The Regenerator

In his search for effective therapies for Parkinson’s disease, Lorenz Studer is uncovering pluripotency switches and clues to what makes cells age.

By | December 1, 2015

LORENZ STUDER
Director and Founder, Center for Stem Cell Biology; Member, Developmental Biology Program, Memorial Sloan Kettering Cancer Center Professor, Department of Neuroscience,
Weill Cornell Graduate School of Medical Sciences 2015 MacArthur Fellow
JOHN D. & CATHERINE T. MACARTHUR FOUNDATION
As a medical school student at the Universities of Fribourg and Bern in Switzerland in the late 1980s, Lorenz Studer had two inspiring mentors who were instrumental in switching him from a clinical track to one in laboratory research. Mario Wiesendanger, a neuroscience professor at the University of Fribourg, “showed me how to think about science and presented what was and was not known in neuroscience, which got me very interested in brain research,” says Studer. Because there was no university-based training hospital at Fribourg, Studer transferred to the University of Bern after he completed the first two years of medical courses. There, he met Christian Spenger, a neurosurgery fellow who introduced him to a then-novel type of therapy—cell transplantations into the brain—for Parkinson’s and other neurodegenerative diseases. “He was not much older than me, and full of energy. He got me excited about cell therapies,” says Studer. “I learned from him that if you believe in an idea, that you can push it forward by your energy and finding the right people to support you. And to not be afraid to be risky or unconventional.” Spenger—and Hans-Rudolf Lüscher, the head of the physiology department, who became Studer’s official advisor—emboldened Studer to do a laboratory research–based thesis rather than the clinical case write-ups that most medical students completed.

“When you don’t get the results you want, you change strategy, make other things happen, and begin to understand basic principles.”

“There was no clear MD-PhD path, so it was a bit unusual for medical students to stay on and do research,” says Studer. After finishing medical school in 1991, Studer remained at the University of Bern for five more years and earned an unofficial PhD, working with Spenger on cell-based neurology therapy, initially in animals, then in humans.

Collaborating first in a tiny makeshift lab, Studer and Spenger worked up to the first Swiss clinical trials of a fetal cell–derived therapy for Parkinson’s disease in 1995. The human study inspired Studer to look for alternative cell sources to treat Parkinson’s. “Seeing how cumbersome the cell procedure was made it clear that it was not that easy to take fetal tissue and cure Parkinson’s, and that we had to come up with something more defined and efficacious.”
Here, Studer talks about what made him to go into research, how the 1996 “blizzard of the century” and then a government shutdown hindered the start of his postdoc, and how he thought the news of his 2015 MacArthur fellowship was just a dream.

Studer Sets Up

Traits on track. Studer grew up in Hägendorf, Switzerland, a small village between Basel and Bern. He says he already had the characteristics of a future scientist—persistence and an aptitude for categorization. In grade school, Studer collected model cars and charted their specs, cataloging each systematically. He also played sports and competed in track and field. “I was very excited about competition. I was very intense about anything that sparked my interest,” he says.

Family history of disease. Studer became interested in medicine after experiencing several deaths in his family from cancer, including brain tumors. “I was amazed by how little could be done about these conditions. I had an aunt and uncle die, leaving their children parentless.” The potential fragility of the human body impressed him, as did the ability of substances like LSD to alter the state of the mind, if only temporarily. “I wanted to understand how the brain could be altered. And I had the naive feeling that one should be able to do more to help people with diseases.”

Brain organoids. “Spenger and I worked with rat fetal tissue, isolating the right brain region with dopaminergic neurons. We developed a technique to identify the correct anatomical marks and then dissect out the tissue to grow in culture. There is a lot of current excitement about organoids. What we had then, a 3-D piece of tissue that grew in media, was an early version of an organoid culture.” Studer measured the dopamine the cells secreted into the medium, learning how to select the highest-quality tissue for transplantation, as loss of dopamine-secreting neurons in the midbrain is one of the causes of Parkinson’s disease. He and his colleagues first tested the technique of human fetal nerve-cell transplantation in rats, and then, in 1995, the first patient received a transplant. It remained unclear at that time whether the transplantations were successful, and the program at the University of Bern fell apart, says Studer, after he and Spenger left. “But in other countries, where similar, independent therapies were being tested, some of the transplantations appeared to work. The graft could have remarkable impact on the dopaminergic system in a 5- to 10-year period, although patients were not perfectly healthy because other systems are still affected. At the time, we didn’t know that you had to wait a few years. We thought you should see results in six months.”

Studer Sprints

Fated for stem cells. Lüscher got him to think beyond fetal tissue to stem cells. “I started to conceptualize a broader project for neurodegenerative diseases,” says Studer. After presenting a paper on neuronal stem cells by Ron McKay’s lab at a journal club, Studer became fascinated by the idea that stem cells could be maintained in a lab dish and turned into neurons. McKay’s group at the National Institutes of Health (NIH) was one of only a handful working on such methods. Studer began a postdoc in McKay’s lab in 1995 with the goal of growing brain stem cell–based dopaminergic neurons as a potential therapeutic implant. There, he learned how to isolate neural stem cells from mice and rats and began to coax them to become mature dopaminergic neurons.

A rough start. Studer’s arrival in Washington, DC, in November 1995 coincided with the federal government shutdown caused by conflicts between President Bill Clinton and Speaker of the House Newt Gingrich. Then in January, just as the shutdown came to an end, a large blizzard hit the East Coast, dumping more than four feet of snow. “I didn’t have the best start. . . . I was very worried whether I made the right decision to come to the U.S.”

Seeing future potential. Despite the setbacks, Studer enjoyed the intellectual environment of his new lab. He first tried to see if neuronal stem cells could form dopaminergic neurons spontaneously, “but this didn’t happen, probably because there are 100 billion neurons in the brain but only 1 million are dopaminergic,” says Studer. “It was not initially clear if neuronal stem cells are a blank slate or if they remember the region of the brain where they came from. We showed that when you isolate a neuronal stem cell, it already has a programmed position.” In 1998, Studer was able to isolate neuronal precursor cells—several steps past pluripotency—from a region of the midbrain containing dopaminergic neurons. He expanded and converted these to dopaminergic neurons in vitro using a 3-D culture system and injected the cells into a rat model of Parkinson’s disease. “It was exciting because the rats partly recovered, and our study was even mentioned in Congress in discussions about the therapeutic potential of stem cells.”

McKay’s lab was already working on deriving neural cells from mouse embryonic stem cells (ESCs), and James Thomson of the University of Wisconsin–Madison had just demonstrated the ability to generate human ESCs from blastocysts. Studer understood the wider potential of using ESCs to form any number of neural cell types. “It clicked for me that this was not just an academic experiment in mouse ESCs, but that we could coax human ESCs into dopaminergic neurons in the lab for therapeutic purposes.” Studer and others in the McKay lab used mouse ESCs to make other mid- or hindbrain neurons on demand, something that was not possible with the neuronal stem cells. “I was blown away,” says Studer.

Studer Stars

An unlikely romance. Studer was offered a position at the University of Bern in 1999 but made the decision to stay in the U.S. because “there was more excitement and energy about stem cell research and more opportunities.” He had met the woman who is now his wife while a postdoc in the McKay lab, where she was also doing research while a medical resident. “We met in the most unromantic way. After injecting cells into the rats’ brains, we had to assess if the experiment worked by observing if the animals could rotate on their own axis, counting the number of times the animals turned. There was lots of time for chatting while you did the counting.” The two married in 1999, and Studer applied for a professorship at Memorial Sloan Kettering Cancer Center (MSKCC) because that’s where his wife, Viviane Tabar, a neuroscientist and neurosurgeon, wanted to do her fellowship work, he says.

Self doubt. Studer became a faculty member at MSKCC in 2000, hired by James Rothman, then chair of MSKCC’s cellular biophysics and biochemistry department. Studer also had a second appointment in the neurosurgery department. “It was strange, at least on paper, because I didn’t work on cancer or on biochemistry. But Rothman had a vision to work on neural cell–based systems, which may explain his motivation of hiring me at the time. Because of the unusual structure of my appointment, I had initial doubts whether this was the right place for me and if I was even wanted.”

Political hindrances. Studer wanted to work on human ESCs, which was initially not possible because of restrictions on using federal funds to support human ESC research. Then, in August 2001, President George W. Bush announced a new, restricted policy that allowed human ESC work, and Studer was able to get started on his vision—to apply what he had learned from mouse (and, later, monkey) ESCs to human cells. In 2004, Studer’s lab derived dopamine neurons from human cells. “It took us 10 years to work out how to do this well with human ESCs, which work quite differently from their mouse counterparts.” Working with Teruhiko Wakayama, Studer also showed it is possible to derive mouse ESCs from somatic cells by nuclear transfer.

From frustration, progress. Implanting human dopaminergic cells derived from ESCs into the brains of mice didn’t work at first. When the animals were dissected there were no new dopamine neurons to be found. “That was a frustrating period because we didn’t know if it was the cells or the environment in the brain that didn’t allow the cells to grow. But in hindsight, it was an exciting period where I widened my horizons to isolate peripheral neural crest stem cells and to pursue human disease modeling.” Now, Studer’s lab is able to make 50 different cell types from human ESCs, each of which corresponds to a specific region of the nervous system. “We could also derive induced pluripotent stem cells (iPSCs) from Parkinson’s patients, differentiate them, and use these for drug screening. So my career bloomed, I think, because when you don’t get the results you want, you change strategy, make other things happen, and begin to understand basic principles.” In 2009, Studer’s lab showed that only two factors—TGFβ and BMP—need to be inhibited for human ESCs to synchronously differentiate into neural cells. Two years later, in what Studer calls one of the most important papers of his career, his lab was finally able to derive dopamine neurons from human ESCs and successfully graft these into animal models of Parkinson’s disease (Nature, 480:547-51, 2011).

Back to the future. In 2013, as part of a multidisciplinary grant from the New York State Stem Cell Science program, Studer, along with his wife and other clinicians and researchers at MSKCC, received a five-year grant to develop human ESC–derived dopamine neurons for Parkinson’s disease cell therapy. The goal is to manufacture the cell therapy and start a clinical trial in 2017. “It links back to my first research. It’s very challenging but also exciting.”

Erasing the past. Studer’s lab routinely takes patients’ skin biopsies, reprograms the cells into iPSCs, and then differentiates these into a cell type of interest. They noted that it is possible to ascertain the age of the original skin cells—whether from a 5-year-old or 99-year-old patient—but that after going through reprogramming, the iPSC-derived, now-differentiated cells had lost the memory of their age. “This is amazing and means that aspects of aging appear to be reversible.” But because the lab wanted to study cell types from patients with degenerative diseases, it was important to establish a way to put back the age information into the reprogrammed cells. In 2013, Justine Miller, then a graduate student in the lab, added a gene responsible for Hutchinson-Gilford progeria syndrome, a rare premature-aging disorder, and showed that the technique could age the differentiated cells that had undergone reprogramming. “We think about recipes of how to make a cell type, but now we can also think about programming an age into a cell,” says Studer. “It’s fascinating how to potentially manipulate this, to speed up or slow time, and potentially prevent age-related diseases.”

A hallucination? “I was sick with a 104-degree fever the day I received the phone call with the news that I got the MacArthur fellowship. By the end of the day, I wasn’t even sure if the phone call had actually happened! But then I got an email, so I knew my mind had not made it up,” Studer recalls. “You don’t even know that you were nominated, so it’s a complete surprise. It’s an amazing honor and it’s encouraging because we do try to think outside the box and come up with nonlinear ideas. So it’s very nice to be acknowledged for this.” 

Greatest Hits

  • Demonstrated that neuronal stem cell precursors can be converted in vitro into dopaminergic neurons, which, when injected into the brains of a rat model of Parkinson’s disease, result in partial improvement
  • Showed that growth and differentiation of neuronal precursor cells into dopaminergic neurons is more efficient under low-oxygen conditions compared with environmental-oxygen conditions
  • Created new methods to coax human pluripotent stem cells to become both neural and neural crest tissues, generating a broad range of cell types for modeling human diseases in a dish
  • Developed methods for the production of large quantities of stable human dopaminergic neurons currently adapted for use in human Parkinson’s patients
  • Established a novel protocol to induce aging of differentiated cells derived from pluripotent stem cells as a model for age-related neurodegenerative disorders

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