WORLD PARKINSON's DAY: Transplantations for Parkinson's disease – A time travel
In the early 1950s, no one knew what caused Parkinson's disease. Then, Arvid Carlsson's discovery of dopamine opened the door to world-leading transplantations for Parkinson's patients. Thanks to the pioneering basic research at MultiPark, stemcell-derived neural cells can now be tested in a clinical trial for the first time.
In Parkinson's disease, the nerve cells in an area of the brain that controls the body's movements gradually stop working. This leads, among other things, to tremors and movement difficulties. Lund University's success story in Parkinson's research started at the end of the 1950s when the future Nobel laureate Arvid Carlsson discovered the neurotransmitter dopamine. Through this discovery, researchers understood that Parkinson's disease was caused by a lack of dopamine in the areas of the brain that control our movements, an insight that became key to developing the first treatments.
Basic research at Lund University paved the way for developing L-dopa, a symptom-relieving treatment where the patient's ability to move is maintained by L-dopa being converted to dopamine inside the brain, thus compensating for the dopamine deficiency; a revolution for patients suffering from the disease. Unfortunately, L-dopa does not prevent the breakdown of the nerve cells. At some point, too many nerve cells have degenerated and L-dopa is no longer efficient. The researchers realized that the patients needed nerve cells that worked properly.
The first-generation transplants
Following in Arvid Carlsson's footsteps, Anders Björklund and his close allies Olle Lindvall and Patrik Brundinat Lund university started to investigate the possibilities of transplanting dopamine cells, collected from aborted fetuses, to the area of the brain where the dopamine-producing nerve cells were lacking. The transplants turned out promising in rats, and the world's first transplant of fetal cells into a Parkinson's patient was carried out in Lund in November 1987. The research world held its breath!
The patients improved, and when the findings were published in Science in 1990, the success was a fact. The method spread internationally, albeit on a small scale, because the transplants required access to aborted fetuses, something that also implies ethical dilemmas. Around the turn of the millennium, a number of cases were also discovered in the US where operated patients exhibited involuntary movements. A wave of scepticism swept over the transplantation field and could have meant the end of an era of very successful Parkinson's research at Lund University.
In 2003, transplants for Parkinson's patients were suspended in Lund. The same year, Malin Parmar completed her dissertation. She and Anders Björklund realized that the stem cells needed to be produced specifically with the purpose of being transplanted so that the procedure could be standardized and made safer. Malin Parmar went back to the cell culture lab. Neither of them knew that it would take nearly a decade of diligent lab work to get the cells to develop properly.
The first nine years consisted of 90% failure
In the end, we managed to confirm a handful of growth factors that stimulated the stem cells to develop into dopamine-producing cells.
“The first nine years consisted of 90% failure!” Remembers Malin Parmar. "In the end, we managed to confirm a handful of growth factors that stimulated the stem cells to develop into dopamine-producing cells. Collaborating with others and getting long-term support has been crucial to our success.”
MultiPark – from molecule to patient
In 2010, MultiPark was established, a strategic research area that conducts interdisciplinary research on Parkinson's disease at Lund University. The scientific legacy stems all the way back to Arvid Carlsson's breakthrough, and the very first transplants form a solid ground for basic researchers and clinicians to meet.
In 2012, there was finally a promising protocol for producing dopamine cells. The second phase of the project began. Now it was a matter of adapting the insights from basic research all the way to the clinic so that the cells could be tested safely in patients. Malin's postdoc at the time, Agnete Kirkeby, became an essential part of this translational work, as did the research network G-force, an international collaboration unique in its kind.
Research is a marathon; it is more manageable if you turn it into a relay with your colleagues
"The journey to adapt the stem cells for the clinic has been a bit like an exercise race. Despite the competition with other prominent research centres worldwide, we have managed to unite and carry the heavy burden all bureaucratic processes entail by sharing experiences with each other. It's a delicate balance between competition and cooperation, but without each other, we probably wouldn't have been able to reach this far. Doing research is a marathon; it is more manageable if you turn it into a relay with your colleagues!” Says Malin Parmar.
The new generation transplants
Autumn 2022 was a milestone for the new generation of transplantation research in Parkinson's disease. The Swedish Medicines Agency approved a new stem cell-based clinical study. A decade of translational work to bring experimental research to the clinic was over. This work has hopefully enabled cultured stem cells for future transplants. In this way, we also avoid using cells from aborted fetuses.
The clinical preparations have involved many research group leaders within MultiPark. Gesine Paul-Visse is clinically responsible for the study, and Håkan Widner is the medical sponsor representative. During the long journey, Anders Björklund has become professor emeritus. But his desk at the biomedical centre is still there. For the new clinical studies, the younger generation of MultiPark researchers sits in the driver's seat. And Anders appreciates his new role as co-driver in the passenger seat.
It is fantastic to be able to follow the research as it develops.
"Of course, the experience is less intense when you are not the one driving. At the same time, it is nice to be spared from the heaviest parts and to give advice about the directions is incredibly stimulating. It is fantastic to be able to follow the research as it develops," he thinks.
In February 2023, the first transplant of stem cell-derived nerve cells was administered to a person with Parkinson's at Skåne University Hospital. The researchers are now investigating the safety and if the transplanted dopamine cells survive in the patient’s brains and whether they can replace the nerve cells lost in the disease. The correct location of the grafted cells has been confirmed by brain imaging. It is not possible to volunteer to participate in the study. Even if the trial turns out successful, several steps remain to make a safe and effective treatment available to large patient groups. Each patient is unique. With more knowledge, the method may be tailored for each individual.
“Parkinson’s disease is more than just a movement disorder, and dopamine is not the only neurotransmitter lacking. In that sense, it might be possible to try to mitigate the cognitive symptoms by also replacing lost cholinergic neurons even though we don’t know if this would be feasible,” says Anders Björklund.
Hopefully, the ongoing clinical trial will be successful so that stem cell transplantations, with future developments, can be offered at an early stage of the disease and thereby extend the good years.
malin [dot] parmar [at] med [dot] lu [dot] se
Link to Malin Parmar's profile in the LU Research Portal
Associate Senior Lecturer
agnete [dot] kirkeby [at] med [dot] lu [dot] se
Link to Agnete Kirkeby's profile in the LU Research Portal
gesine [dot] paul-visse [at] med [dot] lu [dot] se
Link to Gesine Paul's profile in the LU Research Portal
About Anders Björklund
Anders Björklund received his MD and PhD from Lund University in 1969. He was appointed professor of histology in 1983, and since 2012, has remained a senior professor at the Wallenberg Neuroscience Center in Lund. He is a member of the Royal Swedish Academy, and foreign member of the National Academy of Sciences, USA. His research interests are in brain regeneration and repair, with a focus on cell replacement and gene therapy in neurodegenerative diseases.
Anders [dot] Bjorklund [at] med [dot] lu [dot] se
More about stem cell transplantations in Parkinson’s disease
Here you can read more about the research behind the stem cell transplants, which are now being evaluated in a clinical trial:
First patient receives milestone stem cell-based transplant for Parkinson’s Disease
STEM-PD : A bench-to-bedside story by MultiPark researchers
Nerve cells could transform the treatment of Parkinson’s
Swedish Medical Products Agency grants approval for clinical study of new stem cell based Parkinson’s Disease treatment
Seven things you perhaps did not know about the Nobel Prize winner Arvid Carlsson and his research