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How do fingers become fingers and not toes? How does the brain generate the correct number of neurons? How do the kidneys branch into the complex and elegant structure that filters the blood and regulates its pressure?
Renowned biologist Andy McMahon spent decades unlocking these and other mysteries of embryonic development by identifying the role of key regulatory genes. By the time he decided to leave Harvard University for USC, he was ready to take on a new challenge: finding cures for patients with kidney disease.
“I felt like I could figure out how to do things that were interesting,” said McMahon. “Could I figure out how to do things that were relevant?”
With support from a $5.7 million Research Leadership Award from the California Institute for Regenerative Medicine (CIRM), McMahon headed west to find new ways to repair and regenerate the kidney.
One in 10 adults in the U.S. — more than 20 million people — are suffering from some degree of chronic kidney disease. Kidney transplants offer a hope for cure, but thousands of patients die each year due to a shortage of donor organs. Even patients who are lucky enough to receive transplants run the risk of their immune systems rejecting the donor kidneys, and they have to take immunosuppressive drugs with serious side effects for the rest of their lives.
Vito M. Campese, professor and chair of the Keck School of Medicine of USC’s nephrology division, underscores the need to find novel stem cell-based therapies for these patients.
“Despite enormous progress made in the last 50 years, as of today, we do not know the causes of many kidney diseases and how to best treat them,” said Campese, who also chairs the Medical Scientific Advisory Board of the University Kidney Research Organization (UKRO), a Los Angeles-based nonprofit group that recently established the USC/UKRO Kidney Research Center at the Keck School.
As a member of UKRO’s Medical Scientific Advisory Board and medical director of USC’s Kidney-Pancreas Transplant Program, Yasir Qazi can easily envision how stem-cell based therapies could help the patients he treats every day.
“We are looking to partner with Andy McMahon to improve and take the clinical experience of an organ transplant recipient to a completely new level,” he said.
UKRO founder Kenneth Kleinberg, who received a kidney transplant in 2007, added: “If we are to lift the scourge of kidney disease and the staggering financial burdens it imposes, the answers lie in research.”
The promise of such research is to usher in the era of regenerative medicine, which uses the power of stem cells to restore the function of damaged tissues or organs.
As the director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, McMahon is encouraging colleagues across USC to follow his lead in discovering new regenerative therapies for a broad array of diseases.
To this end, he recently recruited three stellar young faculty members: Justin Ichida; Rong Lu; and Min Yu.
Ichida is leading the USC stem cell research center’s newly opened Choi Family Therapeutic Screening Facility, where scientists can test potential drugs on reprogrammed stem cells from patients.
An expert in neurodegenerative diseases, Ichida is conducting some of the facility’s first screens — testing drug-like compounds on motor neurons formed by directly reprogramming skin cells from patients with Lou Gehrig’s disease. If one of these compounds keeps the motor neurons alive in the petri dishes, it may also keep them alive in the patients.
As a postdoctoral scholar at Harvard University, Ichida laid the foundation for his current research by helping identify new ways to make induced pluripotent stem (iPS) cells.
“I just want to do something that really changes people’s lives,” he said.
Lu’s research is equally transformative: her studies of what makes one blood stem cell outcompete another have ramifications for improving bone marrow transplants and preventing blood cancers.
As a postdoctoral scholar at Stanford University, Lu came up with the idea of “barcoding” individual blood stem cells by labeling them with a genetic marker. This allows her to observe individual cells’ behavior, interactions, self-renewal or differentiation, and contributions to forming blood.
“The most important reason I came to USC is the people here,” said Lu. “The stem cell department is growing, and everybody’s having new ideas and really being interactive and collaborative. You can feel the energy here.”
This dynamic, multidisciplinary research environment also attracted Yu, whose research focuses on finding new cures for breast cancer. Recruited in conjunction with the USC Norris Comprehensive Cancer Center, Yu filters out circulating breast cancer stem cells from billions of other blood cells to understand how the disease spreads and stop it in its tracks.
Yu did her postdoctoral work at Massachusetts General Hospital (MGH) in the lab of Daniel A. Haber, MD, PhD, who was collaborating with clinicians and bioengineers to study circulating tumor cells, which enter the bloodstream and metastasize at distant sites.
“Our director Andy McMahon also has a vision of uniting the bioengineering and medical fields, and applying basic science to clinical science,” she said. “He’s very passionate about helping young faculty start their labs and set up collaborations, so I’m excited to join.”
Also new to the center is senior faculty member Neil Segil, who is working to regenerate inner ear cells to treat hearing loss and balance disorders, which affect more than half of all adults in the U.S. by the time they reach retirement age.
To achieve this goal, he studies the developmental processes that shape the complex structures of the inner ear, the mechanisms that allow for the lifelong survival of inner ear cells, and the damage caused by noise, certain antibiotics and chemotherapy.
“Since arriving at USC, I’ve had the opportunity to collaborate with investigators with different kinds of expertise and who have not previously worked together,” Segil said. “This kind of cross-fertilization is very stimulating.”
These and the next wave of recruitments already underway will benefit from a $2 million gift from The Eli and Edythe Broad Foundation. The gift establishes the Broad Fellows Program, provides seed funding to early stage research initiatives and supports the stem cell research center’s state-of-the-art facilities in imaging, therapeutic screening, flow cytometry, and stem cell isolation and culture.
McMahon is mentoring the next generation as the director of the new Department of Stem Cell Biology and Regenerative Medicine, which offers a PhD, Master of Science and undergraduate courses, the first of which was taught by McMahon for 19 students on the University Park Campus this spring. The center also hosts a unique internship opportunity for talented high school students.
To further harness the power of collaboration, McMahon leads the university-wide USC Stem Cell initiative, bringing together more than 100 faculty members from all disciplines.
As part of USC Stem Cell, Keck School Dean Carmen A. Puliafito provided $1.2 million in Regenerative Medicine Initiative (RMI) awards to three disease teams to take early steps towards stem-cell based therapies for certain forms of deafness, bone defects and pediatric leukemia.
A fourth USC Stem Cell Kidney Disease Team is advancing the synergy between different laboratories across USC. Janos Peti-Peterdi is leading monthly meeting with USC kidney researchers McMahon, Campese, Laura Perin, Alicia McDonough and others.
The interdisciplinary effort extends beyond medical research. An economic impact analysis of Proposition 71, which created CIRM to fund stem cell research, is being planned with the USC Marshall School of Business. Students from the USC Roski School of Art and Design have conducted spring coursework in the center, finding inspiration from the beauty of science in action.
In the years to come, USC will continue to shape our future as stem cell biology moves from discoveries to cures.
As McMahon explained, “I need to strongly encourage an atmosphere where people are thinking beyond the basic science and thinking about how they can take that to new therapeutic end points for regenerative medicine.”