The Lundbeck Foundation The Brain Prize 2021 · Information Pack 1
The Brain Prize 2021 INFORMATION PACK
The scientists behind the science that has led to new treatments for migraine. 2 The Brain Prize 2021 · Information Pack The Lundbeck Foundation
The scientists behind the science that has led to new treatments for migraine.
The breakthrough in treatment for migraine was 40 years in the making. The pioneering research journey has now led to award of The Brain Prize 2021. The Lundbeck Foundation The Brain Prize 2021 · Information Pack 3
Four decades of careful research have led to new treatments for migraine that are radically improving the lives of sufferers. An international group of four neuroscientists have discovered a key mechanism that causes migraine, a condition that affects more than a billion people and which according to the World Health Organisation is one of the most prevalent and disabling diseases.
Their research paved the way to the development of an entirely new class of migraine-specific drugs called CGRP antagonists which help provide long-term prevention of migraine attacks.
For this, the four neuroscientists are receiving the world’s most prestigious prize for brain research – The Brain Prize – which is awarded annually by the Lundbeck Foundation.
This year The Brain Prize worth DKK 10 million (€1.3 million) is awarded to:
Lars Edvinsson (Sweden) · Peter Goadsby (UK/USA) Michael Moskowitz (USA) · Jes Olesen (Denmark)
Professor Richard Morris, Chair of The Brain Prize Selection Committee, explains the reasoning behind the award:
“Migraine is one of the most common and disabling neurological conditions affecting humans. The work of the four recipients contributed to the clinically effective classification of the various types of this disorder, and then to unravelling the key mechanisms that cause it. This understanding led to the development of a novel therapy and has opened windows into future ones. Their work on migraine is a remarkable example of bedside- to-bench-to-bedside research that has yielded tangible clinical benefit.” 4 The Brain Prize 2021 · Information Pack The Lundbeck Foundation
What is migraine?
Migraine is much more than a bad head- trigeminal nerve (which is involved in The work of Michael Moskowitz, ache. It is a serious neurological disease controlling movement of, and sensations Lars Edvinsson, Peter Goadsby and Jes with symptoms that include severe in the face) and the meninges and its Olesen has led to the development of throbbing and recurring head pain, associated blood vessels (the meninges new drugs called gepants and CGRP nausea, vomiting, dizziness, extreme is a thin membrane that surrounds the monoclonal antibody treatments. The sensitivity to sound, light, touch, and brain and is the only structure inside the success of these new treatments is smell. Some migraine attacks can last skull that senses pain). Moskowitz pro- remarkable. They are safe and can even for several days and more than 4 million posed that a migraine attack is triggered reduce the likelihood of future people suffer at least 15 migraine attacks when the trigeminal nerve fibres are migraine attacks. Patients have per month. For many, migraine severely activated, leading to release of chemical remarked that the drugs have “given diminishes the quality of life, including signals that dilate (open up) the blood them their life back”. the ability to work, and can lead to vessels of the meninges. This results in depression, anxiety, and sleep distur- local inflammation which ultimately The human brain is staggeringly bances. The economic and societal costs results in severe head pain. But what was complex which means understanding associated with migraine are extremely activating the trigeminal fibres to cause and treating disorders of the brain high - in the tens of billions of dollars a migraine attack in the first place? Prior remains one of science’s greatest chal- - worldwide. to the intense headache, many migraine lenges. We often hear that a major neu- patients experience auras- unusual sen- roscience discovery “could lead” to Treatments for migraine have been sory experiences such as seeing spots of improved treatments for patients. The available for some time, but they can light, flashes, stars, a brief loss of vision, pioneering work of the four Brain Prize have significant side effects and their or tingling sensations in the face or winners has actually done so. efficacy is incomplete. There was there- hands. These auras usually last for less fore an urgent need to develop new than an hour but they often signal the classes of migraine-specific drugs. The imminent arrival of a migraine attack. problem was that doctors were at a loss Moskowitz provided compelling evidence to understand the origin of a migraine that the highly unusual pattern of brain Migraine facts attack. Examinations of migraine activity that results in the auras may also patients between migraine attacks had activate the trigeminal nerve fibres. not revealed anything out of the NUMBERS OF PEOPLE AFFECTED ordinary. However, a major piece of the puzzle • Migraine affects approximately 1 bil- was still missing. What was the nature of lion people worldwide. the chemical signals released by the tri- • Migraine affects 3 times as many geminal nerve fibres which triggered the women as men. attack itself? Working together, Lars • Migraine also affects a considerable Discovering what Edvinsson and Peter Goadsby showed proportion (approx. 7%) of children. that a recently discovered peptide (a • According to the Global Burden of causes migraine small protein-like molecule), calcitonin Disease Study in 2016, migraine is the gene-related peptide (CGRP), was 2nd leading cause of disability and attacks was key to released from the trigeminal nerve accounts for more than all other neu- during a migraine attack and that it was rologic disorders combined. unlocking new ways a potent dilator of blood vessels in the meninges. Based on these findings PREVALENCE AND BURDEN of treating them. Edvinsson proposed that CGRP may be • Migraine is more prevalent than dia- of crucial importance in migraine, but betes, epilepsy and asthma combined. was the release of CGRP from the tri- • Migraine sufferers experience recur- The breakthrough came when four geminal nerve the cause or a conse- rent headaches of moderate-to-severe internationally renowned neuroscientists, quence of a migraine attack? pain lasting 4 to 72 hours. Lars Edvinsson (Sweden), Peter Goadsby • Severe migraine attacks are classified (UK/USA), Michael Moskowitz (USA) This crucial question was answered by the World Health Organization as and Jes Olesen (Denmark) discovered, by Jes Olesen. He showed that when among the most disabling illnesses, over the course of four decades of work, given to migraine patients CGRP could comparable to dementia, quadriple- a cause of a migraine attack. trigger a migraine attack. He then went gia, and psychosis. on to show that drugs which blocked • The financial burden of migraine on The story begins with Michael CGRP could help treat migraine. the UK economy is estimated at £3.42 Moskowitz, an American and a Olesen’s work was not only crucial in billion per year. This figure takes into Professor of Neurology at Harvard showing a causal role for CGRP in trig- consideration the costs of healthcare, Medical School at the Massachusetts gering migraine, but it also demon- lost productivity through absenteeism General Hospital. His worked showed strated that CGRP could be an import- and disability. that a migraine attack involves an inter- ant new target for developing new action between two key players: the treatments for migraine. The Lundbeck Foundation The Brain Prize 2021 · Information Pack 5
• Migraine can run in families, with SYMPTOMS • Anxiety and depression are signifi- 42% of cases thought to be hereditary. • The pain is often throbbing, can be on cantly more common in people with The genetic causes of migraine are not one side of the head, and is aggravated migraine than in healthy individuals. fully understood but it is generally by physical activity. • A significant proportion of migraine thought to be polygenic, meaning that • Other symptoms include, nausea, sufferers experience auras, most com- multiple mutations in different genes vomiting, and sensitivity to light and monly visual and, less often, tingling may cause the disease. sound. sensations and loss of normal speech.
About The Brain Prize
SCOPE over by His Royal Highness, The Crown world leading neuroscience research The Brain Prize, the world’s largest brain Prince of Denmark. nation, and of raising public awareness research prize, is Danish and awarded of the brain, brain disorders and the by the Lundbeck Foundation. Each year, PURPOSE importance of brain research. the Foundation awards the prize worth Following the award of The Brain Prize, 10 million DKK (approx. €1,3 million) to recipients engage in a series of outreach NOMINATION AND SELECTION OF one or more neuroscientists who have activities, organised by The Brain Prize THE BRAIN PRIZE WINNERS had a ground-breaking impact on brain team at the Lundbeck Foundation. Only candidates who are nominated by research. The Brain Prize recognises These activities not only celebrate the others will be considered for The Brain highly original and influential advances achievements of the recipients but also Prize. The rewarded research must – in any area of brain research, from basic serve to establish and strengthen collab- from an international perspective – be neuroscience to applied clinical oration within the Danish and interna- outstanding. It is the task of The Brain research, and recipients may be of any tional neuroscience community. The Prize selection committee to decide in nationality and work in any country Brain Prize is also used to engage with each individual case, what characterises around the globe. The Brain Prize was and educate the public about the impor- the research as outstanding and there- first awarded in 2011 and has so far hon- tance, challenges, and breakthroughs in fore deserves the prize. The current oured 34 scientists from nine different brain research. The Brain Prize is at the selection committee consists of nine countries. The Brain Prize is awarded at heart of the Lundbeck Foundation’s stra- eminent neuroscientists from five coun- a ceremony in Copenhagen, presided tegic priority of making Denmark a tries who are global leaders in their respective fields.
About the Lundbeck Foundation
The Lundbeck Foundation’s history goes As the largest private financial contribu- The Lundbeck Foundation’s commercial back over 65 years. The Foundation was tor to Danish public brain research, it is activities encompass three large subsid- established in 1954 by Grete Lundbeck, a the Foundation’s ambition for Denmark iaries, an international portfolio of 18 visionary businesswoman and widow of to be the world’s leading brain research venture capital companies, a portfolio of the founder of H. Lundbeck A/S, Hans nation. At the same time, it has a strong small biotech companies based on Lundbeck. When she died in 1965, the focus on raising public awareness of the Danish university research and in-house Foundation was sole heir to her assets. brain and brain disorders. administration of assets of around DKK 19 billion. The Lundbeck Foundation is one of The aim of the Lundbeck Foundation is Denmark’s largest commercial founda- to promote the careers of the most At the heart of the Lundbeck tions, worth over DKK 65 billion. The promising scientists and help fund a Foundation’s activities is their purpose: Foundation awards research grants of strong pipeline of biomedical science “To create powerful ripple effects that more than DKK 500 million each year to researchers, regardless of their field of bring discoveries to lives through Danish-based, biomedical sciences research. investing actively in business and sci- research – primarily in the field of brain ence at the frontiers of their fields.” research. 6 The Brain Prize 2021 · Information Pack The Lundbeck Foundation
History and evolution of the migraine field
Marie-Germaine Bousser, Emeritus Professor of Neurology at Paris University
Reported in Mesopotamian poems touch, and smell. Headache is some- post-partum. Attacks usually start in around as early as 3000 BC, migraine times preceded by short lasting neuro- children or in young adults and decrease has always been and still is one of the logical symptoms, mostly visual, in frequency and severity with aging. most frequent diseases in the world. It referred to as « the aura ». « He seemed to Numerous factors have been reported to often runs in families and affects about see something shining before him like a trigger attacks including menstruation, 10% of children and 15 % of adults, with a light, … after a moment, a violent pain stress, various food products, skipping female preponderance of 3 to 1. Among supervened in the right temple, then in all meals, changes in weather, bright or non-lethal diseases migraine is the first the head,…. vomiting, when it became pos- flickering lights, and changes in sleep cause of disability in young adults. sible, was able to divert the pain and render patterns. it more moderate » wrote Hippocrates Migraine is characterised by recur- around 400 BC. Although known and fully described rent attacks of severe, pulsating, often since ages migraine has long been, unilateral headache lasting a few hours The frequency of attacks is highly despite its frequency and its burden, one to 2-3 days. Headache is usually associ- variable, with a median of 1.5 per month. of the most mysterious conditions ated with nausea, vomiting, and In women, attacks usually disappear affecting human beings and the field of enhanced sensitivity to light, sound, during pregnancy but recur during migraine long remained more artistic than scientific. Many famous writers such as Victor Hugo, Lewis Carroll or Sigmund Freud fully described their migraine attacks while others, from Hildegard of Bingen around 1150 to Giorgio de Chirico, painted pictures inspired by their visual aura.
Physicians were deeply puzzled by migraine and at a loss to understand its origin. Clinical examinations of patients between attacks were normal and all investigations they could think of were also normal. There was no specific treat- ment either to abort or to prevent the attacks which were mostly treated by folk remedies, bed rest and later, when they appeared, by ergot derivatives and analgesics. Furthermore, there was no satisfactory animal model. They started to think – as many patients do- that the triggers of the attacks could explain the origin of the disease and this led to a host of theories about migraine, thought to be hormonal, allergic, psychosomatic, or gastrointestinal in origin, only to mention some of the hypotheses. Even the revolution of neuroimaging did not help either to confirm the diagnosis of Migraine Action Art Collection: Image 337, Eve Benjamin, The onset of migraine (1985). migraine or to find the cause of the Available at http://www.migraineart.org.uk/artwork/the-onset-of-migraine/ disease. The Lundbeck Foundation The Brain Prize 2021 · Information Pack 7
It was not until the second half of the twentieth century that migraine was recognised as a disorder of the brain, as suggested by many migraine specialists, such as HG Wolff, JMS Pearce, OW Sacks and JW Lance. There was an agreement that migraine was a complex neurovascular disorder involving the brain and its vessels, but there was still a debate whether the origin of attacks was primarily neuronal, as suggested by the aura, or vascular as suggested by the pul- satile character of the headache. The work of these pioneers paved the way for a more scientific approach to migraine, to which the 4 winners of the Brain Prize 2021 were major contributors.
A crucial step for a scientific approach to migraine was to differenti- ate migraine from other varieties of headache. In the absence of a biomarker for migraine, this was not an easy task, particularly since, for many patients, migraine and headache were synony- mous. The credit goes to Professor Jes The Head Ache, February 12, 1819. After Captain Frederick Marryat. Artist, George Cruikshank. Olesen from Denmark for having (Heritage Images via Getty Images) achieved this goal. In 1985 he gathered many headache specialists in order to discuss and propose operational criteria introduced the trigeminovascular system. He showed in 1985 that over half to define each variety of headache. This hypothesis of migraine headache, point- of the neurons in the trigeminal gan- led to the first International Headache ing to a key role for the trigeminal nerve glion contain CGRP and that lesioning Society (IHS) classification of headaches (one on each side of the head) and its the ganglion led to the elimination of published in 1988. It was a crucial step in vasoactive axonal projections to the CGRP fibres in intracranial arteries. headache research, particularly for pri- meningeal blood vessels. The theory Functional studies showed that CGRP mary headaches such as migraine, focussed on discharging trigeminal was a potent dilator of cerebral arteries because for the first time, it was possible nerve fibres, release of vasoactive neuro- and played a key role in the trigemino- for researchers to speak the same lan- peptides (of unknown identity then) into vascular reflex whereby, in response to a guage. Since then, Professor Olesen has the meninges and ensuing headaches as local vasoconstriction, there is a release chaired all the following editions of the one explanation for unilateral migraine of CGRP by trigeminal nerves causing IHS headache classification. Besides pain. He later coined the term « trigemi- vasodilation. These experimental find- this major achievement, Olesen has had novascular system » to designate the ings led Edvinsson to suggest the over the last 40 years played a key role in relationships between the trigeminal involvement of CGRP in the pathophysi- the field of migraine research. He was nerve, the meningeal vessels, and the ology of migraine attacks. This was con- one of the first to show the spreading central nervous system. The Moskowitz firmed a few years later when he started depression during a migrainous aura by hypothesis of the involvement of the tri- a fruitful collaboration with Goadsby. In studying cerebral blood flow with xenon geminovascular system during migraine the years 1990-94 they found that CGRP and to show that focal cerebral ischemia attacks, plus the emerging age of vasoac- was selectively released from the tri- could trigger migraine attacks with tive neuropeptide transmitters, initiated geminal ganglion during a migraine aura. He particularly studied substances a new era in migraine research. attack and that this release was pre- able to trigger attacks such as NO, Edvinsson was a pioneer, detecting in vented by Sumatriptan, the serotonin CGRP, glyceryl trinitrate and PGE2. 1976 by immunohistochemistry, the agonist discovered in 1988 by the british Overall, he has performed research on presence of a first neuropepide in the pharmacologist Patrick Humphrey and almost every aspect of migraine includ- intracranial vasculature, the vasoactive shown to be the first specific and effec- ing epidemiology, genetics, imaging, intestinal polypeptide (VIP), a potent tive treatment of migraine attacks. This and animal models. vasodilator representing a new class of work on a serotonin agonist and neuro- molecule. peptide release supported research by Most of the research performed by Moskowitz's lab (1988-1994) showing the three other Prize winners, Lars Over the next 10 years, a large that serotonin receptors are expressed Edvinsson from Sweden, Michael A number of neuropeptides were identi- by trigeminal sensory fibers and ago- Moskowitz from USA, and Peter J fied in the cerebrovascular innervation. nists like Sumatriptan and ergots inhibit Goadsby from Australia, was experi- Among those, CGRP (calcitonin neuropeptide release. Sumatriptan mental and orientated towards elucidat- gene-related peptide), discovered by MG became the leader of a new class of acute ing the relationships between the brain Rosenfeld, proved the most interesting. antimigraine drugs called the triptans and the vessels and their implication in Edvinsson set up the methodology to which have changed the life of many migraine. Moskowitz and colleagues study its role in the trigeminovascular migraine sufferers. 8 The Brain Prize 2021 · Information Pack The Lundbeck Foundation
The scene was set for building up the migraine, they markedly improve the and brain stem events consistent with clinical background for CGRP in quality of life of many migraineurs. the development of headache. This was migraine. This was a remarkable They are also the first drugs to have a the first experimental evidence of the achievement of Edvinsson, Goadsby and duality of mechanism, being active in link between aura and headache during their teams. It took them more than 10 both the acute treatment and the pro- migraine attacks. He also showed that years to develop the first CGRP antago- phylaxis of attacks and they have paved cerebral ischemia could induce the CSD nist drug effective in the acute treatment the way for the study of other potential in accordance with Olesen’s previous of migraine attacks, as shown in a large targets. clinical observation. He further trial involving Olesen and his team in explored the link between aura and 1984. This drug was a small molecule The CGRP story was crucial for the headache and showed in 2010 that CSD called olcegepant which became the understanding of the migrainous head- leads to a long-lasting activation of noci- leader of a new class of antimigraine ache but it did not shed light on one of ceptors that innervates the meninges. drugs, the gepants. Two other gepants the most unique feature of migraine Recently, he showed that acute sleep have been approved for the acute treat- attacks, the neurological aura which pre- deprivation, a possible trigger of ment of migraine attacks and others are cedes the headache in about 20% of migraine attacks, enhances CSD. in evaluation in phase 3 trials in both the patients. The study of the neurological acute and prophylactic treatment of aura was one of the main themes of The four recipients of the Brain prize migraine attacks. The idea of blocking research of Moskowitz. In 2001, using 2021 have completely modified the the CGRP pathway took another direc- fMRI, he showed for the first time that migraine world in bringing science, tion with the development of monoclo- during a migrainous aura there are bold both clinical and basic, in this previously nal antibodies (MAbs) towards CGRP or signal changes which share many char- mostly artistic field. The IHS classifica- its receptor as prophylactic treatment of acteristics with the cortical spreading tion of headaches, the identification of migraine attacks. At the moment there depression (or depolarization), CSD. The the trigeminovascular system, the are 4 MAbs that have been shown, when changes developed in the extrastriate CGRP story leading to MAbs, the eluci- administered subcutaneously or intra- cortex, progressed continuously and dation of the link between the aura and venously once a month or once every 3 slowly over the occipital cortex while the the headache during attacks have all months, to reduce by half compared to patients had the typical visual symptoms been major achievements to better placebo the number of migraine days, of the migrainous aura. The CSD phe- understand migraine and improve the with a response rate of roughly 50% of nomenon, described by Leao in 1940, quality of life of migraineurs. migraineurs. Two of these MAbs have had long been suspected to underlie the Furthermore, these four migraine been approved and are already on the migrainous aura but this was the first experts have inspired many young market. The long story of the develop- demonstration in humans. A year later people all over the world, clinicians as ment of CGRP antagonist drugs has Moskowitz showed that the CSD acti- well as basic scientists, to become inter- opened a new era in migraine research vates the trigeminovascular system and ested in migraine. and therapy. Although they do not cure induces a series of cortical, meningeal The Lundbeck Foundation The Brain Prize 2021 · Information Pack 9
The Brain Prize winners, 2021 Short Biographies
LARS EDVINSSON pathway and which is selectively Lars Edvinsson is Swedish and a released during a migraine attack. Based Professor of Internal Medicine at Lund on his findings he proposed that CGRP University. He is also president of The may be of central importance in cerebral International Headache Society and blood flow and migraine. Professor Professor in Clinical Pharmacology at Edvinsson and his group have contrib- Copenhagen University. He trained at uted numerous basic research and clini- Lund University Medical Faculty and cal insights that have enabled the suc- graduated as MD with PhD in 1980. He cessful translation of CGRP drugs from became a full professor at Lund bench to clinic. He is currently studying University and senior consultant at the the female bias in migraine. Recently he University Hospital in Lund in 2002. He showed that the trigeminal CGRP- is also the founder of the Glostrup containing neurons are equipped with Research Park and has been its leader receptors for estrogen and oxytocin, and for the last 15 years. they may hence be regulated by the dynamic changes in levels of these hor- He is a leading expert in the field of mones in females. Typically, both hor- cerebral circulation and migraine. He mones drop just prior to menstruation has been a major contributor to what is and this may be a trigger for migraine Peter Goadsby known about the roles of the cerebral attacks. The molecular understanding is vasculature in health and in stroke and still not solved so more research in this primary headaches. Working with Peter area is on the horizon. Hospital, Sydney as a consultant neurol- Goadsby, he identified calcitonin ogist and became an Associate Professor gene-related peptide (CGRP) as a key PETER GOADSBY of Neurology. He was appointed a transmitter in the trigeminal pain Peter Goadsby is Professor of Wellcome Senior Research Fellow at the Neurology, University of California, Los Institute of Neurology, University Angeles. He is Director, NIHR- College London and was Professor of Wellcome Trust King’s Clinical Clinical Neurology and Honorary Research Facility, King’s College Consultant Neurologist at the National London and Honorary Consultant Hospital for Neurology and Neurologist, King’s College Hospital. Neurosurgery, Queen Square, London He is an Honorary Consultant until 2007. He was Professor of Neurologist at the Hospital for Sick Neurology, at University of California, Children, Great Ormond St, London, San Francisco, 2007-2013. UK. He has studied headache disorders He obtained his medical degree and from bench to bedside, collaborating training at the University of New South with Lars Edvinsson to be the first to Wales (UNSW), Australia. His PhD in show the involvement of CGRP in neural mechanisms involved in head- migraine and cluster headache, which ache disorders and his Neurology train- led directly to the development of gep- ing was with James W. Lance. His clini- ants and CGRP monoclonal antibody cal neurophysiology training was with treatments for migraine. He has David Burke. After post-doctoral work explored migraine and cluster headache in New York with Don Reis at Cornell, mechanisms with laboratory models, Jacques Seylaz at Universite VII, Paris, human experimental medicine, func- and post-graduate neurology training at tional brain imaging and clinical trials, Queen Square, London with C David while maintaining an active clinical Marsden, Andrew Lees, Anita Harding practice that focuses his efforts on real and W Ian McDonald, he returned to translational benefits for patients with Lars Edvinsson UNSW, and the Prince of Wales headache disorders. 10 The Brain Prize 2021 · Information Pack The Lundbeck Foundation
The Brain Prize winners, 2021 Short Biographies
trigeminovascular system and identify- In his thesis he showed for the first ing the first neuropeptide in this path- time in humans that physical activity way, he proposed a migraine road map increased blood flow in the relevant that implicated trigeminal neuropep- brain area. The relation between brain tides and their receptors as therapeutic function and brain blood flow has subse- targets. His laboratory showed that clas- quently developed to an avenue of sci- sical antimigraine drugs (ergots, trip- ence but Jes Olesen did not pursue that tans) inhibited neuropeptide release, path. Instead, he first showed that corti- thereby inspiring use of drugs and bio- cal spreading depression is the likely logicals that block release and inhibit a physiologic mechanism of the migraine meningeal inflammatory response. aura. Next, he developed a human prov- ocation model and showed the crucial Building on this scheme, his labora- importance of nitric oxide, calci- tory looked for upstream endogenous tonin-gene related peptide and pituitary triggers and identified spreading adenylate cyclase activating peptide in depression (underlying migraine aura) migraine mechanisms. Likewise, an as the first candidate that activated the increase in second messengers cyclic trigeminovascular system and as a guanylyl monophosphate and cyclic ade- target of preventative antimigraine nylyl monophosphate activated drugs. Identifying other upstream trig- migraine mechanisms. More recently he Michael A. Moskowitz gers, whether from brain or blood ves- continues his work in animal models of sels, will greatly facilitate our under- migraine and in the exploration of standing of migraine going forward. migraine genetics. Along with his scien- MICHAEL A. MOSKOWITZ tific work he has also initiated and Michael A. Moskowitz is professor of Based on his formulation and chaired the International Classification neurology at Harvard Medical School. research plus the pioneering research of of Headache Disorders and has been the His laboratory has been in the depart- his co-honorees, more than 20 new prime mover organizing the European ments of Radiology, Neurosurgery and drugs and biologicals are now in the Federation of Neurological Society and Neurology at the Massachusetts General clinic that impact the trigeminovascular the European Brain Council. Hospital where he spent most of his system and its upstream and down- career following 8 years as a postdoc- stream targets. toral fellow and faculty member at the Massachusetts Institute of Technology. JES OLESEN His research focuses on translational Jes Olesen is a professor of neurology at mechanisms underlying migraine and the University of Copenhagen and a stroke and is credited with foundational chief physician at the Danish Headache discoveries that ushered in modern day Center, Rigshospitalet Glostrup, migraine therapeutics. Copenhagen, Denmark. He is the father of the International Headache Professor Moskowitz was born in Classification and has identified several Brooklyn, New York. He received his signaling mechanisms in migraine lead- undergraduate and medical degrees ing to new drug targets and registered from Johns Hopkins University and drugs. Tufts University School of Medicine. He became intrigued by migraine after 6 Jes Olesen was born in Denmark, years of clinical training in internal studied at the University at Copenhagen medicine and neurology at Yale and and defended his doctoral thesis on Harvard Hospitals. He was the first to human brain blood flow there. His neu- hypothesize that vasoactive neuropep- rological education included a residency tides contained within trigeminal men- at Cornell Medical School, New York, ingeal nerve fibers participate in and a volunteer period at the National migraine pathophysiology and to sug- Hospital Queen Square, London. He Jes Olesen gest new strategies for prophylaxis and founded and for many years led the treatment. After discovering the sensory Danish Headache Center where he is nerves to the circle of Willis within the still an attending physician. meninges, penning the name The Lundbeck Foundation The Brain Prize 2021 · Information Pack 11
Autobiographies of the winners Fig 1. The Prepared Mind: 1970s-1990s Era of characterizing the Innervation and Neural Regulation of Cerebral Blood Vessels Lars Edvinsson 2012 Lifetime Achievement Reward by American head- ache leaders (Boston). Calcitonin gene- related peptide I trained at Lund University Medical 2012 Honorary Doctorate, (CGRP) discovered in early 1980s as Faculty and graduated as MD 1980 and University of Szeged, an alternative product of the did my PhD in 1975 during my MD stud- Hungary. calcitonin gene; ies. I became specialist in Clinical 2008- Bland Lane International found in neurons Pharmacology 1985 and specialist in Distinguished Professor q Development of functional and neuroanatomical methods Internal Medicine 1988. I chose Internal Award, FAMRI, USA. q Discovery of neuropeptides including CGRP 1 Medicine and became associate profes- 2002- Honorary Fellow, British Edvinsson, L. Uddman R, Brain Res Rev. 2005 sor (docent in internal medicine) 1988 Pharmacology Society. Fig 1. The Prepared Mind: 1970s-1990s Era of char- and full professor in 2002 at Lund 1985- Honorary Fellow, Stroke acterizing the Innervation and Neural Regulation of University and senior consultant at the Council, American Heart Cerebral Blood Vessels University Hospital in Lund. Association In parallel with my clinical duties, cur- The law of Canon stated; one nerve one rently as a senior consultant in ICU, I 2004-2020 Adjunct Professor, Basic and signal molecule, but new data chal- started my own research group where Translational Research lenged this dogma. We were the first to numerous PhD students and post-docs Institute, Xian University, show VIP in perivascular nerves in brain were educated throughout the years at Xian, China vessels. This was a starting point, and Lund University. My students consider 1990-2020 Adjunct Professor in many neuropeptides were identified in me as a very appreciated supervisor and Pharmacology, Southern the cerebral vessels, for me with perivas- teacher. Illinois University, Illinois, cular nerves, both in autonomic and in USA sensory fibers (Figure 1). I was invited to I consider myself an expert in the 1990-1995 Professor II in Neuroscience, The Migraine Trust and to Brain confer- interpretation of the sensory nervous Trondheim University, ences to discuss our findings in relation system and am recognized as a leading Norway to clinical contexts. This educated me expert in the field of vascular innerva- and pointed my research in the direction tion and receptor regulation. My exten- I started my research at the second towards finding the roles of all these sive research has been a major contribu- semester of my medical studies in Lund. newly discovered neuronal signaling tor to understanding roles of autonomic For 5 years I was devoted to the study of molecules. In Glasgow we discovered and sensory mechanisms in regulation innervation, vascular receptors, and the the trigeminovascular reflex 1986 of the cerebral circulation in health and role of autonomic nerves on cerebral cir- (Figure 2). diseases such as stroke and primary culation. These were great years for a Fig 2. The Trigeminovascular Reflex headaches. I have written many young researcher, it was there I got input well-recognized educating books. My and collaborated with laboratories in research has led to the discovery, under- Paris University (Seylaz), and Glasgow standing and development of novel University (Harper, MacKenzie, drugs for the treatment of neurovascular McCulloch). I spent much time there diseases, such as the successful treat- and was educated in new methods and ments of migraine. scientific teachings at the highest level. It was extreme freedom in the scientific I consider the following recogni- arena. When I returned to finish my MD McCulloch J et al. PNAS 1986;83:5731–5735; Edvinsson, L et al. Br J Pharm 1990;100:312–318; 2 tions, honors and awards as highlights it was hard work because in principle I Edvinsson, L et al. Cephalalgia 1995;15(5):373–383. of my career: continued research and MD studies Fig 2. The Trigeminovascular Reflex simultaneously while building my own 2018 Forska Sverige prize; research group at the Lund University. In the following years, I developed awarded to the best scientist Domestically, I met my beloved and excellent collaborations and life-long in all disciplines in Sweden. supportive companion Marie-Louise, friendship with colleagues in Paris, 2014-2019 Elected Trustee, Director and we were married in 1979 and were Glasgow, Copenhagen, Szeged, Sydney President, International blessed by two wonderful boys. and Los Angeles. We were young and Headache Society shared a deep interest in advanced sci- 2013- Member, Steering Board, In 1976 I was at the right position, in ence. We realized that by joining forces European Headache time and location, since people had and sharing technologies we could all Federation developed antibodies towards different get closer to understanding our scien- 2013 Honorary Doctorate, Xián neuropeptides, and it benefitted the tific quests. I was appointed adjunct pro- University, China. vivid scientific environment in Lund. fessor and honorary doctor at many 12 The Brain Prize 2021 · Information Pack The Lundbeck Foundation
Fig 3. Mechanism of Triptans: Suppression of CGRP Release from Trigeminal Nerves via Presynaptic 5-HT1B/D Receptors Universities throughout the world. In equipped with receptors for estrogen Lund I became professor of Internal and oxytocin, and they may hence be Medicine and had a very productive regulated by the dynamic changes in team at the University. In Copenhagen I levels of these hormones in females. was given the opportunity early to set up Typically, both hormones drop just prior a unit and later to build the Glostrup to menstruation and this may be a trig- Research Park and be its leader now for ger for migraine attacks in females. The nearly 15 years. I was honored to be molecular understanding is still not appointed to the position of professor in solved so more research is on the Clinical Pharmacology at Copenhagen Goadsby PJ and Edvinsson L. Ann Neurol 1993;33:48–56 horizon.3 University. Fig 3. Mechanism of Triptans: Suppression of CGRPFig 4. Sites of effects of novel specific anti-migraine Release from Trigeminal Nerves via Presynaptic drugs The new molecular insights on peri- 5-HT1B/D Receptors vascular nerves in the cranial circulation went two ways; into headache disorders sufferers. We have focused much atten- and towards stroke. As the number of tion towards explaining the site of their neuropeptides increased in these nerves action, as shown in Figure 4 (action of it was difficult to identify their individ- CGRP receptors in the trigeminovascu- ual roles. The first clinical studies in pri- lar pathway) and at the nodes of Ranvier mary headaches revealed that the sen- where CGRP in C-fiber boutons is sory neuropeptide, calcitonin released into the nodes where we find gene-related peptide (CGRP), was the CGRP receptors. Edvinsson et al 2018 Nat Rev Neurol. 4 only neuronal messenger reliably released in migraine (Figure 3). This Currently we are examining the Fig 4. Sites of effects of novel specific anti-migraine clearly pointed towards migraine and important question why females domi- drugs this is what we celebrate today with nate in migraine. This year we showed effective medications to treat millions of that the trigeminal neurons are
Peter Goadsby I liked to read about what I consid- most formative in terms of self-reliance ered factual subjects. I would spend and self-discipline. many happy hours reading randomly in I grew up in the Western suburbs of an encyclopaedia or browsing the local I had no interest in medicine or even Sydney, a town called Blacktown. Dad library reference reading room. I recall biology when I was in school. I thought worked hard in a factory job that I am vividly proving the maths teacher wrong biology imprecise, largely driven, I sus- sure he hated, and mum was at home about an obscure point of set theory pect, by the teaching. I did chemistry until my youngest sister went to school, when I was thirteen years old. I spent and liked it greatly. I loved maths and when, as a mathematics teacher, she weeks in the local library reading about more so economics. I first thought about went back to work. My childhood mem- the subject. We were not allowed to use being a teacher, but it seemed a default ories are of my brother and I playing the school library for schoolwork since not a real choice. I recall being forced to together; they were happy days. High our teachers, who were Patrician stop Latin in high school; I objected and School memories are mixed. I blos- Brothers, thought we should be outside – was told it was a subject for “doctors and somed academically in high school and it was healthier by their byzantine world lawyers” and that when I was working in did well in everything I liked: maths, sci- view. I presented the work to the teacher a factory later in life I would have no ence, languages, particularly Latin, his- who gave me a caning for being impu- need for it. The school with its totally tory and in later years economics. I was dent. I presented it to my mother, a anti-intellectual environment really not a fan of music and art, resenting maths teacher, who agreed it was cor- motivated me to be better; not be sucked what I saw as wasted time. I found con- rect, and asked the teacher who said: “a into a world of mediocrity that many of siderable inspiration in my Latin teacher teacher should never admit being wrong the teachers had created for themselves. who encouraged me to be excellent at to a student”. This was a useful lesson as serious subjects. Likewise, my mother a supervisor of students over the years in By the end of high school, I had was never content with anything less how not to behave. The fact that I was decided I wanted to be Treasurer of than perfection. She recognized that correct satisfied me immensely. I’ve Australia. I liked quantitative econom- 100% was the only acceptable score in always loved the precision and beauty of ics. I subscribed to the Reserve Bank maths! She taught me self-discipline and numbers. I spent most of my adolescent statistical bulletin, memorized the rigour; frankly, it is the only reason I years saddened and unhappy by uncuri- quantitative data and thought the then have been at all successful. I found ous and unimaginative teachers. I would treasurer of Australia was rather sub- school socially isolating for many years. sit in my room at home and wonder what par: untrained and not thoughtful, or I became interested in rugby league ref- life would be like in such a world that I apparently knowledgeable about eco- ereeing and to this day recall the excite- did not want to be part of. My junior nomic theory. I subscribed to Federal ment of the match. high school years until year 11 were the Parliament Hansard, the record of oral most miserable years of my life, yet the activity, and spent many happy hours The Lundbeck Foundation The Brain Prize 2021 · Information Pack 13
reading it. I considered the debates gave when I was in year two. He talked It must sound like a theme; the ear- poorly constructed and ill-considered. about non-dominant parietal lobe syn- lier clinical years were awful. I recall I felt I could easily do better. I planned to dromes - including autotopagnosia - it finding internship tedious. When I came do economics and law and join a political struck me that medicine had interesting back from the US, I was able to establish party. Our school library had no infor- aspects, and he had a way of enticing you a physiology laboratory and began to use mation about university courses. One to think about the mechanisms (1). As the quantitative cerebral blood flow and day I had a blazing argument with my these things happen, we saw a case in our metabolism methods I had learned. Jim mother and at the last moment I changed clinical studies tutorial some weeks later Lance found funds for the equipment, by preferences for university to do medi- and I knew I wanted to be a neurologist. I and I began to do experiments on week- cine to prove a point. I was truly dis- read about the relevant physiology from ends or any days off I had. mayed when I got in. Years later I under- Vernon Mountcastle (2), and felt ener- stood politics was not about knowledge gised. It was one of those moments in life I had observed that US doctors had but presentation; I am glad I did not get that completely alter the path. It sounds an MD, and I was MB BS PhD. I thought into law. crazy, but I wanted to be an academic it might be nice to get an MD. I had neurologist doing research and clinical begun doing laboratory work, so I Prior to starting I had an interview work after this combination of the paper, thought enrolling part-time would be by the head of community medicine and Lance’s lecture and seeing the case. I did simple. I had to meet the then Professor a few others. At the time university not do research until after the penulti- of Medicine, John M Dwyer, to sign off places were decided by the outcome of mate year of the course because of finan- the form. He had not long before coming the Higher School Certificate, best cial constraints but I was completely back from Yale to take up the post and mark, most choice. There was no inter- clear about my direction. was an immunologist. We met. He view. The university decided to do inter- advised me not to do an MD, giving me a views to see how their predications I published my first paper in 1982 (3). little talk about burn-out and work-life would develop and design an interview Jim Lance was a patient mentor and balance. At the end of his talk I thanked system to complement the marks in the editor, Geoff Lambert an excellent him and asked him to sign the form high school examinations. My interview teacher in the lab and John Duckworth, since I was going to do the work anyway. was a disaster. I understood I had noth- who was on many subsequent papers, a He was less than pleased as he signed ing in common with the questioners, very detailed and patient educator. They the form. More than 30 years later I and knew the interview meant nothing each, in their way, drew my attention to must be still burning out. since I was already in. I had to take a day my breathtakingly poor writing. I still off work, I had started a job to pay for my have- Why not say it clearly? Echoing my The laboratory work proceeded well. medical books and so on. My commute mind from time to time. Laboratory I was incredible lucky to hear a lecture was two hours, bus-train-bus each way, a members introduced me to PC technol- by Lars Edvinsson at a meeting in Lund routine I was to become accustomed to ogy in 1981. Ross Hand showed me the C in June 1985. He was doing remarkable but never enjoy for several years. I did Programming language book, and Unix work on the trigeminal effects on the not know where the university was and operating system triggering a technical cranial circulation and novel neuropep- had never been there; the first trip was love-affair that has persisted to this day. tides, particularly CGRP. He was very certainly an unpleasant shock. I turned gracious to listen to my pitch over coffee up in shorts, flip-flops and with attitude I went on the following year to stay in and we set up the collaboration that in spades. It was concluded by one of the the laboratory and transitioned from a resulted in the CGRP work. The goal we heads of department saying I was Bachelor of Medical Science to a PhD. I had was to do translational work as we exactly the type of person an interview had found the joy of discovery. Jim went along rather than do years of labo- process would try to identify and keep Lance advised me to start a PhD and ratory work and then take it to humans. out of medicine. delay finishing medicine. It was a leap We showed we could cause release in that I enjoyed. In the following two years humans and experimental animals of So, the first week was weird; I worked reasonably hard and wrote a CGRP. At the same time I was studying I remember thinking I was out of place. two volume, 965-page thesis, which was for the FRACP examination– the I had a long commute. One of my class- submitted two years to the day after Australian specialist board qualifica- mates told me they did not travel that far enrolling. It had a sad element in that my tion. The combination made me not ter- on summer holidays. I soon discovered medical school class moved on and grad- ribly accessible socially, and it did not the Students Union, thinking I could uated and I was working away; but it was work well at some level. I decided to engage in debate for fun. I found it full of incredibly exciting to do research. I went study for the US ECFMG while a resi- entitled, lazy-thinking individuals with back to do the last year of medicine, dent, thinking about returning there. I no life experiences. I certainly thought which was awful. It seemed simply to recall being called into the ICU my class had many rather sheltered delay becoming an academic neurolo- Director’s office to be asked why I sat members. I thought I’d made the wrong gist. At the end of the year I combined away from everyone reading; the nurs- decision and wondered how to change. various elective terms and the first part ing staff had complained I was anti-so- I understood my cultural references of internship and went to Cornell in cial. I explained I was studying and pre- were very different to everyone around New York for a post-doc in the labora- ferred reading; this explanation did not me, so it took many months to find tory of Don Reis, where I was fortunate seem comprehensible, and the Director’s friends, one of whom I am still in contact to work with Steve Arneric, Mark attitude that social interactions were with to this day. Underwood and Costantino Ladecola. more important than studying per- At the end I was offered a position in that plexed me. Professor Dwyer called me to There was no formal research com- laboratory by Don Reis, but Jim Lance his office to say he was concerned that I ponent unless one elected to do it. My life said, no, come back and get your medical did not get on with the nursing staff, was transformed by a lecture Jim Lance training. I took his advice. describing that I was considered a robot 14 The Brain Prize 2021 · Information Pack The Lundbeck Foundation
who would do rounds, write very clear Morgan-Hughes in muscle, PK Thomas anything else in this narrative. I can say notes, carefully chart medicines and not in peripheral nerve, Martin Rossor in I have no hobbies and I do not like read- leave any room for error. He complained dementia, Simon Shorvon in epilepsy, ing books, well fiction books. I like I left no room for “normal social interac- John Scadding in pain and Roman browsing Wikipedia on mathematics and tion”. I asked him if he was asking me to Kocen, ever disciplined, in general neu- computer security. I consciously chose in make errors for conversations sake; this rology. I met colleagues for life; spent 1994 when I decided to move to the UK to was not a discussion I would recom- many weekends in Paris doing cerebro- stop having hobbies and focus on work. mend having with the head of medicine. vascular physiology to learn some more I do not regret that decision at all. I like laboratory skills and was bitten by the mindless action movies. I like travelling I finished ECMFG and started excitement of being in the midst of the to places I have not been, meeting col- studying for the FRACP. Professor action. leagues and, of course, touching base Dwyer felt I was ill-suited to be a physi- with Australia from time to time. cian. He wrote an assessment that said I I applied for Wellcome Trust funding had below average inter-personal skills. to return to Australia and was success- There are two components to success I retain a PDF copy as a reminder of that ful. Returning in 1991, I set up a physiol- in combining research and clinical one can always do better. I was not ogy laboratory for myself drawing on work. The first, and most important, is appointed to the medical training what I had left, and with great generosity your mentor and colleagues. A good scheme that was designed to facilitate and collaboration of Sandrino Zagami mentor will nudge you when off course examination study. Jim Lance had to and Geoff Lambert. I continued the col- and opens doors that are otherwise inac- insist I was appointed as a medical resi- laboration with Lars Edvinsson when cessible. Good colleagues make the dif- dent and vouch that I would keep out of we tested the effect of the recently devel- ficult doable. I have been blessed by trouble; without his intervention I would oped sumatriptan on CGRP levels in both. Jim Lance taught me the job of not have had a job. The situation turned migraine, showing them to be nor- training others; certainly, who we train out to be a boon; unencumbered by the malised (5). We showed shortly after that and how we motivate them is one of the scheme I could work in a self-directed CGRP was involved in a truly horrible exceptional opportunities that academia way, and I had time to get the initial problem: cluster headache (6). These offers. CGRP work done. The then senior medi- studies really cemented the CGRP target cal registrar was delegated to tell me that in migraine and cluster headache that The second thing is totally personal. I could take the examination, a form has proven now to be so useful. I went The degree of success you will have is in needed to be signed, as long as I agreed back to London after four years in proportion to how hard you work. It is that if I passed, I would not pursue a Australia and have never lived in not magic. The more success you want, clinical career but rather a laboratory Australia since. the more you have to be prepared to sac- career. I agreed to the deal, regarding rifice. Work-life balance is a myth in the any agreement as a reasonable ploy for I have been almost indescribably for- sense that it can be achieved at all levels the greater good. tunate to be able to have seen the CGRP of success; in my experience it cannot. story through the last translational mile There is nothing wrong with being I have seldom been totally lost for in recent clinical trials (7);(8). I have unbalanced, if that is what you enjoy. words. On the first medical Grand always wanted to make the world a Rule two: do what you enjoy in propor- Rounds after the FRACP clinical exam- better place for people with disabling tion to its enjoyment. ination at which I passed, Professor headache disorders and have been fortu- Dwyer greeted me with enthusiasm and nate to work with patient groups, such as My greatest fear in life is retirement; hugged me. I have never had a more dis- the Migraine Trust and the Organisation I cannot think of a more painful experi- ingenuous interaction to this day. for Understanding Cluster Headache ence than not being able to work. I feel (UK), who have taken me in and treated privileged to work in medicine with Completing the FRACP let me focus me as one of their own. I understood this headache disorders, to make some small on neurology and my laboratory work. best when the late Michael Pollock, who differences and help the incredibly brave My collaboration with Lars Edvinsson was chair of the cluster headache group patients I see do just a little better. blossomed and culminated in the study and a long term patient, told me on his of neuropeptides in acute migraine (4), death bed that he was more scared of his 1. Lance JW, McLeod JG. A physiologi- which cemented for us the CGRP next cluster attack than dying; and by cal approach to clinical neurology. hypothesis of migraine. We collaborated the way would I speak at his funeral. Sydney: Butterworths; 1981. on cerebrovascular physiology studies of I have spoken in front of large audiences 2. Mountcastle VB, Lynch JC, novel neuropeptides and I could focus and on television and radio, and not to Georgopoulos A, Sakata H, Acuna C. during the day on neurology training diminish these, yet the sense of trust and Posterior parietal association cortex and learning particularly about responsibility I felt the day I spoke at of the monkey: command functions migraine. I completed six full publica- Mike’s funeral still gives me both pause for operations within extrapersonal tions for the MD and submitted it in the and purpose today. space. J Neurophysiol. months before I went to London for fur- 1975;38:871-908. ther training. Jim Lance told me I should More personally, I have three chil- 3. Goadsby PJ, Lambert GA, Lance JW. go and get polished a little; as with all his dren James, an obstetrics/gynaecology Differential effects on the internal advice, it was excellent, and admittedly trainee, David, a recruitment consultant, and external carotid circulation of the needed. Queen Square was arguably at and Georgia, a student of political sci- monkey evoked by locus coeruleus its peak. David Marsden, Anita Harding ence and influencer video producer. stimulation. Brain Research. and Andy Lees in movement disorders, What I lack in intelligence, charm, savvy, 1982;249:247-54. Ian McDonald in MS, Ralph Ross- and goodness, all resides in them with a 4. Goadsby PJ, Edvinsson L, Ekman R. Russell in vascular neurology, John measure that makes me prouder than Vasoactive peptide release in the The Lundbeck Foundation The Brain Prize 2021 · Information Pack 15
extracerebral circulation of humans 6. Goadsby PJ, Edvinsson L. Human in episodic migraine. New England during migraine headache. Annals of vivo evidence for trigeminovascular Journal of Medicine. Neurology. 1990;28:183-7. activation in cluster headache. 2017;377:2123-32. 5. Goadsby PJ, Edvinsson L. The tri- Neuropeptide changes and effects of 8. Goadsby PJ, Dodick DW, Leone M, geminovascular system and acute attacks therapies. Brain. Bardos JN, Oakes TM, Millen BA, et migraine: studies characterizing 1994;117:427-34. al. Trial of Galcanezumab in cerebrovascular and neuropeptide 7. Goadsby PJ, Reuter U, Hallstrom Y, Prevention of Episodic Cluster changes seen in humans and cats. Broessner G, Bonner JH, Zhang F, et Headache. New England Journal of Annals of Neurology. 1993;33:48-56. al. A controlled trial of erenumab for Medicine. 2019;381:132-41.
Michael Moskowitz musical instrument so that he could with swimming and sports, especially travel to border towns with the Russian baseball—between sunburns. army band. He walked across the border The first major breakthrough in treating and came to New York. My paternal migraine happened by accident more grandfather, my namesake, labored as a than 150 years ago, when an Italian coal miner in the Carpathian mountains doctor treated a patient for postpartum until he emigrated with his family to hemorrhage with an extract containing work in the coal mines of Scranton, ergot alkaloids, powerful smooth muscle Pennsylvania. After he was diagnosed constrictors, and discovered it also with black lung disease the family relo- stopped a migraine attack. cated to New York’s lower east side, where he entered the dry goods busi- The modern era of migraine thera- ness. Years later I learned from my peutics, and my part in it, began more mother that our relatives that remained than four decades ago in a much more in Russia were not as fortunate. scientific way—with the generation of a hypothesis based on knowledge of the Me and my siblings at Bear Mt Park tissues within the cranium that sense pain, the proximity of pain fibers to I also developed a love of music, blood vessels, and emerging evidence of which I have sustained to this day, neuromediators released from pain thanks to my mother, older sister and fibers. This hypothesis ultimately led to extended family. Not infrequently I took the discovery of many therapeutical- the bus and subway into Manhattan to ly-relevant drugs and biologicals that buy records or hear concerts at Carnegie have brought lasting relief to tens of mil- Hall, often with my mother. While in her lions of migraine sufferers who once had 70s my mother learned jazz piano and few options other than lying in a dark- played until she died at age 103 (I know ened room. she would enjoy having me mention With my sisters and parents, 1940s this). I played the oboe and piano, and Saturdays were reserved for lessons and My grandparents brought very little woodwind chamber playing with my with them from the “old country,” but family. To this day music remains my they showered us with much love and cathedral and medium for escape; affection, which is what truly matters. I family reunions at music festivals was born in New York in 1942. My remain a highlight. I am forever thank- father, a physician, was away serving in ful to my mom. the armed forces and I only met him for the first time at age 3, when Dad returned from Australia where he had been caring for wounded soldiers. Even Surrounded by maternal grandparents after his return it was my mother who raised me, the second of four children, My own journey to these discoveries with help from her parents and sister’s started, like so many Americans, with family who lived nearby. my European forebearers escaping reli- gious persecution to find opportunity in When I was 10 we moved to the the teeming streets of New York City. Rockaways, a remote part of Queens Both of my Jewish grandfathers endured surrounded by ocean, to a home seven tremendous hardships before fleeing to houses from the beach. It was a glorious the west. My maternal grandfather was place to grow up, with summers filled born in Kiev and learned to play a With my mom, Clara 16 The Brain Prize 2021 · Information Pack The Lundbeck Foundation
I was educated in the public schools a pathway, identify a deficient transmit- explain why many migraine headaches of Brooklyn and Queens and graduated ter, develop animal and human models, were experienced on only one side, with from Far Rockaway High School in and discover a transmitter-modifying pain sometimes stopping abruptly at the 1960—the alma mater of the Nobel therapy that had a huge impact on dis- midline. I reasoned that headaches Laureates Richard Feynman, Baruch ease and greatly benefited patients. This caused by circulating substances should Blumberg, and Burton Richter, well strategy for deciphering complex disor- trigger headache on both sides, since before my time. By then my interest in ders of the nervous system became a both receive the same arterial blood. medicine was beginning to take hold. model for my own work.
At Fenway park with Tali, daughter Jenna and Mattia
At MIT I became inspired by the published writings between 1910-1950 of Cushing, Penfield, Ray, Woolf, and Feindel at the Countway Library. It was My lab circa 1995, at MGH’s historic Bulfinch building fascinating to learn how they discovered that the connective tissue coverings of While training in neurology in the brain (the meninges) were the only My parents and I at college Boston at Peter Bent Brigham, Boston pain-sensitive structures within the cra- Children’s, and Beth Israel Hospitals, I nium, as the brain itself is insensate. My father, a general practitioner, had developed my interest in migraine, a There was a striking lack of evidence of his office in the basement below our mysterious and fascinating condition pain fibers in the arterial connections at apartment and I would often accompany that lacked an obvious pathophysiology the base of the brain, called the circle of him on Saturday house calls. At age 14 I and explanation. The impact on quality Willis, but I was learning from patients was thrown into the deep end of medi- of life was clear, and the illness presenta- that strokes in large meningeal vessels cine when I took a summer job as a mes- tion fascinating. I believed it could tell caused headaches. It was clear that a senger boy at the Jewish Sanitarium for us something very important about the fresh look at the vascular innervation Chronic Diseases, a home for patients organization and function of the brain. was needed. This is where I dropped my afflicted with severe developmental first scientific anchor. The field was defects, dementia, end-stage neurode- Also, though migraine afflicts some awash with possibilities and I was hope- generative diseases, and debilitating 100 million people worldwide, little was ful that out of this chaos might come strokes. I initially felt frightened and known about the disease at the time. clarity. overwhelmed by such severe incapacity, There was no consensus on whether but these desperate patients also roused migraine headaches arose from inside my curiosity about how the human ner- or outside the cranium, or whether vous system could go so awry. The migraine was an organic or psychologi- memory of those extremely ill patients cal disorder. There were no animal or still lingers, and the experience drew me tissue models and no pathology. like a lodestone to an interest in neurol- Treatment options were suboptimal and ogy. I wanted to better understand and the field lacked any coherent dogma to treat disorders of the brain, this mysteri- explain the origins of pain and aura or ous organ. Working at the Sanitarium its diverse manifestations. If it had I gave me a sense of purpose, and a goal. probably wouldn’t have been interested.
I attended Johns Hopkins University My thinking about migraine began and Tufts University School of Medicine, to crystallize as a postdoctoral fellow then trained at Yale in internal medicine. and junior faculty at Massachusetts One of my attending physicians, Melvin Institute of Technology (MIT), in the van Woert, had worked with the Greek Harvard-MIT Division of Health Our annual photo in the daffodils American scientist George Cotzias to Science & Technology. I questioned the discover L-DOPA for Parkinson’s dis- commonly-held hypothesis that In 1979, my MIT colleagues and I ease. Dr. van Woert regaled me with sto- migraine was caused by swelling of the proposed a hypothesis based on scant ries about one of the most exciting blood vessels in the head and scalp, pos- evidence. Little was known then about bench-to-bedside discoveries in the his- sibly due to vasoactive substances the role in nerve fibers of vasoactive pep- tory of neurology. How ideal: to discover within the circulation. This failed to tides, substances that can dilate blood The Lundbeck Foundation The Brain Prize 2021 · Information Pack 17
vessels. Our hypothesis was based on named this important pathway the tri- possibly explaining why treatment meager evidence from other organ sys- geminovascular system. reduces the frequency of migraine epi- tems and included substance P, the only sodes. In addition to genes, more than known vasoactive peptide, established likely vascular, metabolic, and psycho- in spinal sensory nerves. We emphasized logical stresses will be recognized that in a seminal paper published that year in modulate and contribute to CSD suscep- The Lancet the importance of the tibility as well as novel mechanisms to “release of substance P or as yet uniden- be discovered that activate the trigemi- tified peptides and other transmitters novascular system. from the fifth cranial nerve,” and sug- gested that “peptides and other neu- Recently, by linking migraine aura rotransmitters may participate in the with meningeal inflammation, pathophysiology of migrainous head- Nouchine Hadjikhani and colleagues at ache and might suggest new strategies the MGH Athinoula A. Martinos Center for prophylaxis and treatment.” for Biomedical Imaging discovered upregulated inflammatory signaling The paper was a major breakthrough, within the meninges and surrounding the first to introduce the concept of the tissues following repeated episodes of trigeminal nerve and vasoactive pep- migraine aura in 11 patients, opening tides stored and released from sensory promising new avenues to investigate. fibers in meninges. It changed the direc- With my wife upon hearing the news of The Brain Prize Much future study remains but advances tion and orientation of thought and over the past 40 years represent a tri- focus in the field. Using the trigeminovascular system umph of translational medicine and a as a template, Gabriella Buzzi in my near-seamless transition from bench to group was the first to provide pharmaco- bedside in the service of providing logical evidence that ergot alkaloids and better treatments and a roadmap for triptans inhibited CGRP and substance future discovery. P release, thus abrogating inflammation caused by peptide release. This work For my work with trainees, I am emphasized the expression of serotonin immensely proud to have been recog- receptors on sensory fibers that led to nized by Harvard Medical School with the commercial discovery and develop- the William Silen Lifetime Achievement ment of a 5-HT1F receptor agonist that in Mentoring in 2007. One of the most relieves migraine headache but does not rewarding aspects of my research has constrict blood vessels. It is now avail- been training and mentoring more than able clinically for acute therapy. 110 postdoctoral fellows and graduate students. More than a quarter are now It doesn’t get any better than this Summarizing the first decade of full professors, department chairs, insti- research, our team provided a template tute directors, and world-wide research Following publication of our Lancet and roadmap leading to the present, but directors; a number have become close hypothesis, my lab discovered the tri- we still had much work to do. Although colleagues and friends. geminal (sensory) nerves supplying the trigeminal activation, peptide release, circle of Willis by using novel axonal and neurogenic inflammation were My most enduring relationships, tracing techniques, aided by a polymeric important in treating migraine, the however, have been family, especially slow-release system developed by MIT upstream trigger was still unknown. My my daughter Jenna who lives just four colleague Robert S Langer. Marc lab found such a trigger—an intense, miles from me with her husband Jacob Mayberg ran this project; Lee-Yuan Liu metabolically-demanding brain activity and my grandchildren Mattia and Tali. Chen and he performed studies that called cortical spreading depression They bring great joy and meaning to my identified the first vasoactive peptide (CSD), the brain mechanism that under- life. My wife Mary has kept it all within this pathway. We described these lies migraine auras. together and has been my constant com- discoveries in seven papers between 1981 panion, plus a wonderful stepmom and and 1984. Several multidisciplinary studies grandmother. I cannot imagine a more have shown that CSD activates the tri- generous and loving partner. Because less than 50 percent of the geminovascular system and causes pain. trigeminal neurons projecting to the Hayrunnisa Bolay along with collabora- I write this autobiography from meningeal coverings of the brain con- tor David Boas provided convincing evi- home during a raging pandemic. It tained substance P, we also anticipated dence that CSD activates a pain reflex makes me realize how interconnected the discovery of other vasoactive neuro- and causes meningeal inflammation. we all are, and how fortunate I am to peptides. Our work on this first candi- Moreover, my close associate Turgay belong to an international community of date was accepted for publication or Dalkara discovered in his lab a signaling medical scientists who recognize and published before the discovery of a pathway to inflammation in the brain respond to the needs of the suffering. second and more therapeutically rele- that activates the trigeminovascular That 14-year-old messenger boy could vant vasoactive neuropeptide called system after CSD. Hong-Wei Jin and never have imagined the scientific jour- CGRP, found in nerve fibers surround- Cenk Ayata on my team found that ney he would embark on, nor how well ing intracranial blood vessels, and drugs used in migraine prevention make served he would be by the legacy of his before discovery of a third, PACAP. We the brain more resistant to CSD, parents and grandparents. 18 The Brain Prize 2021 · Information Pack The Lundbeck Foundation
Jes Olesen closed his fist, the regional brain blood brain blood flow was decreased during flow increased in the hand area of the the aura and into the headache phase corresponding hemisphere. I also after which it normalizes and then I was born in a small town in the western showed that during visual stimulation increases above normal but without part of Denmark called Jylland. There blood flow increased in the visual cortex, temporal relation to the headache. The were no gymnasiums (the Danish equiv- but I thought that it was hardly worth- ischemic theory of migraine was eradi- alent of high school) so instead I went to while to publish when I had already pub- cated but lingered on in textbooks for the boarding school called Herlufsholm, lished the effect of hand movement. It another 25 years. far away from my hometown. The school was a complete misjudgment because made me very independent and, since it the relation between brain functioning At the end of the eighties, I realized was full of pupils from the higher circles and brain blood flow and metabolism that with existing technologies there of Danish society, it also made me ambi- has later become a huge avenue of was nothing more to gain from studies tious if this had not always been my research with thousands of publications. of patients during attacks since sponta- nature. My dad was a general practi- My own findings have more or less been neous attacks cannot be studied at onset. tioner in the countryside and my mom a forgotten because they were published There had also already been several neg- dentist, so my choice of medicine at the already in 1970. ative biochemical studies confirming University of Copenhagen was no big this view. I decided to focus on provoca- surprise. Instead, I pursued my interest in tion of migraine attacks. Migraine neurology and watched out for a big neu- attacks are very unpleasant and painful rological disease where brain blood flow but cause no damage and are treatable. was expected to contribute. These unique features made it ethically possible to experimentally induce attacks in volunteer patients. I therefore developed an experimental human model for the study of migraine provok- ing substances. The first study was on histamine, already known to cause headache. In migraine patients it caused a migraine-like attack while in ten- sion-type headache patients it caused Here at my confirmation party with Mom and Dad less severe headache and in normal con- trols even less headache. Later, in a dou- After medical school, the only thing ble-blind trial, we showed that headache I knew was that I should not be a surgeon. induction was caused by activation of Internal medicine was an obvious the H1-receptor independently of nitric choice, but I was not quite sure that I was oxide. Unfortunately, it was also clear intelligent enough to match all the that anti antihistamines did not work in extremely clever people I met at the Young dr. Jes examining a headache patient migraine. So, the experimental model Department of Internal Medicine and did not always predict the effect of an Hematology. I sought something easier My chief, professor of neurology antagonist. The next series of studies and considered pediatrics but ended up Erik Skinhøj, and my friend Olaf B focused on the gaseous neurotransmit- with neurology. The choice was strongly Paulson had already done a study in ter nitric oxide (NO). The NO donor influenced by my close friend professor migraine patients demonstrating nitroglycerin caused a short-lasting Olaf B. Paulson who was already reduced brain blood flow during the headache in normal individuals and in engaged in an advanced research project aura using relatively simple equipment. migraineurs, but the migraineurs also lead by the world-famous scientist and Their findings seemed to support the got a delayed more severe headache expert in brain circulation, Niels A. then popular ischemic theory proposing attack that fulfilled the diagnostic crite- Lassen. Olaf told stories about many for- that the aura symptoms were due to arte- ria for a migraine attack. Several studies eign and particularly about American rial vasospasm and cerebral ischemia investigated different aspects of visitors to the lab, trips to international and the headache due to reactive hyper- NO-induced headache/migraine. Nitric conferences which in those days were a emia. Soon after I was able to show, with oxide was thus of importance in genera- very rare thing and first and foremost equipment allowing 254 hemispheric tion of migraine attacks. It was, however, about the exciting studies of brain blood areas to be measured, that blood flow also important for the entire duration of flow in real human beings. I got accepted changes started at the back of the brain the attack because an inhibitor of all 3 in Lassen’s group and was the first to use and spread gradually forward not nitric oxide synthase (NOS) enzymes a new type of equipment, the only one in respecting territorial supply of major was effective in treating spontaneous the world, that allowed the measure- cerebral arteries. These changes were migraine attacks. Unfortunately, ment of regional cerebral blood flow very similar to the animal experimental non-selective NOS inhibitors are not from 35 areas of a hemisphere. We used phenomenon called cortical spreading suitable as drugs. Selective inhibitors of the intracarotid injection of radioactive depression and soon after Olaf B. inducible NOS were not effective in xenon and I did several studies of the Paulson and Martin Lauritzen did more migraine. No good selective compounds pharmacology of the cerebral circula- detailed studies further validating the have been developed for eNOS and tion and of the physiological regulation idea of cortical spreading depression as nNOS and no drugs have been tested of human brain blood flow. Rather hap- the underlying phenomenon of the that modulate the further downstream hazardly I became the first person to migraine aura. Finally, in 1990 I com- reactions in the NO-cyclic guanylyl show that when a person opened and bined several studies and showed that cyclase cascade. Several possibilities are The Lundbeck Foundation The Brain Prize 2021 · Information Pack 19
right there waiting for the pharma industry. Next, we studied the influence of calcitonin gene-related peptide (CGRP). Like nitroglycerin, it caused headache in normal individuals and migraine attacks in migraine sufferers. This was a crucial finding for the indus- try in combination with Goadsby’s and Edvinsson’s finding of increased secre- tion of CGRP from the head during migraine attacks. Together they led to the development of a CGRP receptor antagonist, olcegepant. We showed that olcegepant did not affect hemodynamic parameters or brain blood flow and therefore was safe. Olcegepant in a dou- ble-blind study was highly effective in the treatment of migraine attacks. The first CGRP receptor antagonist olcegep- The second headache classification committee left. Top right meeting of the management committee of the ant was however not developed because European Federation of Neurological Societies and bottom right explaining the coalition European Brain Council of its unsuitable pharmacokinetic char- acteristics. But the proof of concept had In asthma trials during the 1990s, Classification of Headache Disorders. been made, and it greatly stimulated the openers of the ATP-sensitive potassium The fact that different headache disor- development of human monoclonal channel Katp had headache as a very ders became clearly defined by explicit antibodies against CGRP or its receptor. prominent side-effect. At the time we diagnostic criteria has had a great They are now widely used and represent could not get a Katp channel opener impact on headache science throughout a revolution in migraine prophylaxis. because companies producing it tried to the world. I was also the prime organizer Small molecule CGRP receptor antago- find other clinical indications, but it was of the European Federation of nists that are orally available have also possible to study the channel in our Neurological Societies EFNS, later now been marketed. Pituitary adenylate animal experimental models. Together fused with the European Neurological cyclase activating peptide (PACAP), like with my wife Inger Jansen-Olesen we Society into the European Academy of CGRP, is present in trigeminal nerve showed that one of many isoforms of the Neurology. Finally, I took the initiative fibers. It has several similarities with Katp channel, the SUR2B/Kir6.1 chan- to form and was the first president of the CGRP. It also induced headache in nel was most likely responsible for head- European Brain Council EBC which is a normal volunteers and migraine in ache induction. Colleague professor coalition of European -wide organiza- migraine sufferers. That was not the Messoud Ashina managed a couple of tions of neurologists, psychiatrists, neu- case, however, for the related peptide years ago to get the Katp channel opener rosurgeons, basic neuroscientists and vasoactive intestinal peptide (VIP). levcromakalim in a form that could be patient organizations within neurology used in human patients. He showed that and psychiatry. The activity of this orga- every single patient in a double-blind nization over a decade in Brussels has cross-over trial developed migraine been a significant factor behind a twen- after infusion of levcromakalim. ty-fold increase of funding for brain Unfortunately, there are no Katp chan- research by the European Union. nel antagonists that selectively block the SUR2B/Kir6.1 isoform available for What about my private life? It is human use. We were able, however, to probably not a surprise that I have been validate non-selective KATP channel a workaholic all my life, usually working inhibition in animal models of migraine around 70 hours a week. It has had its by demonstrating that it had a signifi- consequences in the form of two broken cant therapeutic effect on spontaneous marriages but fortunately ending hap- allodynia in rats and on allodynia pily with my present wife whom I mar- induced by nitroglycerin injection in ried 27 years ago. She is also an interna- mice. Currently we are further exploring tionally recognized scientist in the these channels in animal studies. migraine field. Thus, we share not only our bed but also our scientific interests. These were my most important sci- I also have 4 wonderful children who are entific achievements in a nutshell. Along all successful. At my present age of 79 I with my scientific work I have always have decreased my workload to maybe been interested in professional organi- 40 hours a week which has allowed zations. I started a patient organization more time for my children and grand- for Danish stroke patients and was pres- children. Apart from a prostate cancer ident of the International Headache and a vascular stenosis that were suc- Society. I chaired the International cessfully operated I have enjoyed excel- Wife Inger and daughter Astrid during sabbatical Headache Classification Committee for lent health. I still play tennis 4 hours a in Boston in 1999 visiting New York. We all love almost 30 years and published 3 subse- week and I bicycle around 100 kilome- the United States and come back very often quent versions of the International ters a week.
20 The Brain Prize 2021 · Information Pack The Lundbeck Foundation
In the middle of my family a few years ago
Fortunately, there are still new hori- typical aura and migraine without aura. cannot. Therefore, it should soon be pos- zons to explore. One of them is the The other major horizon I want to sible to find out how all the signaling genetics of migraine in which I have explore together with senior scientist molecules work together in causing a been increasingly active over the last David Møhbjerg Kristensen is to finally migraine attack. But if that is to be 20 years, but now we have an extremely get the puzzle about migraine’s bio- achieved, I must continue a bit longer and strong group lead by Thomas Folkmann chemical mechanisms a bit more why not? Is anything in life more inter- Hansen and fantastic materials that will together. Three decades of provocations esting than science? Family of course, allow, I hope, to solve at least part of the and experimental work have revealed but apart from that my answer is no. mystery of the inheritance of the preva- many substances that can induce a lent types of migraine, migraine with migraine attack and substances that The Lundbeck Foundation The Brain Prize 2021 · Information Pack 21 22 The Brain Prize 2021 · Information Pack The Lundbeck Foundation