, photographed in July 2016. (© Jiji)

The iPS cells have the potential of changing not just regenerative medicine but the entire face of clinical medicine. By comparing a patient’s diseased tissue with iPS cells produced from the same patient’s reprogrammed cells, for instance, the mechanism of the disease might be unraveled and new drugs developed. Even US President George W. Bush and Pope Benedict XVI, who had been opposed to ES cells on ethical grounds, welcomed the development of iPS cells. In 2012, before his discovery had saved a single human life, Yamanaka was awarded the Nobel Prize in Physiology or Medicine.

The development of human iPS cells signaled the start of a race to realize the dream of regenerative medicine.

The initially developed method of producing iPS cells was plagued by the risk of tumor formation and was highly inefficient. After enhancing cell safety by adjusting the choice of the genes used and the method of production, clinical tests were launched in 2014. On September 12, iPS-cell-derived retinal pigment epithelial sheets prepared from the patient’s skin cells were transplanted to the eye of a woman in her seventies suffering from exudative age-related macular degeneration, an intractable disease. The operation was conducted at the Institute of Biomedical Research and Innovation Hospital in Kobe, Hyōgo Prefecture.

The ongoing tests are being headed by Takahashi Masayo, project leader at the Riken scientific research institute and an eye surgeon. The primary objective of the trial is to evaluate the safety of the treatment; the study will track the engraftment and check for tumor formation over a period of more than four years. No problems have been found in the two years that have elapsed so far. But the second clinical trial, which had been scheduled to begin in 2015, was canceled after researchers found multiple genetic mutations in the iPS cells sourced from the patient’s cells.

  • [2016.10.26]

Journalist. Has written prolifically, primarily in the areas of medical science, healthcare, and science, and technology, after working as a reporter for the Yomiuri Shimbun. Received an undergraduate degree in natural sciences from International Christian University, a master’s degree in systems management from Tsukuba University, and a master’s degree in medical administration from Tokyo Medical and Dental University.

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