McMahon discusses central role of stem cell biology in medicine of the future

Andy McMahon (Photo by Phil Channing)
Andy McMahon (Photo by Phil Channing)

USC scored a major coup when it brought scientist Andrew McMahon to the Keck School of Medicine of USC from Harvard University, where he had served for almost two decades as a star research biologist, and more recently as a professor in the Department of Stem Cell and Regenerative Biology and the Department of Molecular and Cellular Biology, as well as principal faculty member in the Harvard Stem Cell Institute.

Indeed, McMahon’s arrival at USC on July 1 was perceived to be so potentially transformative for the university and state’s regenerative medicine and biology communities that the California Institute for Regenerative Medicine presented him with a prestigious Research Leadership Award worth $5.7 million to foster his recruitment.

Now a Provost Professor and inaugural holder of the W.M. Keck Professorship of Stem Cell Biology and Regenerative Medicine at USC, McMahon has quickly lived up to his reputation as a scholar, administrator and mentor. His lab includes a team of accomplished researchers brought in tow from Harvard. Within months of his brief tenure, he published three articles in peer-reviewed journals, two in key areas of his research.

McMahon’s charge at USC is, in fact, broad: In addition to conducting research and leading USC’s regenerative medicine and biology efforts, he will recruit a new generation of top scientists to USC and teach undergraduate and graduate students. Appropriately, he also holds an appointment in the Department of Biological Sciences in the USC Dornsife College of Letters, Arts and Sciences, serves as chair of the newly created Department of Stem Cell Biology and Regenerative Medicine at the Keck School, and directs the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC.

McMahon received his bachelor’s degree from St. Peter’s College of the University of Oxford, and his PhD from University College in London. He subsequently worked as a postdoctoral fellow at the California Institute of Technology.

At a recent meeting of the Keck School Board of Overseers, McMahon spoke with Dean Carmen A. Puliafito about the future of stem cell research and medicine.

Puliafito: You were at Harvard for 19 years in the Department of Cellular and Molecular Biology, and for a while, you were the chair. You were there when Harvard organized its stem cell program. Could you talk a little bit about Harvard’s approach in setting this up?

McMahon: The person who was instrumental in setting this up was my good friend and colleague Doug Melton, the person who recruited me to Harvard. We were talking in 2005, and it was Doug’s idea that people hadn’t really thought or acted enough on the properties of stem cells and the potential of stem cells. By harnessing all the things that were going on across Harvard, this could be a rapid, highly visible and fun new initiative.

Whereas many other places about the same time thought this was a good idea, they waited until they physically could construct a building where they could house people and say that this was a stem cell center. What Harvard did that was very savvy was to say, we’ve got all these people working on things; they don’t need a building. Let’s get them to collaborate and interact and do things that they’re not currently doing. It takes time for that to happen, but it’s happened very effectively.

CP: Why did you decide to come to USC?

AM: I came because I felt like there were great opportunities to apply much of what I’d learned at Harvard to a place where I felt it would have potentially more impact.

CP: You have talked about the potential central role that stem cell biology and regenerative medicine will occupy in medicine of the future. What do you think the potential capability of cellular therapies is? If you were an investment banker and you had to make decisions about where to invest resources that would have the greatest yield in this field, what would you do?

AM: I would say that from the cellular therapy side, it’s very tough. USC is one of three institutions that I think is involved in the best first pass test of a new cellular therapy. This is Mark Humayun’s study of retinal degeneration secondary to degeneration of the retinal pigment epithelium. That’s a great test of the principle. This is a relatively simple case where you know the cell type, you could make the cell type, you know exactly where the problem is, you can put the cells exactly where that problem is and potentially restore sight to somebody who’s lost sight or at least prevent the further loss of sight in a patient. There aren’t many cases where you can be quite so precise.

I do think that the area of drugs, which we are quite used to using, is still going to be a conventional way of treating people, where we can now develop new drugs that are going to augment stem cell-based processes in people. I do see that as being the avenue that’s going to be the most successful.

CP: The stem cell governing board of the state of California has really two constituencies — academic leaders and patient advocates. The patient advocates — their dream really is for diseases of the nervous system, that you can replace cells for a cure.

AM: I think that the very best example within the nervous system is Parkinson’s disease. The problem with the work that’s happened to date around Parkinson’s disease is having a reproducible number of high quality cells that one can do a really high quality clinical trial. But for what has been done, I think the indicators are that you can have some effective treatments for Parkinson’s disease. Now with our understanding of how we can take stem cells and make the dopaminergic cells that are lost in Parkinson’s disease and get reproducible high quality cells in large numbers, I think you can actually really tackle developing effective treatments.

CP: Talk about what we mean by an embryonic stem cell, why they’re important and why they’re maybe even relevant to this issue of cell manufacture.

AM: What’s important about the embryonic stem cell is that it comes from an embryo before all of the cell types of our bodies are formed. So it has the potential to give rise to any cell type of the body. Many of our organ systems are maintained daily by specialized stem cells, which don’t have the broad potential of the embryonic stem cell to make every type of cell, but they make a broad spectrum of cell types for a certain tissue.

For example, the cells in our gut make the lining of our gut and replace that gut tissue once every five days. That gut tissue is made up of a complex mixture of different cell types. The hematopoietic stem cell makes all the cells of our blood. It’s making around about 1.5 million red blood cells a second. Those two cell types, the gut stem cell and the hematopoietic stem cell, one makes gut, one makes blood. But the embryonic stem cell has the potential to make anything under the right set of conditions. A very important development happened six years ago — and this was the discovery by the Japanese scientist Shinya Yamanaka for which they won the Nobel Prize this year. This was that you could take a small number of programming factors and add those to any cell and make them like an embryonic stem cell.

CP: So, you could take a skin biopsy, culture the skin fibroblasts and then what were the factors that they treated them with?

AM: They’re transcriptional regulators, a type of protein that regulates the activity of genes. They can then reprogram a differentiated cell to a state that’s like an embryonic stem cell [called an induced pluripotent stem, or IPS, cell]. So now that cell has the potential to generate any cell type. So that’s one hugely important development.

CP: And since they were derived from you, those cells would not have the threat of being rejected immunologically.

AM: You can make a cell line that would be compatible with putting those cells back into you. For example, you could make dopaminergic neurons from those cells and put those back into a patient such that those cells would not be rejected because those would be exactly matched to that patient. So that’s very important.

CP: So IPS has tremendous potential therapeutic implications, but it also has another important implication, which is what you might call the “disease in a dish” concept. Explain why that may revolutionize medical research.

AM: Let’s say that a drug company has developed a drug that has efficacy in being able to treat something, but it has a toxic side effect that in a certain subset of the population it causes liver disease. So let’s say we took a thousand people who represented the genetic diversity of the human population. And we made IPS cells from those thousand people and then we differentiated in a dish liver cells — hepatocytes. Now we have a thousand different types of hepatocytes that represent the diversity of the human population. We take that drug and test to see whether it causes toxicity in those hepatocytes in a dish. We can see whether we could alter the drug so it still has efficacy but it doesn’t have toxicity. None of that’s gone through a patient. It’s all gone through using our knowledge of how to make those cells from an induced pluripotent stem cell and capture the diversity of the human population.

CP: The first recruit that you brought in, Justin Ichida, who got his undergrad degree at [the University of California, Los Angeles], PhD at Harvard, is working on Lou Gehrig’s disease.

AM: In Lou Gehrig’s disease the motor neurons that control our movement and our breathing degenerate so that ultimately the patient can’t breathe and the patient will die. Ten percent of the disease in the human population comes from genetic sources. A parent has a mutation that their children inherit, and in a large proportion of the children, that mutated gene will cause the disease. For 90 percent of them, we have no idea why they come down with the disease. Now what we can do is, using the cellular reprogramming approach, you can take a skin sample from somebody who has the disease and make the motor neurons from the induced pluripotent cells and try to understand the nature of the disease within a dish — trying to understand what’s different about those cells from the cells from people who don’t have the disease. If you can get at the core of the disease, now you’ve got an assay to try and screen for drugs that can prevent whatever the pathology is in those cells.

CP: It’s very exciting.

AM: My prediction for the future is that with what we discovered with this reprogramming, these IPS cells, you could take a cocktail of transcriptional regulators, the proteins that control gene activity, you can take any cell, you can put these in and they can reprogram that cell back to an embryonic cell type. Now people are starting to think, is there a small cocktail of these transcriptional regulators that can program any cell type? In principle, if you could just go into your freezer and take these particular four transcriptional regulators and put those into a skin cell, you can directly make any cell type without even having to go back to an IPS cell.

There’s some evidence to suggest this. People are now finding you can directly program cells. You don’t have to go, for example, from skin to embryo-like induced pluripotent cell to heart. You can potentially go straight from skin to heart. That’s going to be another big area.

Mentioned in this article: Andrew P. McMahon, PhD, FRS