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On the Shoulders of Giants
Meet four Johns Hopkins “greats” who made seminal contributions in the early years of the school of medicine—and their contemporary counterparts who have grabbed the baton to move their fields forward farther still. Our second installment in a yearlong series.
Illustrations by Peter Strain
Celebrating 50 Years of CPR: A simple discovery, with a profound effect. It's been more than 50 years since researchers at Johns Hopkins Medicine in Baltimore discovered that cardiopulmonary resuscitation could prolong someone's life long enough to get them to a medical professional.
Innovators in CPR
William Kouwenhoven & Elizabeth Hunt
William Kouwenhowen, who first arrived at Johns Hopkins in 1914 as an instructor of electrical engineering, didn’t receive an M.D. from Johns Hopkins until 1969, at the age of 83. It was the first honorary degree ever granted by the school of medicine, in recognition of his 50-year career dedicated to saving lives.
In 1925, Kouwenhoven joined a team working to learn why linemen were dying from even minor electrical shocks as they hung wires for in-home electricity. They soon discovered that low-voltage shocks cause ventricular fibrillation—the cells of the ventricles fire rapidly in discord, losing their ability to pump blood through the heart.
By 1933, Kouwenhoven had the beginnings of a solution. He found that direct application of a second burst of electricity could “defibrillate” a dog’s heart, restoring its normal rhythm, but first he had to surgically open the patient’s chest. Electrocuted linemen didn’t have time for surgery, so Kouwenhoven started developing a closed-chest defibrillator. In 1954, he retired as dean of the school of engineering, only to join the Department of Surgery at the school of medicine. He took with him recent undergraduate engineering grad Guy Knickerbocker. Three years later, a 200-pound prototype was ready and began saving lives.
While continuing their work on defibrillation, Knickerbocker noticed that the pressure applied when the defibrillator paddles simply were placed on a dog’s chest—without the application of electricity—caused a rise in blood pressure after its heart had stopped beating, suggesting that blood was again flowing to the body’s organs. The team, which included cardiovascular surgeon James Jude, started experimenting with applying pressure by hand at different rates and in different locations. Over the next two years, they resuscitated 20 Johns Hopkins cardiac arrest patients using closed-chest cardiac massage, as reported in their 1960 landmark publication. They combined this technique with artificial respiration (perfected by Johns Hopkins anesthesiologist Peter Safar) in 13 of these original 20 patients, in what soon became known as cardiopulmonary resuscitation (CPR).
Since then, CPR has saved countless lives, and portable automated external defibrillators (AEDs) are readily available at stadiums, airports and schools. But Elizabeth Hunt, a pediatric intensive care specialist who directs the Johns Hopkins Medicine Simulation Center, says that even within hospitals, CPR isn’t always performed properly: Chest compressions are often too slow, fast or shallow, or they aren’t started right away.
In the Simulation Center, Hunt studies how community members and clinicians administer CPR and defibrillation to mannequins to perfect their practice and teaching. The American Heart Association (AHA) recommends defibrillation within 180 seconds of a cardiac arrest, but delays are common. One of Hunt’s studies, published in 2009, found that most who failed to defibrillate within 180 seconds had never discharged a defibrillator before.
“Today’s AEDs can literally talk you through a defibrillation, but most people, even hospital staff, hesitate at first,” she says. Once she had data showing that those who had defibrillator practice were 87 percent faster at delivering shocks, she was able to insist upon its inclusion in training at Johns Hopkins. The AHA has incorporated it into its best practices.
Then, five years ago, Hunt requested replacing traditional defibrillating paddles with newer technology: sticky pads embedded with an accelerometer that measures the depth, rate and timing of chest compressions. The quantitative feedback they provide, together with a training method she developed called Rapid Cycle Deliberate Practice, has ensured that Johns Hopkins staff members comply with the 180-second rule 95 percent of the time. That’s up from 64 percent in 2014. That in turn has nearly doubled patient survival: An average of 14 more lives are saved each year at Johns Hopkins alone.
Inspired by her predecessors’ curiosity and persistence, Hunt has spent hours in the Alan Mason Chesney Medical Archives poring over Johns Hopkins’ contributions to the history of CPR. Now she’s adding to that history herself.
Celebrating 50 Years of CPR: A simple discovery, with a profound effect. It's been more than 50 years since researchers at Johns Hopkins Medicine in Baltimore discovered that cardiopulmonary resuscitation could prolong someone's life long enough to get them to a medical professional. Watch a video featuring 2008 interviews with CPR pioneers Guy Knickerbocker and James Jude.
Experts in Autism
Leo Kanner & Dan Arking
Johns Hopkins psychiatrist Leo Kanner met Donald for the first time in 1938, when he was 5 years old. Kanner’s observations of Donald, together with insights from the boy’s parents, became part of Kanner’s 34-page report on 11 children with what he called infantile autism. The year was 1943, and it was the first report of its kind. Little could Kanner suspect that today, some 75 years later, autism’s broadened diagnostic criteria would include one in 68 American children.
Born in Austria, Kanner emigrated to the United States in 1924. In 1928, he came to Johns Hopkins for a fellowship at the Henry Phipps Psychiatric Clinic. Two years later, he began a psychiatric consultation service for children, the first such academic clinic in the U.S. And in 1935, he published the first English-language textbook on child psychiatry—creating a new medical subspecialty in the process.
According to James Harris, a developmental neuropsychiatrist who studied with Kanner as a resident and founded the Johns Hopkins autism program, Kanner was a stalwart advocate for children. Kanner also refused to blame parents for causing autism. He emphasized that children with autism come into the world with an “innate inability” to relate to those around them, and he recognized autistic traits in many of their parents, suggesting a role for genetic inheritance. However, instead of claiming there was nothing parents could do to help, he acknowledged that parenting techniques do affect outcomes, and he helped parents understand what works best.
In 1959, Kanner officially retired but continued to see patients. His last paper, published in 1973 at the age of 79, described the triumphs of social worker Jeanne Simons and her self-sacrificial efforts on behalf of 34 children at the Linwood Center she founded. After five to seven years of intensive treatment and the tireless involvement of their parents, Kanner declared 10 of the children to be in “a state of near-full or full recovery.”
While early intervention for children has come a long way, autism’s underlying biological factors are still murky. Dan Arking began seeking the genes involved in autism spectrum disorder when he came to Johns Hopkins in 2002 as a postdoctoral fellow. He appreciated it as a complex disease—a good candidate for a genomewide association study, or GWAS. The power of a GWAS lies in the unbiased analysis of thousands of single “letters” in the genetic code, uncovering variations that could account for observed attributes.
Now a member of the McKusick-Nathans Institute of Genetic Medicine, Arking recalls that he and mentor Aravinda Chakravarti naively thought there were 15 to 30 genes impacting autism spectrum disorder, but scientists now think there are hundreds.
In 2017, Arking and his team collaborated with an international group on the largest study ever done, with data from 7,387 cases. They identified one new risk variant that disrupts several genes, including genes involved in the maturation of neurons thought to correlate with social skills. They also identified 12 new variants that overlap with sites implicated in schizophrenia.
This overlap with schizophrenia was found again when Arking’s group analyzed gene activity—instead of genetic code—in the brains of people with autism. They also found that the brain’s supportive microglial cells were overactivated, but how that causes damage is unclear.
“Regrettably, the causes of autism have become a societal debate,” says Arking. “Kanner was prescient and courageous to emphasize the importance of nature and nurture. He never could have imagined just how complex the nature component is, but, little by little, we are proving him correct.”
Mark the Date: Scientific Symposium celebrating 75 years since Leo Kanner identified autism:
Sept. 25, 2018. Contact: firstname.lastname@example.org.
Vernon Mountcastle ’42 & Shreesh Mysore
The humming of your computer, the movement of someone walking by, the feeling of hunger pangs, the words of this article. These are just a fraction of the stimuli impinging on your senses at any one moment. How does your brain—made up of 100 billion neurons organized into dozens of discrete structures—take in all that information and process it coherently?
Initially, Vernon Mountcastle was more interested in patient care than in questions on the inner workings of the brain. After earning his M.D. from Johns Hopkins in 1942, he planned to practice neurology, but a stint in Philip Bard’s neurophysiology lab changed his mind forever. By 1983, he was recognized as “the intellectual progenitor” of the field of neuroscience, receiving a Lasker Award—“the American Nobel Prize”—for discoveries “which illuminated the brain’s ability to perceive and organize information, and to translate sensory impulses into behavior.”
Mountcastle’s most fundamental discovery came in 1955, before he was 40. Working with anesthetized cats, he used tiny electrodes to record the responses of individual neurons in the brain’s cortex, or gray matter, as he touched the cat’s skin. As he gradually pushed an electrode down through the six layers of the cortex, he found that vertically aligned neurons responded to sensations from the same patch of skin but in different ways, giving the brain a more robust impression of the stimulating object. The finding that the cortex was organized in vertical columns—as well as horizontal layers—was so radical that his collaborators refused to be listed as authors on the paper. But it was this finding that still stands as an intellectual framework for the field, says Shreesh Mysore, assistant professor of psychological and brain sciences.
Mountcastle was proudest of his work in the 1970s with awake and behaving monkeys. After training monkeys to perform certain tasks, he recorded neural activity in the posterior parietal cortex, which handles higher-order functions, like abstraction, judgment and attention. “Neural responses to stimuli occurred only if the animal attended to them—that is, if they seemed of interest to him,” he wrote in his autobiography. Mysore explains that this was an important clue about why we better recall those things on which we focus: Attention is something the brain uses to prioritize stimuli.
Mysore’s research focuses on the mechanism that creates this attention, hopefully shedding light on the attentional dysfunction of psychiatric disorders like schizophrenia, autism, Alzheimer’s disease and attention-deficit hyperactivity disorder.
Mysore says research on turtles in the 1980s suggested the importance of the superior colliculus, a small structure in the midbrain, now known to help determine where in the world to direct one’s gaze and focus attention based on sensory input of all kinds. The key was a nearby patch of inhibitory neurons. Curiously, each inhibitory neuron received input from a small group of neurons in the superior colliculus and then sent signals back to every other neuron there—except the ones it received input from.
Thinking those neurons might be suppressing “unimportant” information, Mysore studied them in barn owls for their exceptional hearing and vision and well-organized midbrain. “We presented awake owls with visual and auditory stimuli while turning off the inhibitory neurons for just one of the stimuli,” he says. By monitoring the activity of neurons in the superior colliculus, Mysore and colleagues found that, without the suppression those neurons provide, the brain is unable to select one stimulus over another.
To see how this affects animal behavior, his team is studying free-ranging mice, whose midbrain is more jumbled, like ours. Mysore says this work is ongoing, but he’s eager to see how it will help elucidate the workings of attention that Mountcastle first started teasing apart.
Leslie Gay & Sandra Lin
The USS General C. C. Ballou was a high-riding troop transport ship bound for Germany with soldiers assigned to its postwar occupation. It was known for its roll and pitch even on calm seas, but the weather on the north Atlantic that November of 1948 was far from calm—perfect for “Operation Seasickness.”
“Within 12 hours after [the ship] left New York harbor, the corridors of compartments were congested by sick men, so ill that they were unable to reach the latrines,” declares a report of the voyage. But 372 of the 1,366 soldiers were unaffected. Thanks to allergist Leslie Gay, they had received an experimental drug called Dramamine. Only 17 unlucky patriots received the drug without benefit.
Dramamine, originally called compound 1694, wasn’t concocted to cure motion sickness. It, and others like it, was formulated by the company G.D. Searle as an experimental combination of two drugs designed to provide relief to both hay fever and asthma sufferers.
Gay received his M.D. from Johns Hopkins in 1917 and spent his whole career caring for patients with allergies and asthma. He founded the Allergy Clinic at The Johns Hopkins Hospital in 1923 and directed it for 36 years. A year before Operation Seasickness, G.D. Searle gave him several drug combinations to test on his patients. One patient, a pregnant woman, was suffering from hives so badly that she braved her inevitable motion sickness and took a trolley to Johns Hopkins. Gay gave her some of compound 1694 on the spot. (Things were different back then!) While the woman’s hives weren’t helped, she reported that her ride home was nausea-free.
Though motion sickness was outside of his purview, Gay took the result seriously and began testing the drug on family and friends before approaching the Army with his idea. And Dramamine was born.
For his allergy patients, Gay tested many different drugs and was also an early adopter of immunotherapy. Multiple times a week, he gave patients injections of extracts from the grass or ragweed they were allergic to, in order to gradually desensitize their immune systems.
Sandra Lin still provides immunotherapy to allergy sufferers but in an updated format: drops or tablets that dissolve under the tongue. A sinus and nasal surgeon in the Department of Otolaryngology–Head and Neck Surgery, she became interested in allergies because of their close relationship to sinus infections and nasal disorders.
As early as 2008, she began offering so-called sublingual immunotherapy by giving patients oral drops of what standard allergy shots contain. Lin explains that holding the allergen under the tongue, instead of swallowing it, allows the body to take it up and present it to the immune system. At the time, this off-label use was the only method available here since the Food and Drug Administration had not yet approved the tablets available in Europe.
“Immunotherapy treats the root cause of allergies, not just their symptoms as medications do. It can decrease or even abolish the unpleasant symptoms caused by environmental allergies,” says Lin.
In 2013, she helped conduct a systematic review of 63 studies of sublingual immunotherapy for the treatment of asthma and other symptoms caused by allergies. The evidence supported the overall effectiveness of under-the-tongue therapies and got the conversation going in the U.S. One year later, the FDA approved the first sublingual allergy tablets. Now, Lin says, there are four on the market: for ragweed, dust mites and two grasses.
“Patients can administer the pain-free tablets themselves,” says Lin. “That’s a big win for underserved populations.”
Next, Lin wants to find factors that could predict who will most benefit from immunotherapy—and the reasons others don’t. Like Gay, she won’t settle for the status quo.
Watch a Video featuring one patient’s success using sublingual immunotherapy treatment provided by Sandra Lin.
Celebrating 125 Years
More of a Good Thing: "On the Shoulders of Giants" will appear in each issue of the magazine in 2018. Look for more pioneering pairs in our Fall edition, due out in October. And check out the featured pairings from our Winter issue.
“Immunotherapy treats the root cause of allergies, not just their symptoms as medications do.”