Guiding a recent tour of a Kyoto University lab, a staff member holds up a transparent container. Inside are tiny pale spheres, no bigger than peas, floating in a clear liquid. This is cartilage, explains the guide, Hiroyuki Wadahama. It was made here from human iPS cells.

A monitor attached to a nearby microscope shows a mass of pink and purple dots. This is the stuff from which the cartilage was grown: induced pluripotent stem cells, often called iPS cells. Scientists can create these seemingly magical cells from any cell in the body by introducing four genes, in essence turning back the cellular clock to an immature, nonspecialized state. The term pluripotent refers to the fact iPS cells can be reprogrammed to become any type of cell, from skin to liver to nerve cells. In this way they act like embryonic stem cells and share their revolutionary therapeutic potentialand as such, they could eliminate the need for using and then destroying human embryos. Also, iPS cells can proliferate infinitely.

They can also give rise, however, to potentially dangerous mutations, possibly including ones that lead to cancerous tumors. Thus, iPS cells are a double-edged swordtheir great promise is tempered by risk. Another problem is the high cost of treating a patient with his or her own newly reprogrammed cells. But now Japanese researchers are trying a different approach.

When Kyoto University researcher Shinya Yamanaka announced in 2006 that his lab had created iPS cells from mouse skin cells for the first time, biologists were stunned. In 2007, along with James Thomson of the University of WisconsinMadison, Yamanaka repeated the feat with human skin cells. Many hailed the opening of an entirely new field of personalized regenerative medicine. Need new liver cells? No problem. Patients could benefit from having their own cells reprogrammed into ones that could help treat disease, potentially eliminating the prospect of immune rejection. In 2012 Yamanaka shared the Nobel Prize in Physiology or Medicine with John Gurdon for discovering that mature cells can be converted to stem cells. By reprogramming human cells, scientists have created new opportunities to study diseases and develop methods for diagnosis and therapy, the Nobel judges wrote. To capitalize on the discovery, Kyoto University set up the $40-million Center for iPS Cell Research and Application (CiRA), which Yamanaka directs.

A decade after the Yamanaka teams groundbreaking discoveries, however, iPS cells have retreated from the headlines; to the layperson, progress seems scant. There has only been one clinical trial involving iPS cells, and it was halted after a transplant operation on just one patienta Japanese woman in her 70s with macular degeneration, a condition that can lead to blurry vision or partial blindness. Doctors at Kobe City Medical Center General Hospital used her skin cells to grow iPS cells, which were reprogrammed into retinal cells and implanted in her eye. The treatment stopped the degeneration but the trial was halted in 2015 because genetic mutations were detected in another batch of iPS cells intended for another patient. Regulatory changes, under which the Japanese government allowed the distribution of iPS cells for clinical use, also prompted researchers to switch the study to a more efficient process of using cells from third-party donors instead of using a patients own cells. The Japanese government has a lot of incentives to considerwere developing a new science, a new technology and also a new economic market, says CiRA spokesperson Peter Karagiannis. So theres the ethical issues, but theres also money to be made. How do we balance the two?

The Kobe clinical trial had a lot riding on it. And the setback followed a major stem cell scandal in which biologist Haruko Obokata of the Riken Center for Developmental Biology was found to have falsified data in studies, published in 2014, that claimed a new method of achieving pluripotency. Then, earlier this year, Yamanaka had to apologize at a news conference after it was discovered that a reagent used to create iPS cells at CiRA was mislabeled, which could mean the wrong reagent was used. Although the mix-up is being examined, the center has halted supplies of some of its iPS cells to researchers across Japan; the error also set back by a few years a CiRA project to produce clinical-grade platelets from iPS cells.

But Yamanaka says he remains focused on the bigger picture of iPS cells and is still optimistic they can not only help researchers but may be key to transformative clinical therapies. CiRA still has a bank of tens of millions of iPS cells that have already been reset and checked for safety, so they can be used in patient applications. In terms of regenerative medicine, things have gone quicker than I expected, Yamanaka says, adding, iPS cells have exceeded expectations because of their potential for disease modeling, which allows us to elucidate unknown disease mechanisms, and drug discovery.

Those hoping for quick clinical success should remember it takes time for revolutionary treatments to go from lab bench to bedside, says Andras Nagy, a stem cell researcher at Mount Sinai Hospitals LunenfeldTanenbaum Research Institute in Toronto, who has not been directly involved in Yamanakas work. If you fully appreciate the paradigm-shifting nature of iPS cells, tremendous progress has in fact been made over the past 10 years, says Nagy, who in 2009 established a method of creating stem cells without using viruses (which had initially been used to deliver reprogramming genes into targeted cells). By comparison, penicillin was discovered as an antibiotic in 1928, but it was not available in the clinic until the early 1940s.

Researchers in Japan are meanwhile using iPS cell technology to pave the way to better drugs. For instance, CiRAs Kohei Yamamizu recently reported developing a cellular model of the bloodbrain barrier made entirely from human iPS cells. It could become a useful tool for testing drugs for brain diseases.

All eyes, however, are back on Kobe City Medical Center General Hospital, which is resuming its retina trialthis time with iPS cells from donors instead of cells from patients themselves. Using CiRAs bank of iPS cells, there are significant time and cost savingsit could be one fifth the cost of cell preparation and patient transplant or less. The initial study, with its personalized approach, reportedly cost about $875,000 for just one patient. We plan to evaluate the efficacy of transplanting the [donor] cells and consider the feasibility of using this method as a routine treatment in the future, accessible to the wider society, study co-leader Masayo Takahashi of the RIKEN Center for Developmental Biology said at a February press conference in Kobe. Her husband Jun Takahashi, a researcher at CiRA, is also planning to use donor-derived iPS cells for a clinical applicationto help treat patients with Parkinsons disease.

Nagy admits the promise of personalized cell regeneration is probably too costly for mainstream use, and he believes genomic editingin which DNA is inserted or deletedis key to safe iPS cell implants. For his part, Yamanaka is cautiously optimistic about iPS cells as a therapeutic tool.

Regenerative medicine and drug discovery are the two key applications for iPS cells, Yamanaka says. With the use of iPS cell stock, we are now able to work quicker and cheaper, so thats the challenge going forward.

Read the rest here:
Waiting to Reprogram Your Cells? Don't Hold Your Breath - Scientific American

The most exciting aspect of our findings is that no matter what kind of brain tumor we tested it against, this treatment worked really well in the animal models, said Cheshier, who is also a pediatric neurosurgeon at Lucile Packard Childrens Hospital Stanford. In mice that had been implanted with both normal human brain cells and human brain cancer cells, there was no toxicity to normal human cells but very, very active tumor-killing in vivo, he said.

Given the encouraging results of the new study and the ongoing research on anti-CD47 antibodies in adults, the antibodies are expected to reach clinical trials in children with brain cancer in one to two years, he added.

The anti-CD47 antibodies help the immune system to detect an important difference between cancerous and healthy cells: Cancer cells make eat me signals that are displayed on their cell surfaces, while healthy cells do not. However, cancer cells hide these eat me signals by producing large quantities of CD47, a dont eat me protein that is found on the surface of both healthy and malignant cells. When CD47 is blocked by antibodies, immune cells called macrophages can detect the cancer cells eat me signals. Macrophages then selectively target, engulf and destroy the cancer cells without harming healthy cells, because normal cells lack the eat me signals.

The Stanford team conducted a long series of experiments using different combinations of tumor cells and healthy cells in culture, as well as in various mouse models in which human brain cancer cells had been implanted in mice. Highlights of their experiments included the following:

The anti-CD47 antibodies did not completely eliminate all tumors, suggesting that the antibodies may not be able to completely penetrate large tumors, the researchers noted.

To maximize their effects, the antibodies will likely need to be combined with other forms of cancer treatment, a concept the researchers plan to investigate further, Cheshier said. In the future, patients may receive combinations of immune therapies and lower doses of standard cancer treatments, he said, adding, The question is: Can we wisely combine immune therapies and other approaches to make cancer treatment more efficacious and less toxic?

Anti-CD47 antibodies also may have an advantage over other immunotherapies in that they activate macrophages, which completely engulf and eat cancer cells, Cheshier noted. In many forms of immunotherapy, the cells you target die and spill their contents, which can cause dysregulated immune responses, he said. Anti-CD47 antibodies may produce fewer such side effects, though the idea remains to be tested.

Other Stanford co-authors of the paper are medical students Abdullah Feroze, Rogelio Esparza and Michael Zhang; postdoctoral scholars Suzana Kahn, PhD, Anne Volkmer, MD and Stephen Willingham, PhD; research assistants Anitha Ponnuswami, Theresa Storm, Cyndhavi Narayanan and Pauline Chu; senior research associate Jie Liu, MD, PhD; undergraduate research associate Chase Richard; Aaron McCarthy, a former life sciences research professional and animal colony manager; Patricia Lovelace, research and development engineer; Simone Schubert, life science researcher; visiting scholar Gregor Hutter, MD, PhD; Griffith Harsh, MD, professor of neurosurgery; Michelle Monje, MD, PhD, assistant professor of neurology; Yoon-Jae Cho, MD, a former assistant professor of neurology and neurological sciences; Ravi Majeti, MD, PhD, associate professor of medicine; senior scientist Jens Volkmer, MD; Paul Fisher, MD, professor of pediatrics; Gerald Grant, MD, associate professor of neurosurgery; Gary Steinberg, MD, PhD, professor of neurosurgery; Hannes Vogel, MD, professor of pathology and of pediatrics; and Michael Edwards, MD, professor of neurosurgery.

Cheshier, Monje, Majeti, Fisher, Grant and Edwards are members of Stanfords Child Health Research Institute. Cheshier, Weissman, Harsh, Monje, Majeti, Fisher, Grant, Vogel and Edwards are members of the Stanford Cancer Institute. Weissman is the director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine and of the Ludwig Center for Cancer Stem Cell Research and Medicineat Stanford.

Scientists from SickKids, the Hospital for Sick Children in Toronto; University Hospital, Dusseldorf; and Johns Hopkins University also contributed to the study.

The study was funded by National Institute of Neurological Disorders and Stroke (grant NINDSK08NS070926); the National Cancer Institute (grant P30CA006973); the California Institute for Regenerative Medicine; the Price Family Charitable Fund; the Center for Childrens Brain Tumors at Stanford; St. Baldricks Foundation; the American Brain Tumor Foundation; the Seibel Stem Cell Institute; the Pew Charitable Trusts; the Dr. Mildred-Scheel Foundation/German Cancer Aid; the German Research Foundation; the McKenna Claire Foundation; the Matthew Larson Foundation; Alexs Lemonade Stand Foundation; The Cure Starts Now; the Lyla Nsouli Foundation; the Dylan Jewett, Connor Johnson, Zoey Ganesh, Dylan Frick, Abigail Jensen, Wayland Villars and Jennifer Kranz memorial funds; the Virginia and D. K. Ludwig Fund for Cancer Research; the Lucile Packard Foundation for Childrens Health; the National Institutes of Health (grant UL1TR001085); the Tashia and John Morgridge Endowed Pediatric Faculty Scholar and Fellowships Awards; and the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases. The study was also funded by gifts from George Landegger; Rider and Victoria McDowell; Charles Comey and Judith Huang; and Colin and Jenna Fisher.

Stanfords Department of Neurology & Neurological Sciences also supported the work.

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