ARTICLE IN BRIEF
Lorenz Studer, MD, PhD, a stem cell biologist and the recipient of a MacArthur Foundation “genius” grant, discusses his 20-year quest to develop stem cell therapies for Parkinson's disease.
In October, the MacArthur Foundation announced the 24 recipients of its prestigious “genius” grants, with awardees spanning disciplines such as the arts, education, sociology, chemistry, engineering, biology, and neuroscience. Among them was Lorenz Studer, MD, PhD, founding director of the Center for Stem Cell Biology and a member in the developmental biology program and the department of neurosurgery at Memorial Sloan Kettering Cancer Center and a professor of neuroscience at Weill-Cornell Medical School in New York. The MacArthur Fellows Program awards a “no strings attached” grant of $625,000, paid out in quarterly installments over five years.
Dr. Studer's pioneering stem cell research includes the discovery of a method for generating large quantities of functional dopaminergic neurons from human pluripotent stem cells — a decades-long undertaking that could ultimately help treat patients with Parkinson's and other neurodegenerative diseases. He also developed a protocol for aging induced pluripotent stem cells to more accurately model late-life diseases. Dr. Studer spoke with Neurology Today about the long and winding road to these discoveries, and his reaction to receiving the prestigious MacArthur fellowship.
Minutes after Dr. Studer hung up the phone after being informed that he would be awarded one of the MacArthur Foundation's prestigious “genius” grants, he wondered whether it had been a fever dream. He had a temperature of 103 degrees, which had climbed to 104 by day's end. (It was unusual for Dr. Studer to fall ill; an avid cyclist, he exercises daily and rarely misses a day of work.) Luckily, an email arrived shortly afterward to confirm the award — concrete evidence of this tremendous honor.
Then came the hard part: keeping quiet for two weeks until the MacArthur Foundation made the official announcement. Dr. Studer was allowed to tell one other person, so he shared the news with his wife, Viviane Tabar, a neurosurgeon and neuroscientist at Memorial Hospital. “At least together we could celebrate a little bit,” he told Neurology Today just days after the announcement. They couldn't even tell their two children, aged 12 and 14. “But now that's over, and it's time to celebrate.”
Dr. Studer has been interested in the brain as far back as he can remember. “I was always amazed at how seemingly relatively small things, like a chemical compound, can completely change how someone behaves and change their personality,” he said. “So I got really interested in the brain, and I went to medical school to study that in the context of disease.”
It was in medical school, at the University of Bern in his native Switzerland, that Studer met a young neurosurgery fellow named Christian Spenger, who introduced him to the concept of cell transplantation in patients with Parkinson's disease. This was before the discovery of embryonic stem cells, so the young scientists were working with cells derived from fetal tissue. The project quickly blossomed. In just four and a half years, Studer and Spenger went from conducting their research in what was essentially a repurposed broom closet in the university hospital to the first clinical trial of this cell therapy in Parkinson's patients in 1995.
“It was clear to me immediately that the use of fetal tissue was not going to be a good solution,” Dr. Studer said. For one, there were the ethical concerns involved in using aborted fetal tissue. For another, the tissue simply wasn't a great source of working cells. There would be no way to generate enough viable cells to treat thousands or millions of Parkinson's patients, he realized.
By this time, stem cells had arrived on the scene, and in 1996, Dr. Studer moved to the US to work in the lab of Ronald D. McKay, PhD, who was conducting stem cell research at the National Institutes of Neurological Disorders and Stroke. There, Dr. Studer began working with brain stem cells, implanting lab-grown dopamine cells into rats with Parkinson's disease. The researchers demonstrated that transplantation could, indeed, restore brain function in the animals. But again, there seemed to be no way to generate the massive quantities of cells that would be needed for a large-scale therapy. “Yes, you didn't need that much fetal tissue anymore, maybe only 10 percent, but you still needed some,” Dr. Studer said. “You couldn't really get away from a source.”
In 2000, Dr. Studer started his own research program at Memorial Sloan-Kettering Cancer Center, where he began to work instead with embryonic stem cells. Initially, that work chugged along at a satisfying pace. He and his colleagues fairly quickly developed a technique to turn embryonic stem cells into dopamine neurons in mice. But then they started working with human cells, and promptly hit a wall. “They just would not work,” Dr. Studer said.
For eight years, Dr. Studer and his colleagues puzzled over their inability to generate dopaminergic neurons from human stem cells, when the mouse cells had worked so well. They were even able to derive other specialized cell types from human pluripotent stem cells, Dr. Studer said, including cell types from the central and peripheral nervous system. And yet the dopamine cells remained elusive. “It took a really long time to figure out that there was something in the way we made the cells, most fundamentally, that was wrong,” Dr. Studer said.
Normally, as a cell begins its journey from a fertilized egg to a young nerve cell — a process that takes about eight weeks — it is exposed to a number of molecular signaling pathways that essentially nudge the cell toward becoming a brain cell and not, for instance, a liver cell, Dr. Studer explained.
“It's a sequential set of decisions that the cell has to make to ultimately end up at a very specific cell fate. I compare it with playing a music piece,” he said. “You can play jazz and get the liver [cell], or you can play classical and get something else. By now, we can do that for about 40 cell types, and nearly all the time we can go from the stem cell to the young neural cell, then to a specialized subtype of nerve cell.”
But dopamine neurons were an exception to that process, he and his colleagues discovered. These neurons did not develop out of young nerve cells, but rather from the floor plate, a structure that's crucial to nervous system development in the embryo. “We found that the dopamine cells come from this signaling center itself,” Dr. Studer said.
Once they understood that, they were able to generate essentially unlimited quantities of stable, functional dopaminergic neurons. In several studies, Dr. Studer and his colleagues showed that these neurons were able to integrate into the brain and function as effectively as the neurons that die in Parkinson's disease, and that they did not proliferate (which could increase the risk for tumors).
And in a seminal 2011 paper published in Nature, more than 20 years after he had begun investigating cell transplantation for Parkinson's, Dr. Studer and his colleagues demonstrated that transplantation of these stem cell-derived dopamine neurons improved parkinsonian symptoms in mice, rats, and monkeys. [Read the Neurology Today article about the study, “Investigators Create Functional Dopamine Neurons: Clinical Trials in PD Could Be a Few Years Away,” at http://bit.ly/NT-studer.]
“The embryonic stem cell is like the manna in the Bible,” Dr. Studer said. “It never stops, it always grows back. You can literally make billions and billions of these stem cells, and therefore you can also, at least theoretically, make as many of those dopamine cells as you want, and they are exactly equivalent to the dopamine cells that you would have in the brain during development.”
In 2013, Dr. Studer received a consortium grant from New York State Stem Cell Science, an arm of the Empire State Stem Cell Board, which seeks to accelerate the development of stem cell therapies, to pursue a clinical trial in humans. “We are about two and a half years into a four-year project that should lead us, in 2017, to test, for the first time in the field, those lab-grown dopamine cells in patients with Parkinson's disease,” Dr. Studer said. He and his colleagues are currently working on generating the data necessary to apply for investigational new drug (IND) status from the US Food and Drug Administration.
As Dr. Studer was working on the puzzle of turning embryonic stem cells into dopaminergic neurons, another investigator, Shinya Yamanaka, MD, PhD, a Japanese stem cell researcher with appointments at the University of Kyoto and the University of California, San Francisco, was trying to do the opposite — taking a different cell type, adult mouse fibroblasts, and turning these cells back into induced pluripotent stem cells, the “blank slate” cells from which any other cell type can be derived. He ultimately succeeded, and won a Nobel Prize for the discovery in 2012.
Using Dr. Yamanaka's technique for turning mouse fibroblasts back into pluripotent stem cells, Dr. Studer was able to turn different cell types — including a patient's skin cells — back into stem cells, he explained. Then, he cultured those stem cells into dopamine neurons using the technique he and his colleagues had developed.
The next piece to the puzzle was to figure out how to age the cells. Dr. Yamanaka's technique essentially turned the cells' biological clock back to zero, Dr. Studer said. “If you make these cells, you cannot distinguish whether they came from a 90-year-old or a five-year-old. It looks like the reprogramming process erases the age signature of the cell. That's really amazing, because it indicates that a big part of what makes cells aged is reversible. But it also posed a challenge, because if the cells are young, how do we make them old again to study a disease that happens only late in life, like Parkinson's disease?”
To age these cells, Dr. Studer and his colleagues added progerin, a protein generated by a genetic mutation responsible for progeria, a rare disease that causes children to age prematurely. This sped up the cellular aging process. “So now you have an old neuron in a dish,” Dr. Studer said, “and suddenly it has symptoms of Parkinson's disease that we couldn't study before.”
Now, Dr. Studer is faced with yet another challenge: Deciding how he will spend his MacArthur grant.
“I haven't completely decided,” he said, “but I would like to use it in a number of ways.” For starters, he's considering using some of the funding to test other specialized cell types that might be therapeutic for a range of neurodegenerative disorders and musculoskeletal diseases. He also hopes to use some of the money as a mini-grant of sorts, funding creative research projects and ideas from young members of his lab that might otherwise require a great deal of working through red tape and jumping through institutional hoops to get off the ground.
“I think it's important that you don't always follow the cookie-cutter system in science,” he said. “I like this analogy: What would happen if tomorrow you were abducted by an alien? Would anything change in your field? Would there be any difference? It's interesting to try to do something that's a bit out of the box. It might fail, but at least for me, that keeps me motivated and excited.”
With that unconventional, creative spirit in mind, and knowing that he's come up with some of his best ideas while cycling, he is also planning to set aside some of the MacArthur money for a new bicycle, he said. “The one I'm using is about 15 years old by now.”