Pluripotent Profiles

Joseph C. Wu
Joseph C. Wu
Professor, Dept of Medicine & Radiology and Director, Stanford Cardiovascular Institute, Stanford University

As a dual MD/PhD, Joseph Wu is both a practicing cardiologist and active stem cell researcher with a unique perspective on the future applications of stem cell research for patients. The Wu lab works on understanding the biological mechanisms of several major stem cell types. In the area of pluripotent stem cells, the lab works on mechanisms of differentiation, novel iPSC derivation techniques, and creation of iPSC-derived cellular based assays for drug screening and drug discovery.

1. Tell us about yourself:
I did my MD at Yale, medicine residency and cardiology fellowship at UCLA, and PhD in molecular pharmacology at UCLA. Afterwards, in 2004, I started working at Stanford. I balance my time among basic research, clinical care, and administrative responsibilities.

We are very much interested in the translational aspect of pluripotent stem cells. For example, I currently have a CIRM funded grant to work on human embryonic stem cells with the goal of obtaining an IND for heart failure treatments. Stem cell therapy will bring tremendous advances for the treatment of a variety of diseases, but we first have to address issues that are potential clinical hurdles, such as immunogenicity, tumorigenicity, differentiation, safety, and efficacy in both small animal and large animal models.

2. How did you decide on a career in research?
When I was at Yale School of Medicine, we had to complete a research thesis component to graduate. During that time, I realized that I enjoyed doing research. So after graduation, I decided to pursue my interest in research and was accepted to the UCLA Specialty Training and Advanced Research (STAR) Program. The STAR program allows fellows and residents to combine their medical training with research training to pursue a PhD, and provided a really solid foundation for me as a researcher.

3. Who is your scientific idol?
When I was a medical student, my scientific idol was Dr. Barry James Marshall, who demonstrated that the cause for most peptic ulcers is H. pylori infection. He eventually received a Nobel Prize for this discovery in 2005 for its major impact in the medical field. His first paper on H. pylori and peptic ulcer disease was published in the Medical Journal of Australia, a relatively obscure journal. His theory was not widely accepted at first because it was too different than conventional wisdom at the time. However, the discovery had such a dramatic impact that it has revolutionized the way physicians treat peptic ulcer disease.

On PSC Research

1. What is your opinion on the equivalency of ES and iPS cells?
Overall, I think ES and iPS cells are very similar, but if you compare them on a deeper level, there would be some minute cellular differences. As an analogy, for example, people will claim that overall, identical twins are the same. However, if you look more closely at the finer features, you can spot minute differences between them. That said, I’m not certain that biological differences between ES and iPS cells will translate into functional differences. That needs to be further tested and it’s one of the things I’m currently focused on studying in our lab.

2. In terms of iPS cell research, what do you think will make the biggest impact for your patients?
We are convinced that 10 to 20 years from now, patients will have medicine tailored to them at the cellular level by using surrogate iPS cell derivatives for drug efficacy testing. Currently, when a patient shows up at a clinic with high blood pressure, the doctor will prescribe one of the popular anti-hypertensive medications. A week later, the patient may come back claiming that the medication isn’t working and the doctor will switch to another drug, for example switching from beta-blocker to a calcium channel blocker. When the patient does not come back or call back to the clinic, it probably means that the prescribed drug is working. However, this is a hit-or-miss approach because we’re operating on educated guesses. The reality is that we have a variety of drugs out there to treat the same disease, but we don’t know which one works best for each individual. In this scenario, the patient is the guinea pig. Our goal is to eliminate the guess work by personalizing medicine to each individual patient.

I am a firm believer that 10 to 20 years from now, we should be able to draw blood, make iPS cells, differentiate them into cardiac cells or other cell types, and expose these cells to different drugs to find out what would be the ideal drug for that patient. This is the future of personalized medicine. To get there, we need to develop standardized assays for evaluating the effectiveness of the drugs objectively and accurately. I think it is a matter of time before we get there.

3. Do you see iPSCs being used to assess the cardiotoxicity of drug candidates?
I think if you look at drug companies, one of the most common causes for drugs being withdrawn post-marketing is because of cardiotoxicity. Most drug companies currently do not have access to human cardiomyocytes, so drug candidates cannot be tested for cardiotoxicity. Instead they test the drugs in either animals models or cell lines such as Chinese Hamster Ovary (CHO) cells or Human Embryonic Kidney (HEK) cells. In the late 1980s, the hERG channel gene was discovered and was cloned into CHO cells. The hERG channel is a delayed rectifier potassium channel that is found in human cardiomyocytes. Since scientists can’t readily access cardiomyocytes for drug testing, they use the alternative CHO cells genetically manipulated to overexpress hERG. However, a significant difference is that cardiomyocytes express several different major channels, whereas CHO cells only express the genes for hERG channels. As a result, there are many examples of false positive or false negative results in drug toxicity screening tests in CHO cells.

One example of a false positive is verapamil. It’s an L-type calcium channel blocker that acts on the phase 2 action potential duration and causes short QT interval. It also has a potent hERG blocking effect which causes long QT interval, so the net result is neutral. However, if you test verapamil on CHO cells, the results will say that it’s toxic because it is only measuring the hERG blocking effect. But it is quite safe in patient-specific iPS cells that we’ve tested in our lab because these cells have more than just the hERG channel. The reason verapamil is on the market is because it was pushed to market prior to the development of the CHO cell model and there weren’t any significant adverse effects in patients. That’s why I think you will see in the next 10 years, many pharmaceutical companies switching their drug testing model to iPS cells. It will take time, because you’re asking them to give up on the model they’ve been using for the past 20 years and switch to something new, which will require developing new assays.

4. Do you foresee any other technical hurdles to having iPS cells accepted as the drug testing model?
I think the issues of electrophysiological maturation, cost of production, and standardization will first need to be worked out. After that, I think it’s just a matter of time for iPS cells to become the accepted model for drug testing. Once one or two pharmaceutical companies have positive beta test results and switch from the CHO cell model to iPS cell model, other pharmaceutical companies will likely follow suit as well. The advantages of iPS cells over the conventional model are too great to ignore.

On mTeSR™1

1. How long have you been using mTeSR™1 and why did you start using it?
We started using mTeSR™1 about five years ago, because of STEMCELL Technologies’ well known reputation for quality reagents.

2. How has mTeSR™1 enabled your research?
Before mTeSR™1, the media used to culture pluripotent stem cells was conditioned media, which meant more cell work time to obtain the media and the presence of undefined components in human cell cultures. mTeSR™1 was the first defined media which allowed us to grow human pluripotent stem cells in a more reliable way avoiding the variability from batch to batch of conditioned media and in a more clinically relevant manner by eliminating mouse embryonic feeder cells from our cultures.

3. Have you had any experience with E8-based media, or had a chance to compare it to mTeSR™1?
Overall, we’re happy with the media STEMCELL Technologies provide for us. We did find that certain cell lines didn’t differentiate as well when transitioned from mTeSR™1 to E8. It may be partly because the lines have adapted to mTeSR™1. Also, a large number of variables are involved in cell differentiation and our current protocol for differentiation is quite well-established.

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