For the 10th anniversary of the discovery of iPSCs, CIRM spoke to three of their grantees about the impact of iPSC technology on their research and the regenerative medicine field as a whole.
In August 2006, the landmark Takahashi/Yamanaka Cell paper was published which described the successful reprogramming of adult skin cells into an embryonic stem cell-like state, a.k.a. induced pluripotent stem cells (iPSCs). What do you remember about your initial reactions to the study?
Sheng Ding, MD, PhD (Senior Investigator, Gladstone Institute of Cardiovascular Disease): Shinya had talked about the (incomplete) iPSCs work well before his 2006 publication in several occasions, so seeing the paper was not a total surprise.
Alysson Muotri, PhD (Associate Professor, UCSD Dept. of Pediatrics/Cellular & Molecular Medicine): At that time, I was a postdoc. I was in a meeting when Shinya first presented his findings. I think he did not give the identity of the 4 factors at that time. I was very excited but remember hearing rumors in the corridors saying the data was too good to be true. Soon after, the publication come out and it was a lot of fun reading it.
Joseph Wu, MD, PhD (Director, Stanford Cardiovascular Institute): I remember walking to the parking lot after work and a colleague called me on my cell phone and he asked if I had seen “the Cell paper” published earlier that day. I read it that night and found it quite interesting because the concept was simple but yet powerful.
How soon after the publication did you start using the iPSC technique in your own research? At that time, what research questions were you able to start exploring that weren’t possible in the “pre-iPSC” era?
Ding: I think many of us in the (pluripotent stem cell) field quickly jumped on this seminal discovery and started working on the iPSC technology itself as, at the time, there were many aspects of the discovery that would need to be better understood and further improved for its applications.
Muotri: Immediately after the first mouse Cell paper, but I started with human cells. There were some concerns if the 4 factors will also work in humans. Nonetheless, I start using the mouse cDNA factors in human cells and it worked! Thus, I started to apply this to model disease, my main focus. In 2010, we published the modeling of the first neurodevelopmental disease using the iPSC technology. It is still a landmark publication, and I am very happy to be among the pioneers who believed in the Yamanaka technology.
Wu: We started working on iPSCs about a couple of months after the initial publication. To our surprise, it was incredibly easy to reproduce, and we were able to get successful clones after a few initial attempts, in part because we had already been working on human embryonic stem (ES) cells for several years. I think the biggest advantage of iPSCs is that we can know the medical record of the donor. Therefore, we can study the correlation between the donor’s underlying genetic makeup and their resulting cellular and whole-body characteristics using iPSCs as a platform. Examining these correlations is simply not possible with ES cells since no adult donor exists.
Dr. Ding, what do you think made you and your research team especially skilled at pioneering the use of small molecules to replace the “Yamanaka” reprogramming factors?
Ding: We had been working on identifying and using small molecules to modulate stem cell fate (including cell proliferation, differentiation, and reprogramming) before iPSC technology was reported. So when the iPSC work was reported, it was obvious to us that we could apply our expertise in small molecule discovery to better understand and improve iPSC reprogramming and replace the genetic factors by pharmacological approaches.
Now, come back to the present and reflect on how the paper has impacted your research over the past 10 years. Describe some of the key findings your lab has made over the past 10 years through iPSC studies.
Ding: We’ve worked on three aspects that are related to iPSC research: one is to identify small molecule drugs that can functionally replace the genetic reprogramming factors, and enhance reprogramming efficiency and iPSC quality. The second is to better understand the reprogramming mechanisms, that would allow us to improve reprogramming and better utilize cellular reprogramming technology. The third is to “repurpose/re-direct” the iPSC reprogramming into directly generating tissue/organ-specific precursor cells without generating iPSC (itself, which is tumorigenic and needs to be differentiated for most of its applications).
Muotri: My lab has focused on the use of iPSCs to model autism spectrum disorder, a condition that is very heterogeneous both clinically and genetically. Previous models for autism, such as animals and postmortem tissues, were limited because we could not have access to live neurons to test experimentally several hypotheses.
While the modeling in a dish was a great potential, there were some clear limitations too: the variability in the system was too high for example. My lab has worked hard to develop a chemically-defined culture media (iDEAL) to reduce the variability in growing iPSCs. Moreover, we have developed robust protocols to analyze the properties of cortical neurons derived from iPSCs. We have used these methods to learn more about how genes impact neuronal networks and to screen drugs for several diseases.
We also used these methods to create cerebral organoids or “mini-brains” in a dish and have applied this technology to test the impact of several genetic and environmental factors. For example, we recently showed that the Zika virus could target neural progenitor cells in these organoids, leading to defects in the human developing cortex.
Wu: Our lab has taken advantage of the iPSCs platform to better understand cardiovascular diseases and to advance the precision medicine initiative. For example, we have used iPSCs to elucidate the molecular mechanisms of diseases and have also used iPSCs for testing the safety and efficacy of various cardiovascular drugs (i.e., “clinical trial in a dish”).
How are your findings important in terms of accelerating stem cell treatments to patients with unmet medical needs?
Ding: Better understanding the reprogramming process would allow more effective generation of safe stem cells with reduced cost for treating diseases or doing research.
Muotri: We work with two concepts. First, we screen drugs that could repair the disorder at a cellular level in a dish, which could help a large fraction of autistic individuals. This strategy should help future clinical trials. In parallel, we also work with the idea of personalized medicine by using patient-derived cells to create “disease in a dish” models in the lab. We then examine the genomic information of these cells to help us find drugs that are more specific to that individual. This approach should allow us to better design the treatment, testing ideal drugs and dosage, before prescribing it to the patient.
Wu: With iPSCs, we should be able to better understand how cardiac and vascular cells regenerate in the heart during different phases of human life and also during times of stress such as in the case of a heart attack. Equally importantly, we need to understand how transplanted cells integrate into the patient because based on our experience so far, most of the injected cells die upon transplant into the heart. Finally, the economics of this type of personalized regenerative medicine is a daunting challenge.
Finally, it’s foolhardy to predict the future but, just for fun, imagine that I revisit you in August 2026. What key iPSC-related accomplishments do you think your lab will achieve by then?
Ding: We are hoping to have cell-based therapy and small molecule drugs developed based on iPSC-related research for treating human diseases. Particularly, we are also hoping our cellular reprogramming research would lead us to identify and develop small molecule drugs that control tissue/organ regeneration in vivo [in an animal].
Muotri: We hope to have improved several steps on the neural differentiation, dramatically reducing costs and increasing efficiency.
Wu: We would like to use the iPSC platform to discover several new drugs (or repurpose existing drugs) for our cardiovascular patients; to replace the current industry standard of drug toxicity testing using the hERG assay (which I believe is outdated); to predict what medications patients should be taking (i.e., precision cardiovascular medicine); and to elucidate risk index of genetic variants (in combination with genome editing approach).
(Ed: This interview was edited for length. The original interview can be read here.)