Prize Winners 2021: Award-winning diagnosis of brain tumours
Hai Yan and Andreas von Deimling have been awarded the International Prize for Translational Neuroscience 2021
Cancer cells multiply uncontrollably, thereby displacing healthy cells and destroying tissue. But that’s where the similarities end. Uncontrolled cell division can have various causes, and the individual cancers must therefore be treated accordingly. The more precisely the characteristics of the respective cancer cells are known, the more specifically the malignant cells can be combated.
Until now, brain tumours had been classified mainly by staining tissue samples and comparing the appearance under a microscope. However, the origin and molecular characteristics of cancer cells, which are often decisive for further therapy, are not always visible with this type of diagnostics. It had therefore not been possible to distinguish between the different tumour types in some cases.
Hai Yan has researched the characteristics of the most common types of brain tumours: gliomas. Sub-forms of these incurable glial cell tumours form typically modified proteins. IDH1 and IDH2 have been found by his team and his collaborators to be frequently altered with an amino acid replaced at a specific position in certain types of gliomas. This distinguishes tumour cells from normal body cells as well as from other tumour sub-types in which the proteins are present in their natural form.
Hai Yan found that one sub-group of gliomas can be simply distinguished from others by looking at the distribution of the commonly mutated proteins. He and his collaborators identified diagnostic biomarkers that significantly improve the differentiation of these sub-groups. The World Health Organisation has included the tumour types they discovered in the classification of tumours of the central nervous system. Yan and his team also investigated how the altered proteins affect the metabolism and immortality of the tumour cells. Tailored therapies against these forms of glioma are based on these findings.
Andreas von Deimling also works on diagnostic markers of brain tumours. He and his team have developed an antibody that binds to mutated IDH1 protein. The highly specific antibody recognizes the mutation and binds to the protein only when exactly this mutation is present. It had previously not been possible to distinguish between normal and mutated IDH1 using conventional staining methods.
With the help of the antibody, sub-types of gliomas – astrocytomas and oligodendrogliomas – can be diagnosed beyond doubt and differentiated from other types of brain tumours. The patented antibody is now routinely used worldwide in brain tumour diagnostics. With the help of this antibody, researchers can visualize the tumour cells and their immediate surroundings in the brain tissue. This has already allowed important insights into the development and progression of these tumour diseases.
Von Deimling and his colleagues have also developed a diagnostic system based on the DNA methylation pattern in the tumour cells. These chemical modifications in the genetic material can be used to determine from which cell type a tumour originally arose. In the highly modified cancer cells, this can often no longer be clearly determined. However, knowing the origin is important for designing an effective therapy against the malignant cells.
Prize Winners 2020: Award for excellence in Alzheimer research
Roy Weller, Maiken Nedergaard, and Mathias Jucker honoured for their findings on brain cleansing and its importance in dementia
Alzheimer’s disease is the most common form of dementia and affects at least 50 million people worldwide. The progressive death of nerve cells is associated with the deposition of protein aggregations known as amyloid plaques. With increasing age, such aggregations are more difficult to dissolve and remove from the brain. This year, the Gertrud Reemtsma Foundation honours Roy Weller, Maiken Nedergaard, and Mathias Jucker, three neuroscientists who have investigated the removal of waste products from the brain. The researchers’ findings offer new approaches for treatments and preventive measures for Alzheimer’s and other neurodegenerative diseases. The International Prize for Translational Neuroscience of the Gertrud Reemtsma Foundation (previously known as the K.J. Zülch Prize) valued at € 60,000 will be awarded on 10 September 2020 in Cologne.
Cellular waste products are transported into the blood via lymph vessels and nodes, degraded in the liver, and recycled or excreted in the urine. An exception to this is the brain, in which there are no conventional lymph vessels. The brain is nevertheless highly active and consumes around one quarter of the body’s total energy. This enormous metabolic output also produces a considerable amount of waste. If they are not properly removed, the waste products deposit in the brain. This can lead to the death of nerve cells and possibly dementia.
In Alzheimer’s disease, the amyloid β protein (Aβ) is deposited as plaques around nerve cells that suffer damage consequently. In our younger years, such amyloid plaques are only rarely present in our brains. But as we age, these proteins are less effectively removed. Roy Weller from the University of Southampton wanted to find out how waste products are removed from the brain – and why this often fails with increasing age.
His experiments have shown that waste products from the brain are drained via the walls of arteries. In this process, the brain fluid and the waste products it contains flow to the arteries. From there they are transported to the lymph nodes in the neck by the wave-like contraction of the smooth muscle cells in the walls of the arteries. The extremely narrow pathways of this unique system allow proteins and metabolic products to be removed. However, the pathways are too narrow to allow the traffic of immune cells from the brain to lymph nodes. This has a significant effect on immune reactions in the brain.
Because the arteries lose smooth muscle cells over time and stiffen, this drainage becomes less efficient as we get older. Insoluble Aβ protein can block the narrow drainage pathways and thus further impair its removal. Strengthening of smooth muscle cell contractions and the dissolution of the Aβ proteins to ensure the outflow of Aβ could act as the starting point for therapies for the prevention and treatment of Alzheimer’s disease.
Maiken Nedergaard from the Medical Centre of the University of Rochester and University of Copenhagen has researched the major supportive glial cell type in neuronal diseases, the so-called astrocytes. They surround blood vessel with their processes. This create donut-shaped perivascular tunnels that enables cerebrospinal fluid to flow into brain and literally flush waste products, such as Aβ, out of the brain.
Maiken Nedergaard showed that astrocytes play an important role in distributing fluid in the brain. The transport of Aβ is enabled by the dense expression of the water channel, AQP4. Due to the importance of this predominant glial cell type in the brain’s plumping system, she entitled the brain fluid transport the »Glia-lymphatic« or the »glymphatic system«. In essence, brain waste products are transported along the blood vessels to the lymph nodes.
According to Nedergaard, the glymphatic system is mainly active and removing waste products during sleep. As we sleep, astrocytes shrink and allow larger intercellular spaces into which cerebral fluid can penetrate along the blood vessels. From there, Aβ and other waste products can be removed. These findings could be used to develop new approaches to the prevention and treatment of Alzheimer’s disease.
Mathias Jucker from the Hertie Institute for Clinical Brain Research and the German Center for Neurodegenerative Diseases in Tübingen uses the fluids that cleanse the brain to diagnose neurodegenerative diseases. Jucker identified biomarkers for neurodegeneration in the blood and cerebral fluid of genetically modified mice. These results can be transferred to clinical application in humans. For example, in the cerebral fluid of mice that develop Aβ plaques like Alzheimer’s patients, he discovered molecules with which the progression of Alzheimer’s disease can be predicted early on.
Jucker’s studies also suggest that the clearing of Aβ depends on the proper folding of the protein. As is the case with prions, misfolded Aβ trigger the misfolding of other Aβ proteins in a kind of self- reinforcing domino effect. Misfolded proteins can then no longer be cleared. By the time the first neurological symptoms appear, the brain has already been severely damaged because so many amyloid plaques have formed. Many therapies are therefore no longer effective at this time and a preventive therapy is even more important.
Prize Winners 2019: Therapy for muscle weakness
Adrian Krainer and Richard Finkel receive the Prize for their development and testing of a drug for spinal muscular atrophy
Although spinal muscular atrophy is a rare condition, it is the most common gene-related cause of death in children. This year, The Gertrud-Reemtsma Foundation is awarding the K. J. Zülch prize to a scientist and a clinician who have been developing and testing a new drug to combat this condition: Adrian Krainer at the Cold Spring Harbor Laboratory led a research team that developed antisense agents to combat spinal muscular atrophy, and tested them in mice. These tests met with such success that they led to testing of the drug Nusinersen in clinical trials led by Richard Finkel, a physician at Nemours Children’s Hospital. This was the first time a drug improved patients’ motor skills and significantly extended their survival. Nusinersen was approved at the end of 2016, and more than 7,500 patients have benefitted from its effects. The K. J. Zülch Prize, with a value of 50,000 euros, will be awarded on 12 September, 2019 in Cologne.
In Germany, about 300 children are born every year with spinal muscular atrophy, a degenerative disorder of a type of nerve cells. Up until just a few years ago, the diagnosis was a death sentence for many newborns.
About half of the patients develop the severe type I form of the condition. These children develop the first symptoms of muscle weakness either in the uterus or during their first months of life. They never learn to sit or crawl and usually die of respiratory failure and related infections before their second birthday. Children with the intermediate type II form usually live longer and can sit independently, but are confined to a wheelchair for life and have a shortened life expectancy. In the milder type III and type IV forms, the onset of the condition does not occur until later in childhood or adulthood and allows those affected to live a broadly normal life, albeit with a decline or loss of ambulation.
All patients with spinal muscular atrophy have one genetic defect in common: they lack SMN1, the gene responsible for production of the SMN (survival of motor neurons) protein. This protein is required to prevent the progressive death of a specific type of nerve cells in the spinal cord and brain stem, cells which are responsible for transmitting signals from the brain to the body’s muscles. However, humans have an almost identical second version of the gene: the SMN2 gene. Unfortunately, a largely defective transcript is made from this gene, and only a small amount of functional protein is produced as a result. The more copies of the SMN2 gene a patient has, the more functional SMN protein can be produced by that backup gene, and the milder the effects of the condition. Various research approaches are therefore focused on increasing the protein production from the SMN2 gene.
As a biochemist, Adrian Krainer has been researching for decades how genes are transcribed and translated into proteins, and how the underlying mechanisms can be influenced. During gene transcription into RNA, sequences containing information for the protein, called exons, must be separated from non-coding sections (introns) and joined together. This editing process is known as RNA splicing. However, a mutation in an exon of the SMN2 gene causes that exon to be omitted most of the time during RNA splicing, producing only a truncated protein, which rapidly degrades.
Adrian Krainer has been researching a type of molecule that can be used to correct the defective RNA splicing. The so-called antisense oligonucleotides, are short RNA-like segments which bind to specific sites on the transcript of a gene and influence how the information from the gene is converted into protein. In the case of defective SMN2 RNA splicing, Krainer found a short segment of 18 nucleotides that would aid production of the entire protein.
In collaboration with Ionis Pharmaceuticals, Krainer used mice that do not produce their own SMN protein, but instead have two copies of the human SMN2 gene, to test their antisense oligonucleotides, called Nusinersen. These mice develop severe spinal muscular atrophy and die within ten days of birth. However, when Krainer’s team administered Nusinersen before the onset of symptoms, the mice developed no muscle atrophy, and survived for over 250 days.
Clincal studies with Nusinersen
Following these promising results, Richard Finkel and colleagues investigated the effectiveness and potential side effects of Nusinersen in clinical trials. These trials also produced astonishing results. In a study of infants with the type I disorder, the original intention was to determine whether the survival of non-ventilated patients was extended by administering Nusinersen. However, it soon became clear that patients were also developing well and achieving motor milestones, as a result of Nusinersen treatment.
The results of an interim analysis of the study were so positive that it became ethically unreasonable to withhold Nusinersen from the placebo group. These infants were then enrolled into another study, in order for them to also benefit from the drug. Finkel realized that for the first time a drug significantly alleviates or reverses the reduction in patients’ movement and extends survival. As a result of the successful clinical trials, Nusinersen was approved as a drug in the US at the end of 2016, with approximately 7,500 patients worldwide being treated with it to date.
The Prize Winners
Adrian Krainer studied biochemistry at Columbia University and earned his doctorate in biochemistry and molecular biology from Harvard University. To continue his research career, he moved to Cold Spring Harbor Laboratory, where he first carried out postdoctoral research, and then obtained a professorship. He has been a full professor there since 1994 and St. Giles Foundation Professor since 2009.
After studying chemistry and medicine, Richard Finkel moved to Harvard Medical School where he specialized in paediatrics and neurology. He subsequently worked as a paediatrician and neurologist in hospitals in Denver and Philadelphia. He is currently Professor of Neurology at the University of Central Florida and Head of Neurology at Nemours Children’s Hospital in Orlando.
Prize Winners 2018: Autoimmunity in neurological diseases
Jerome Posner, Angela Vincent and Josep Dalmau have uncovered new diseases and have improved outcomes for neurological deficits
Cancer, infections and other still undescribed factors can trigger the body’s immune system. In some patients this results in an autoimmune attack against healthy tissue such as cells of the nervous system. This can lead to deficits such as memory loss, seizures, movement disorders, muscle weakness, and psychosis. The Gertrud Reemtsma Foundation has now paid tribute to Jerome Posner, Angela Vincent and Josep Dalmau for their research into how autoimmunity produces these neurological disorders that include paraneoplastic and non-paraneoplastic neurologic syndromes and the antibody-mediated autoimmune encephalitis syndromes. Their work has been pivotal in ensuring that many of these disorders are now recognised and patients promptly treated offering the best opportunity for neurologic improvement. In recognition of their outstanding achievements, the researchers have been awarded the Gertrud Reemtsma Foundation’s K. J. Zülch Prize worth 50,000 euro. The award ceremony will take place in Cologne, Germany on the 21th of September 2018.
Medical practitioners have long been aware that autoimmune brain diseases can occur in patients with cancer. The scientists have made crucial advances in research into these immune diseases by providing detailed clinical descriptions and through the development of simple diagnostic tests, allowed practitioners to quickly recognize, diagnose, and treat these patients. Their work has also provided insights into how cancers and other triggers such as viral infections initiate the autoimmune attack. This has opened new avenues to research into how to prevent and optimally treat these diseases. For some patients, recognition of the autoimmune neurologic symptoms leads to the detection of a previously undetected cancer, allowing early cancer treatment and an increased chance of cure.
These diseases were largely unknown to the public but gained attention when in 2011 a polar bear named Knut drowned in his pool at the Berlin Zoological Garden. An autopsy revealed that one of the antibody-mediated autoimmune encephalitis syndromes known as anti-NMDA receptor encephalitis caused his unexpected demise. Then in 2012, a patient with this same disease wrote a best-selling novel about her experience.
The American Jerome Posner is considered a pioneer in the field of research into these syndromes and their causes, having systematically described many of the paraneoplastic diseases for the first time and developing the first blood tests used to diagnose these disorders. His former colleague from Barcelona, Spain, Josep Dalmau is known for discovering several autoimmune encephalitis syndromes, developing diagnostic tests, and revealing the mechanisms whereby the autoantibodies are directly responsible for the brain dysfunction.
British-born Angela Vincent initially studied autoimmune diseases of the peripheral nervous system in which signal transmission between nerves and muscles are impaired. This led her to the then revolutionary insight that certain antibodies can also attack the central nervous system. She subsequently developed the diagnostic methods widely used in hospitals today.
The Prize Winners
For many years, Jerome Posner was Head of Neurooncology at the Memorial Sloan-Kettering Cancer Center in New York and Professor of Neurology and Neuroscience at Cornell University in New York. Following his medical studies in Barcelona, Josep Dalmau initially worked as a neurologist before continuing his scientific career in Jerome Posner’s laboratory. He currently holds professorships at the University of Pennsylvania and the University of Barcelona.
Angela Vincent, a medically-qualified neuroimmunologist, worked at University College in London with the late Ricardo Miledi, and the Royal Free Hospital with the late John Newsom-Davis. She spent the last 30 years at the University of Oxford where until recently she ran a national and international diagnostic antibody service and research group. She currently holds honorary positions in Oxford and London.
The Zülch Prize
The K. J. Zülch Prize 2018 will be awarded at 10 o’clock on the 21th of September 2018 in the Hansasaal (main hall) at Cologne’s historic City Hall. Following the laudations by Uwe Schlegel and Thomas Münte, Angela Vincent will talk about her research into autoimmune diseases of the peripheral and central nervous system. Following the laudation by Mathias Bähr, Josep Dalmau will talk about the discovery of anti-NMDA receptor encephalitis.