Human cortex grown in a petri dish. Eye diseases treated with retinal cells derived from a patients own skin cells. New drugs tested on human cells instead of animal models.

Research and emerging treatments with stem cells today can be traced to a startling discovery 10 years ago when Shinya Yamanaka, M.D., Ph.D., and his graduate student Kazutoshi Takahashi, Ph.D., reported a way to reprogram adult mouse cells and coax them back to their embryonic state pluripotent stem cells.

A year later, they accomplished the feat with human cells. For this research coup and his leading role pioneering stem cell work, Yamanaka who holds academic appointments at Kyoto University and UC San Francisco was the co-recipient of the 2012 Nobel Prize in Medicine or Physiology.

The breakthrough provides a limitless supply of induced pluripotent stem cells (iPSCs) that can then be directed down any developmental path to generate specific types of adult cells, from skin to heart to neuron, for use in basic research, drug discovery and treating disease.

The achievement opened up a practical way and in some critical cases, the only way to directly study human diseases in a dish, and track the early stages of both healthy and abnormal development. It also allowed researchers to screen new drugs directly in human cells rather than relying on animal models, which more often than not fail to accurately predict a new drugs effects on people.

The dazzling iPSC breakthrough has spurred rapid progress in some areas and posed major challenges in others. It has already proved a boon to basic research, but applying the new technology to treat diseases remains daunting. Some types of cells have proved difficult to reprogram, and even the protocols for doing so are still in flux as this is still a very young field.

For many basic biomedical scientists, the capability offered by iPSCs technology is like a dream come true, says neuroscientist Arnold Kriegstein, M.D., Ph.D., director of UCSFs Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research.

Induced pluripotent stem cells have given us a window into human development unlike anything we had before, Kriegstein said. Im interested in the early development of the brains cortex. Of course, weve never had unrestricted access to living human brain cells. Now we can take skin cells and grow human cortex in a dish. Its a game-changer for discovery about early human development.

Kriegstein is enthusiastic about what researchers can learn from organoids a pea-sized stage of a developing organ derived from iPSCs. By this stage, cells are already clumping together and starting to signal and differentiate into what will become the adult organ.

Its a very close model of the real thing, Kriegstein says. We have recently discovered that even in this early stage, the organoids are able to develop intrinsic organization, including a front-and-back orientation, and different parts start to look like they do in the embryonic brain.

Some scientific papers have suggested that organoids can model diseases found in adulthood even disorders of late adulthood such as Alzheimers disease.

Even though organoids can reveal developmental steps not seen before, Kriegstein worries that some researchers are getting too far ahead of themselves.

Its an embryonic brain, he stresses. The longest period of growth we can model would be full fetal development. How likely is it that gene expression, cell signaling and a myriad of other interactions at this organoid stage could accurately represent the development of Alzheimers disease, a disease that affects people at 60 or 70?

I think we need to take some of these studies with a grain of salt. Stem cell technology now is so variable that replication is difficult. We need to establish protocols to reliably compare different methods and then use these standardized methodologies to advance research and treatment. But I am 100 percent convinced that we will get there.

Yamanaka currently directs the 500-person Center for iPS Cell Research and Application at Kyoto University, runs a research lab at the Gladstone Institute for Cardiovascular Disease in San Francisco, and serves as a professor of anatomy at UCSF, and Takahashi is a visiting scientist at the Gladstone Institutes and runs Yamanakas lab there. Both have continued to build on their iPSC work, as have other researchers.

In their seminal work, Yamanaka and Takahashi had introduced four genetic factors to prompt adult cells back to the pluripotent state. Soon after their iPSC breakthrough, Sheng Ding, Ph.D., who has a lab at the Gladstone Institutes and is a professor in UCSF's Department of Pharmaceutical Chemistry, began refining the reprogramming cocktail.

Eventually, Ding was able to substitute drug-like molecules for these gene transcription factors, eliminating the risk of new genetic material altering the cells. Today, labs around the world pursue and tout different chemical recipes, often depending on the type of cell they are trying to reprogram.

Other recent advances to induce pluripotency harness different kinds of proteins that influence gene activity in the cell nucleus. Robert Blelloch, M.D., Ph.D., a stem cell scientist at UCSFs Broad Center, has shown that some small RNA molecules called microRNAs promote adult cell de-differentiation and others promote the reverse: ability of stem cells to differentiate into adult cells. By tweaking microRNA activity, his lab has been able to improve reprogramming yields a hundred-fold.

He and colleagues have also become intrigued by the role of so-called epigenetic factors naturally occurring or introduced molecules that modify proteins in the nucleus. Manipulation of these molecules too can affect the efficiency of inducing pluripotent cells.

Six years after Yamanakas iPSCs discovery, researchers in a very different field developed a new gene-editing technology of unprecedented speed and precision, known as CRISPR-Cas9. The potent new tool has revolutionized efforts to cut and paste genes and has been very quickly adopted by thousands of researchers in basic biology and drug development.

CRISPR has provided us with an extraordinary new capability, Kriegstein says. It allows us to tease apart the genetic causes or contributors to developmental diseases. We can edit out mutations to determine if they are critical to early developmental defects.

CRISPRs speed and precision may some day allow stem cell researchers to reach their most ambitious goal: Genetically abnormal cells from patients with inherited diseases such as sickle cell anemia or Huntingtons could be reprogrammed to the pluripotent stem cell state; their genetic defects could be edited in a petri dish before being differentiated into healthy adult cells. These cells could then be transplanted into patients to restore normal function.

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Induced Pluripotent Stem Cells: 10 Years After the ...