INFORMATION PACK The Brain Prize 2021 - The scientists behind the science that has led to new treatments for migraine - King's College ...
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
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) d iscovered, 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 nameThe 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
Lars Edvinsson 2012 Lifetime Achievement
of Cerebral Blood Vessels
Reward by American head-
ache leaders (Boston). Calcitonin gene-
related peptide
I trained at Lund University Medical 2012 Honorary Doctorate, (CGRP)
discovered in
Faculty and graduated as MD 1980 and University of Szeged, early 1980s as
an alternative
did my PhD in 1975 during my MD stud- Hungary. product of the
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
q Discovery of neuropeptides including CGRP
Internal Medicine 1988. I chose Internal Award, FAMRI, USA.
Medicine and became associate profes- 2002- Honorary Fellow, British
Edvinsson, L. Uddman R, Brain Res Rev. 2005 1
sor (docent in internal medicine) 1988 Pharmacolog y 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 Pharmacolog y, 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
tions, honors and awards as highlights it was hard work because in principle I
McCulloch J et al. PNAS 1986;83:5731–5735; Edvinsson, L et al. Br J Pharm 1990;100:312–318; 2
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 many12 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 horizon.
Goadsby PJ and Edvinsson L. Ann Neurol 1993;33:48–56 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.
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 hoursThe 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 robot14 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 theYou can also read
