When Michael A. Moskowitz, M68, was a young researcher at MIT in 1975, he published an article on 10 neurological diseases whose causes were still unknown. Then he put away the records for all but one: migraine.
“There are about a billion people on this planet who suffer from migraines,” he says. “It is the most common neurological disorder and the leading cause of long-term disability in people under 50.”
Yet at the time, researchers had no idea what caused this debilitating condition, which can affect people with severe headaches, vomiting and extreme sensitivity to light and sound.
Some thought it had to do with dilation of blood vessels in the brain, or with platelets in the blood, or with sex hormones, since migraine affects women three times more often than men. The main researcher at the time thought it was largely psychosomatic. Moskowitz put the file in his lower right drawer, where it would be nearby.
“Every time I opened the drawer, I said, I have to think about this problem,” he says. After two years of intensively reading the literature and studying the anatomy of the brain, Moskowitz came up with a whole new theory: that migraines were caused by tiny neuropeptides – small chains of amino acids – that nerve fibers release into the tissue covering the brain, known as the meninges, causing inflammation and other harmful effects.
The seminal 1979 article he wrote for The Lancet proposing the idea revolutionized migraine research, leading to more than 40 years of breakthroughs in the field.
In recognition of his contribution, Moskowitz received the Lundbeck Foundation Brain Prize last year. Denmark’s Crown Prince presented the prize, the most important in the field of brain research, to Moskowitz and three other researchers who together helped develop new drugs targeting neuropeptides that finally provide relief to migraine sufferers.
“It is with great satisfaction for me, both intellectually and personally, that this approach to identifying and targeting these chemicals has worked,” he says. “I went into medicine because I wanted to help people, and it exceeded my wildest imagination.”
Growing up in Rockaway, New York, Moskowitz never doubted he would go into medicine. Her father was a doctor who took her on house calls; when he explained the cases, Moskowitz was endlessly fascinated. “It was an easy decision for me,” he says. “It didn’t complicate my life.”
At Tufts University Medical School, he became captivated by anatomy, winning an award for the subject in his freshman year. Although he only began to focus on neurology after graduating with honors and starting rotations at Yale, he says “the anatomical approach to thinking about problems of the nervous system has really developed during my early years as a medical student at Tufts”.
For migraine, this approach involved focusing on the trigeminal nerve, the largest nerve whose fibers rest on the meninges and which has been associated with migraine-like pain sensations. Working with animals, Moskowitz used tracer chemicals to show that transmitters from these nerves could travel into pain-sensitive meninges, something that had not previously been accepted.
Within a few years, he had identified an 11 amino acid peptide called substance P that seemed to wreak havoc in these tissues, causing blood vessels to leak and heightening an inflammatory response. When he blocked the release of the peptide with two classes of drugs used in migraine patients called triptans and ergots, he showed that he could decrease these effects.
Later, Peter Goadsby from the UK and Lars Edvinsson from Sweden located another peptide, called CGRP, in the trigeminal fibers that elicited an even more powerful response in the meninges. Jes Olesen from Denmark has tested a drug in clinical trials that could attack CGRP without some of the side effects of other drugs, and could be introduced as a monoclonal antibody to provide long-term relief to many patients who regularly suffer from migraines. All three shared the Lundbeck Prize with Moskowitz.
A professor at Harvard Medical School and a research physician at Massachusetts General Hospital since 1990, Moskowitz has focused on an electrical storm of nerve activity that triggers the trigeminal nerve and leads to the release of neuropeptides in the first place.
Doctors have long recognized that many patients experience a “migraine aura” of flashing lights and dizziness before the migraine pain itself begins. Moskowitz hypothesized that this wave of electrical activity called cortical propagation depression could trigger the release of peptides from pain fibers, which some scientists even doubted was possible in humans.
To investigate, Moskowitz and his colleagues worked with a patient volunteer who could induce a migraine attack through strenuous physical activity. “He slept at the YMCA next to the brain imaging center and played basketball until he knew he was going to have a migraine attack, then he came to see our team, who filmed what was happening,” said Moskowitz, whose suspicions of cortical depression were confirmed.
His research also led to the discovery of another drug currently used in treatment that blocks the release of peptides but does not compress blood vessels. Overall, more than 20 new drugs are in use or in development to target the pathway he discovered and bring relief to more migraine sufferers.
Along with the personal satisfaction Moskowitz derives from the recognition of his life’s work, he says the award is good for the migraine field as a whole. Although it affects more than a billion people, he says, migraine has been almost overlooked as an ‘orphan disorder’ by brain researchers, perhaps due to its reputation as a disease affecting women. .
“I can only think how much faster the pace of knowledge would be if more researchers studied it,” he says. “This award means a lot for the recognition of migraine as an important public health problem.”