The brain can be its own worst enemy. In a host of those diseases, the merest whisper of which is enough to send a streak of black dread through a formerly happy family, the instigator is not a virus, or a bacterium, but rather the brain’s own protection mechanisms which, when kicked into overdrive, wreak havoc throughout our nervous system. Sixty years ago, there was little a family could do for a loved one diagnosed with Parkinson’s or Alzheimer’s Disease besides make them comfortable and wait for the dark times to come, but then there arose a dedicated phalanx of neurochemists, emerging from the 1960s rush to identify and lay out the pathways for the brain’s various neurotransmitters, whose steady and brilliant work in delineating the chemical systems involved in neural disease have placed us tantalizingly close to understanding and treating some of the most heinous examples of our brains’ autodestructive tendencies.
At the center of that vanguard of neurochemists for the last half century and more lie two figures, a married couple who participated in the great neurotransmitter revolution, and then gave us our first paths towards understanding the chemistry of Alzheimer’s and aging, Edith Graef McGeer (b. 1923) and Patrick Lucey McGeer (1927-2022). Edith was born in New York, New York on November 18, 1923 to Charles and Charlotte Graef. Her father was an ear, eye, nose, and throat specialist who could afford to send her to private school for her elementary and high school years. She attended Swarthmore College on an Open Scholarship, though when she attempted to register for classes with the chemistry department, its head informed her that she was wasting her own and the department’s time, since women did not make good chemists. With the draining of the department’s manpower in response to World War II, however, Edith became a much more valued component of the student body, and received her degree in chemistry in 1944.
As difficult as her Swarthmore years were, however, they provided her with an excellent education centered around small discussion groups instead of traditional lectures, and when she moved to the University of Virginia for her graduate work she found that she was so in advance of the other students, and of the expectations of the faculty there, that she was able to wrap up a PhD in organic chemistry by 1946. As a PhD chemist, she had little difficulty finding work in the post-war industrial scene, and soon landed a job with DuPont, which at the time was such a powerhouse of chemical research that it alone was responsible for hiring half of the entire country’s PhD chemistry graduate population. Edith worked in the Intelligence Division of the Chemicals Department, which was tasked with thinking up new ideas for chemicals and doing ground-level research for chemical lines in development.
It was while working at DuPont that Edith Graef met Patrick McGeer. He was a former regional basketball star and amateur pilot who had attended Princeton during its Golden Age, when its faculty was flush with the displaced cream of the European universities including John von Neumann and Albert Einstein. His interest in science was fired in that environment, and in 1951, fresh from his PhD work, he began working at DuPont in the Polychemicals Department. The two met when they moved into apartments across from each other in a block of flats DuPont had constructed for its workers. Neighborliness soon turned to romance, and by 1954 the couple were married and had moved to the University of British Columbia, where Patrick had been accepted as an MD student. These were the heady days when neurobiologists were honing their focus on the chemicals of the brain, and their differential concentrations within different neural structures. Prior to the 1940s, the reigning theory had been that neurons talk to each other through electrical signals, but in the late 1940s Marthe Vogt had discovered acetylcholine’s potential as a neurotransmitter, and with new studies in the early 1950s about the effect that different antipsychotic drugs had on neurochemical concentrations, the race was on to catalogue the constellation of chemicals that neurons use to send signals to one another.
The McGeers were fortunate at this stage of their careers to work in the lab of William C. Gibson (not to be confused with William Gibson, the author of the classic cyberpunk novel Neuromancer, or with William Clyde Gibson, the serial killer - they are all very different people), a neuroscientist with a deep interest in the underlying chemistry of psychological phenomena who had studied with Wilder Penfield, the brain probing surgical superstar whom we have met in the tale of Brenda Milner. For some years, Edith worked with Gibson in a part-time capacity as she split her time between research and the raising of three children, born in 1957, 1958, and 1960.
While the McGeers were honing their skills, the Swedish neuropharmacologist Arvid Carlsson was studying the impact of dopamine levels on Parkinson-like symptoms, Marthe Vogt was reporting on the unusual levels of noradrenaline in the hypothalamus, and a small army of researchers were finding regions of the brain with heightened serotonin concentrations. By 1960, the McGeers, armed with new radioactive isotope tagging techniques, were ready to join the neurotransmitter hunt, which aimed not only to identify what chemicals were and were not neurotransmitters, and where they were most concentrated, but to lay out their life-cycle, i.e. the chemicals that triggered their production, the chemicals that they were formed from, the enzymes that aided those formations, the regions of a neuron they interfaced with, and the mechanisms of their eventual degradation. Knowing more about the different chemicals involved in the life-cycle of a neurotransmitter was additionally useful because some transmitters were unstable in a way that made them difficult to measure, but some of the proteins involved in their production or break-down were entirely stable, and thus an easier source of information about what transmitters existed where, and in what quantities. Researchers at the McGeer lab used choline acetyltransferase, an enzyme that catalyzes the creation of acetylcholine, as their guide to the eventual complete mapping of the cholinergic system, which plays a role in memory and learning, and the degradation of which is a key event in Alzheimer’s Disease.
Similarly, when they wanted to map which neurons use the inhibitory GABA neurotransmitter, the members of the McGeer lab used GABA Transaminase (GABA-T) as a guide. Unlike choline acetyltransferase, which is an enzyme which synthesizes acetylcholine, GABA-T is an enzyme that breaks down GABA, and thus its presence or absence can also be taken as a sign of GABA’s presence or absence in a region, and what’s more, GABA-T can interact with certain dyes that would then produce a beautiful and definite map of where GABA is and isn’t in the brain.
And as if mapping the GABA and acetylcholine neurons in the brain weren’t enough, the McGeers also oversaw the confirmation of glutamate’s role as a neurotransmitter, a particularly difficult task given how many different roles glutamate plays in the body, creating an obfuscating omnipresence which is analytically tricky to penetrate in order to catch glutamate in one particular role. Tricky, but for the McGeers and their crack staff, not impossible, and in 1977 they were able to announce to the world glutamate’s neurotransmitter nature.
By the 1980s, the great neurotransmitter hunt was largely wrapped up, and the McGeers, after being challenged by the leader of an Alzheimer’s support group to use their knowledge and expertise to do something immediately useful for people suffering from brain disease, took up the challenge, and began investigating the role that autotoxicity, or neuroinflammation, played in neural diseases like Parkinson’s and Alzheimer’s. They looked at the complement system, which usually forms part of our normal immune response by creating a sequence of compounds called cytokines which enable us to attack the cell membranes of pathogenic cells.
What the McGeers found was that the membrane attack complex created by the complement system was richly abundant on the damaged neurons of Alzheimer’s patients. Something about the brain’s own immune system was being weaponized against it, with inflammatory cytokines apparently playing a central role. Edith and Pat wondered if anti-inflammatory drugs might offer protection against the worst aspects of Alzheimer’s, and began pulling together statistics from rheumatology clinics (where anti-inflammatory medication is often prescribed) about the prevalence of the disease among their patients, and followed up a lead about leprosy patients in Japan who seemed to have very low Alzheimer’s rates, ultimately tracing that effect to the drug dapsone that they were prescribed, an anti-inflammatory medicine that seemed to cut Alzheimer’s incidence from 6.5% among those who went off the drug down to 2.9% for those currently prescribed it.
In 2012, the McGeers founded Aurin Biotech, a private company centered around the promise that Aurintricarboxylic Acid (ATA) seemed to show as a medicine to inhibit the complement system, and with it the inflammatory cytokines that attack neurons directly, and weaken the blood-brain barrier, allowing peripheral immune cells into the brain, augmenting neural inflammation further.
Photo by Martin Dee
Delineating what among the many contributions of the McGeer lab can be attributed to Edith, and which to Patrick, is a difficult task, made somewhat easier by the knowledge that, from 1962 to 1986, Patrick was heavily involved with a political career as a member of the legislative assembly, and therefore had to leave much of the running and directing of the lab to Edith when the assembly was in session, indicating a major role for her during precisely the era when the lab was doing its most fundamental work in mapping neurotransmitters. Beyond that, we have to rest content with the assertion that theirs was a partnership of equals, resulting in over 500 publications, including some truly foundational discoveries about the chemical workings of our brain and the diseases it is prone to. For their decades of service, the McGeers were Officers of the Order of Canada in 1995, Fellows of the Royal Society of Canada in 2002, and members of the Order of British Columbia in 2005, but their greater legacy will likely lie in that future day when families only have to read of Alzheimer’s as a thing that happened to people once upon a time, in that age before the McGeers and their colleagues used the full measure of their chemical genius to illuminate the first steps on the way to safeguarding our minds through the treacherous valleys of late life.
FURTHER READING:
Relative to what they accomplished, there is not nearly enough out there about the McGeers, but one of your best sources is the autobiographical sketch they wrote for the third volume of A History of Neuroscience in Autobiography, edited by Larry Squire, a critically important resource that encompasses some twelve volumes that are all, incredibly in this day and age, free to access, so I’d head over there and give it a read before they change their mind!
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