We spoke to Andrew P. McMahon, Ph.D., director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at the University of Southern California, about the nature of his innovative stem cell research and what it could mean for people living with advanced kidney disease.
Andrew P. McMahon, Ph.D.
Director, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California
“This kidney project is extremely complex — nothing like this has been attempted before.”
What should the average person know about stem cell research?
Many of our body systems have stem cells that repair and regenerate the body systems on a daily basis. So skin, the blood, the intestine, those can all be replaced by stem cells. But many organs don’t have their own stem cells.
We have the ability to make cells that are very similar to cells that are in development in the embryo from a simple tissue sample from anyone. And those cells can, under the right conditions, make any cell type.
Stem cells have been used therapeutically for over five decades for the bone marrow transplant most people are familiar with. But now people are using these new types of stem cells to generate disease models and better understand human disease biology, to look for drugs that could treat those diseases, and to actually engineer cells that can themselves be therapeutic.
Do you have any suggestions for people who are considering joining a clinical trial for stem cell therapy?
It very much depends on the type of indication they’re looking at. I would try to understand the nature of the trial — what people are trying to learn from that trial. And to make sure, of course, that the trial is a proper FDA-approved trial.
I found, just like with the UKRO [University Kidney Research Organization], that the patient advocate groups that are there to help patients with specific diseases are wonderful resources to talk to about these types of questions. I would suggest anyone considering a clinical trial contact the patient advocate groups within their own disease areas, as they are usually the best informed about what’s going on.
What is so exciting about research in stem cell regeneration?
We’re very interested in using these pluripotent, self-renewing stem cells that are embryo-like to make kidney cell types that are like stem cells, called progenitor cells. The key difference between stem cells and progenitor cells is that stem cells can replace themselves indefinitely, as well as making a whole bunch of specialized cell types. But progenitor cells have a more limited lifetime. The kidney is built from a certain number of different progenitor cell types, and the interactions amongst those progenitor cells. Once you’ve made a kidney, those progenitor cells are lost — there are no stem cells. So, the kidney has limited capability of repair and regeneration, compared to many other organs.
My USC colleague Dr. Zhongwei Li is developing strategies to engineer each progenitor cell type — creating the building block for making a kidney. He takes pluripotent stem cells and perfects the making of each individual stem cell. And then by combining those progenitor cells together, just like what occurs in the first stages of development of the kidney in utero in the fetus, those cells interact with one another and actually self-organize and build a kidney. The early results are truly impressive — self-organizing, synthetic kidneys displaying critical kidney activities.
The idea is that the process will generate a new kidney that can go into a patient and will be able to function where that patient has lost kidney function. Ultimately, we want to aim at patients that are on the waitlist, have entered the process of dialysis — which has poor morbidity and poor mortality — and keep them off dialysis so they can live a healthy end of life.
The goal isn’t to make a kidney that’s as functional as the average person’s, but to provide maybe 15% of a kidney’s function, which will keep those people off dialysis.
There is a great significance for those patients that actually will benefit from getting these kidney implants, because many of those patients have secondary problems (e.g., cardiac problems, liver problems) because of the problems with malfunctioning kidneys. But the whole concept of engineering functional organs has a much larger potential to generate functional systems for any of our functioning body systems.
What led you to this research? And where can this research take us in the future?
I’ve been working in this area for quite some time trying to understand how the kidney is built, because the understanding about how you build a kidney enables you to build the new kidneys. There’s a wonderful collaboration that’s been enabled through the resources of the UKRO, which has allowed us to take our expertise in kidney development to help Dr. Li’s efforts to direct stem cells toward generating functional kidney structures.
This kidney project is extremely complex — nothing like this has been attempted before. So, at this stage, we’re aiming to make prototypes that can be assayed in animal model systems within the next five years. And then on the basis of those animal model systems, we want to move forward in the next 10 years toward making kidneys that could be assessed in patients.
Can people join clinical trials to aid this kind of research?
Nationally, you can go to National Institutes of Health’s clinicaltrials.gov and look to see what clinical trials are going on, and what’s going on in the stem cell area. There is a real need for people to be engaged in bonafide high caliber, highly scrutinized stem cell research, because this is still at a very early stage. And we really need to find out much more about the properties of stem cell-generated systems through clinical trial. It is really at the building and modeling stage.
I think the way people could get more engaged in this is supporting this type of research effort. Research like that supported in Dr. Li’s laboratory by the UKRO is contingent upon funding to make advancements and strides — research dollars and support funding is critical to expediting that process.
This is an important biomedical problem that we’re trying to solve here, and it requires considerable research to push forward. And the funding of research is a little strange. In many respects, this is research that’s aimed at making a product: a functional kidney.
You might believe that’s exactly the sort of thing that the National Institutes of Health and major government research fund, but it’s not. What they tend to fund is hypothesis-driven, question-orientated research, rather than direct, goal-orientated research like this. So, we really need to find other mechanisms of funding to be able to push forward this type of approach therapeutically.
UKRO has been incredibly helpful in spearheading this effort. We’ve become a sort of center of expertise for all things related to generating kidney structures.
I also really want to give a shoutout to the California Institute for Regenerative Medicine, a unique California tax-payer initiative to advance stem cells toward regenerative therapies. In order to get their sponsorship, we need outside support to push the research far enough along to get their additional support and have them help propel the research toward the clinic.
I want to emphasize the incredible team effort — including Dr. Nils Lindstrom’s group pioneering alternative approaches to kidney engineering through directed stem cell differentiation. It’s this wonderful synergism between the expertise of a large number of people coming together. It isn’t just me who’s involved, but there are many scientists and clinicians involved in this effort to change the lives of millions of Americans.