Japanese stem cell researcher

Shinya Yamanaka ( , Yamanaka Shin'ya, born September 4, 1962) is a Japanese stem cell researcher and a Nobel Prize laureate.[2][3][4] He serves as the director of Center for iPS Cell (induced Pluripotent Stem Cell) Research and Application and a professor at the Institute for Frontier Medical Sciences at Kyoto University; as a senior investigator at the UCSF-affiliated Gladstone Institutes in San Francisco, California; and as a professor of anatomy at University of California, San Francisco (UCSF). Yamanaka is also a past president of the International Society for Stem Cell Research (ISSCR).

He received the 2010 BBVA Foundation Frontiers of Knowledge Award in the biomedicine category, the 2011 Wolf Prize in Medicine with Rudolf Jaenisch,[6] and the 2012 Millennium Technology Prize together with Linus Torvalds. In 2012, he and John Gurdon were awarded the Nobel Prize for Physiology or Medicine for the discovery that mature cells can be converted to stem cells.[7] In 2013, he was awarded the $3 million Breakthrough Prize in Life Sciences for his work.

Yamanaka was born in Higashisaka, Japan, in 1962. After graduating from Tennji High School attached to Osaka Kyoiku University,[8] he received his M.D. degree at Kobe University in 1987 and his Ph.D. degree at Osaka City University Graduate School in 1993. After this, he went through a residency in orthopedic surgery at National Osaka Hospital and a postdoctoral fellowship at the J. David Gladstone Institutes of Cardiovascular Disease, San Francisco.

Afterwards, he worked at the Gladstone Institutes in San Francisco, US, and Nara Institute of Science and Technology in Japan. Yamanaka is currently a professor at Kyoto University, where he directs its Center for iPS Research and Application. He is also a senior investigator at the Gladstone Institutes as well as the director of the Center for iPS Cell Research and Application.[9]

Between 1987 and 1989, Yamanaka was a resident in orthopedic surgery at the National Osaka Hospital. His first operation was to remove a benign tumor from his friend Shuichi Hirata, a task he could not complete after one hour when a skilled surgeon would have taken ten minutes or so. Some seniors referred to him as "Jamanaka", a pun on the Japanese word for obstacle.[10]

From 1993 to 1996, he was at the Gladstone Institute of Cardiovascular Disease. Between 1996 and 1999, he was an assistant professor at Osaka City University Medical School, but found himself mostly looking after mice in the laboratory, not doing actual research.[10]

His wife advised him to become a practicing doctor, but instead he applied for a position at the Nara Institute of Science and Technology. He stated that he could and would clarify the characteristics of embryonic stem cells, and this can-do attitude won him the job. From 19992003, he was an associate professor there, and started the research that would later win him the 2012 Nobel Prize. He became a full professor and remained at the institute in that position from 20032005. Between 2004 and 2010, Yamanaka was a professor at the Institute for Frontier Medical Sciences.[11] Currently, Yamanaka is the director and a professor at the Center for iPS Cell Research and Application at Kyoto University.

In 2006, he and his team generated induced pluripotent stem cells (iPS cells) from adult mouse fibroblasts.[2] iPS cells closely resemble embryonic stem cells, the in vitro equivalent of the part of the blastocyst (the embryo a few days after fertilization) which grows to become the embryo proper. They could show that his iPS cells were pluripotent, i.e. capable of generating all cell lineages of the body. Later he and his team generated iPS cells from human adult fibroblasts,[3] again as the first group to do so.A key difference from previous attempts by the field was his team's use of multiple transcription factors, instead of transfecting one transcription factor per experiment. They started with 24 transcription factors known to be important in the early embryo, but could in the end reduce it to 4 transcription factors Sox2, Oct4, Klf4 and c-Myc.[2]

The 2012 Nobel Prize in Physiology or Medicine was awarded jointly to Sir John B. Gurdon and Shinya Yamanaka "for the discovery that mature cells can be reprogrammed to become pluripotent."[12]

There are different types of stem cells.

These are some types of cells that will help in understanding the material.

Theoretically patient-specific transplantations possible

Much research done

Immune rejection reducible via stem cell bank

Pluripotent

Abnormal aging

No immune rejectionSafe (clinical trials)

The prevalent view during the early 20th century was that mature cells were permanently locked into the differentiated state and cannot return to a fully immature, pluripotent stem cell state. It was thought that cellular differentiation can only be a unidirectional process. Therefore, non-differentiated egg/early embryo cells can only develop into specialized cells. However, stem cells with limited potency (adult stem cells) remain in bone marrow, intestine, skin etc. to act as a source of cell replacement.[13]

The fact that differentiated cell types had specific patterns of proteins suggested irreversible epigenetic modifications or genetic alterations to be the cause of unidirectional cell differentiation. So, cells progressively become more restricted in the differentiation potential and eventually lose pluripotency.[14]

In 1962, John B. Gurdon demonstrated that the nucleus from a differentiated frog intestinal epithelial cell can generate a fully functional tadpole via transplantation to an enucleated egg. Gurdon used somatic cell nuclear transfer (SCNT) as a method to understand reprogramming and how cells change in specialization. He concluded that differentiated somatic cell nuclei had the potential to revert to pluripotency. This was a paradigm shift at the time. It showed that a differentiated cell nucleus has retained the capacity to successfully revert to an undifferentiated state, with the potential to restart development (pluripotent capacity).

However, the question still remained whether an intact differentiated cell could be fully reprogrammed to become pluripotent.

Shinya Yamanaka proved that introduction of a small set of transcription factors into a differentiated cell was sufficient to revert the cell to a pluripotent state. Yamanaka focused on factors that are important for maintaining pluripotency in embryonic stem (ES) cells. This was the first time an intact differentiated somatic cell could be reprogrammed to become pluripotent.

Knowing that transcription factors were involved in the maintenance of the pluripotent state, he selected a set of 24 ES cell transcriptional factors as candidates to reinstate pluripotency in somatic cells. First, he collected the 24 candidate factors. When all 24 genes encoding these transcription factors were introduced into skin fibroblasts, few actually generated colonies that were remarkably similar to ES cells.Secondly, further experiments were conducted with smaller numbers of transcription factors added to identify the key factors, through a very simple and yet sensitive assay system.Lastly, he identified the four key genes. They found that 4 transcriptional factors (Myc, Oct3/4, Sox2 and Klf4) were sufficient to convert mouse embryonic or adult fibroblasts to pluripotent stem cells (capable of producing teratomas in vivo and contributing to chimeric mice).

These pluripotent cells are called iPS (induced pluripotent stem) cells; they appeared with very low frequency. iPS cells can be selected by inserting the b-geo gene into the Fbx15 locus. The Fbx15 promoter is active in pluripotent stem cells which induce b-geo expression, which in turn gives rise to G418 resistance; this resistance helps us identify the iPS cells in culture.

Moreover, in 2007, Yamanaka and his colleagues found iPS cells with germline transmission (via selecting for Oct4 or Nanog gene). Also in 2007, they were the first to produce human iPS cells.

Some issues that current methods of induced pluripotency face are the very low production rate of iPS cells and the fact that the 4 transcriptional factors are shown to be oncogenic.

In July 2014, a scandal regarding the research of Haruko Obokata was connected to Yamanaka. She could not find the lab notes from the period in question[15] and was made to apologise.[16][17]

Since the original discovery by Yamanaka, much further research has been done in this field, and many improvements have been made to the technology. Improvements made to Yamanaka's research as well as future prospects of his findings are as follows:

Yamanaka's research has "opened a new door and the world's scientists have set forth on a long journey of exploration, hoping to find our cells true potential."[18]

In 2013, iPS cells were used to generate a human vascularized and functional liver in mice in Japan. Multiple stem cells were used to differentiate the component parts of the liver, which then self-organized into the complex structure. When placed into a mouse host, the liver vessels connected to the hosts vessels and performed normal liver functions, including breaking down of drugs and liver secretions.[19]

In 2022, Yamanaka factors were shown to effect age related measures in aged mice.[20]

In 2007, Yamanaka was recognized as a "Person Who Mattered" in the Time Person of the Year edition of Time Magazine.[21] Yamanaka was also nominated as a 2008 Time 100 Finalist.[22] In June 2010, Yamanaka was awarded the Kyoto Prize for reprogramming adult skin cells to pluripotential precursors. Yamanaka developed the method as an alternative to embryonic stem cells, thus circumventing an approach in which embryos would be destroyed.

In May 2010, Yamanaka was given "Doctor of Science honorary degree" by Mount Sinai School of Medicine.[23]

In September 2010, he was awarded the Balzan Prize for his work on biology and stem cells.[24]

Yamanaka has been listed as one of the 15 Asian Scientists To Watch by Asian Scientist magazine on May 15, 2011.[25][26] In June 2011, he was awarded the inaugural McEwen Award for Innovation; he shared the $100,000 prize with Kazutoshi Takahashi, who was the lead author on the paper describing the generation of induced pluripotent stem cells.[27]

In June 2012, he was awarded the Millennium Technology Prize for his work in stem cells.[28] He shared the 1.2 million euro prize with Linus Torvalds, the creator of the Linux kernel. In October 2012, he and fellow stem cell researcher John Gurdon were awarded the Nobel Prize in Physiology or Medicine "for the discovery that mature cells can be reprogrammed to become pluripotent."[29]

Yamanaka practiced judo (2nd Dan black belt) and played rugby as a university student. He also has a history of running marathons. After a 20-year gap, he competed in the inaugural Osaka Marathon in 2011 as a charity runner with a time of 4:29:53. He took part in Kyoto Marathon to raise money for iPS research since 2012. His personal best is 3:25:20 at 2018 Beppu-ita Marathon.

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Shinya Yamanaka - Wikipedia

Specially treated stem cells derived from a single individual have been successfully implanted into that same individuals eyes in a first-of-its-kind clinical trial testing ways to treat advanced dry age-related macular degeneration (AMD).

The therapy, currently in its first phase of testing to ensure that its safe for humans, involves harvesting and processing a persons blood cells and using them to replace the persons retinal cells that had succumbed to AMD, a leading cause of vision loss globally.

The procedure was performed by researchers from the National Eye Institute (NEI), a branch of the National Institutes of Health in Bethesda, Maryland, and from the Wilmer Eye Institute at Johns Hopkins School of Medicine in Baltimore. The NIH researchers have been working on the new treatment for a decade.

The scientists, who previously demonstrated the safety and effectiveness of the therapy in rats and pigs, took blood cells from the patient and, in the laboratory, converted them into patient-derived induced pluripotent stem (iPS) cells. These immature, undifferentiated cells have no assigned function in the body, which means they can assume many forms. The researchers programmed these particular iPS cells to become retinal pigment epithelial (RPE) cells, the type that die in AMD and lead to late-stage dry AMD.

In healthy eyes, RPE cells supply oxygen to photoreceptors, the light-sensing cells in the retina at the back of the eyeball. The death of RPE cells virtually dooms the photoreceptors, resulting in vision loss. The idea behind the new therapy is to replace dying RPE cells with patient-derived induced iPS ones, strengthening the health of the remaining photoreceptors.

Before being transplanted, the iPS-derived cells were grown in sheets one cell thick on a biodegradable scaffold designed to promote their integration into the retina. The researchers positioned the resulting patch between atrophied host RPE cells and the photoreceptors using a specially created surgical tool.

The patient received the transplanted cells during the summer and will be followed for a year as researchers monitor overall eye health, including retina stability, and whether any inflammation or bleeding develop, says Kapil Bharti, PhD, a senior investigator at the NEI and for the clinical trial.

Safety data are critical for any new drug, says Gareth Lema, MD, PhD, a vitreoretinal surgeon at New York Eye & Ear Infirmary, a division of the Mount Sinai Health System. Stem cells have added complexity in that they are living tissue, Dr. Lema says. Precise differentiation is necessary for them to fulfill their intended therapeutic effect and not cause harm."

This therapy also requires a surgical procedure to implant the cells, Lema says, adding that its an exquisitely elegant surgery, but introduces further risk of harm. For those reasons, he says, Patients must know that ocular stem cell therapies should only be attempted within the regulated environment of a nationally registered clinical trial.

The rules of a clinical trial dont generally allow specifics to be discussed this early in the process, says Dr. Bharti. Announcing that we were able to successfully transplant the cells now hopefully allows us to recruit more patients, since we can take up to 12 in this phase, he says. We also hope that it will give some optimism to patients with dry AMD and to researchers studying it.

It took seven months to develop the implanted cells, says Bharti, and although the federal Food and Drug Administration (FDA) approved the clinical trial in 2019, the onset of the COVID-19 pandemic delayed the start by two years, he says.

Macular degeneration comprises several stages of disease within the macula, the critical portion of the retina responsible for straight-ahead vision. Aging causes retinal cells to deteriorate, generating debris, or drusen, within the macula, setting the stage for early (aka dry) AMD. Geographic atrophy represents a more advanced stage. If the disease progresses to the relatively rare wet AMD, so named for the leaking of blood into the macula, central vision can be snuffed out.

Risk of AMD increases with age, particularly among people who are white, have a history of smoking, or have a family history of the disease.

Treatment to slow wet AMDs progression includes eye injections with anti-VEGF (or VEGF-A for vascular endothelial growth factor antagonists), a medication that halts the growth of unstable, leaky blood vessels in the eye. Some people may undergo photodynamic therapy, which combines injections and laser treatments.

Currently, there is no cure for dry AMD; it cant be reversed. Nor are there treatments to reliably stop its onset or progression for everyone at every stage of the disease. (Research has confirmed that a specialized blend of vitamins and minerals, available over the counter as AREDS, or Age-Related Eye Disease Studies supplements, reduces the risk of AMDs progression from intermediate to advanced stages.)

There are other, ongoing clinical trials for the treatment of dry AMD. Regenerative Patch Technologies, in Menlo Park, California, for example, is a little further along in testing a different stem cell treatment. Patients have been followed for three years, and 27 percent have shown vision improvement, says Jane Lebkowski, PhD, the companys president. There are a number of AMD clinical trials ongoing in the U.S., and patients should ask their ophthalmologists about trials that might be appropriate.

ClinicalTrials.gov, the NIHs clinical trials database, lists close to 300 AMD clinical trials at various stages in the United States.

Ferhina Ali, MD, MPH, a retinal specialist at the Westchester Medical Center in Valhalla, New York, who isnt involved in the trial, describes the newest stem cell therapy as elegant and pioneering. These are early stages but there is tremendous potential as a first-in-kind surgically implanted stem cell therapy and as a way to achieve vision gains in dry macular degeneration, Dr. Ali says.

Bharti says that in laboratory animals the implanted cells behaved as retinal cells should maintaining the retinas integrity. Over the next few years, he and his colleagues will determine whether they function effectively in humans.

Does that mean, however, that the same AMD disease process that destroyed the original retinal cells could destroy the transplanted ones? It takes 40 to 60 years to damage human cells, Bharti says, and if we get that long with the transplanted cells, well take it.

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Implanting a Patient's Own Reprogrammed Stem Cells Shows Early Positive ...