The conundrum of  multiple sclerosis is that the brain can—at least in theory—repair itself. Larry Sherman is trying to figure out why the healing process gets derailed.

The conundrum of  multiple sclerosis is that the brain can—at least in theory—repair itself. Larry Sherman is trying to figure out why the healing process gets derailed.

Sciences

Signal Master

Neuroscientist Larry Sherman ’86 wants to regenerate your brain.

By Geoff Koch | March 1, 2013

Irreversible. Incurable. Fatal. 

Those three facts about multiple sclerosis were drilled into every doctor’s head, starting with the great French neurologist Jean-Martin Charcot, who in 1868 first described the sinister autoimmune disorder that targets the brain and spinal cord.

In the last 30 years, each of these certainties has begun to wobble. Patients live longer. The attacks, which result in symptoms from fatigue to blindness, can now be treated. And it is no longer preposterous to contemplate reversing the brain lesions that are the hallmark of the disease—thanks to the work of Oregon Health and Science University neuroscientist Larry Sherman ’86, who in October published his most significant scientific result yet. 

The study, in the Annals of Neurology, hints at an answer to one of the central mysteries of MS and points the way—potentially—to a mechanism for doing what doctors have tried to do for centuries: help the brain to heal itself.

Roughly 400,000 Americans and 2.5 million people worldwide suffer from MS. Although there are some nuances in its population distribution—it strikes more women than men and is more common in Caucasians of northern European origin—it doesn’t discriminate based on age, race, or class. Last fall, Ann Romney, wife of former presidential hopeful Mitt Romney, spoke openly of her struggles with the disease. Michelle Obama often speaks about the travails and courage of her father, who died in 1991 after a long and painful battle with MS. In an interview that aired in September on The Dr. Oz Show, the famously health-conscious First Lady said that thinking about her father’s condition triggers her biggest health fear—“sudden illnesses that may be genetically linked that you don’t have any control over.”

MS treatment has come a long way since Larry was a biology major at Reed. Back then, conventional wisdom held that the brain was incapable of repairing itself. Since then, a slew of drugs and other interventions have been developed that can control the disease, at least partially, by preventing the immune system from launching attacks in the first place. Unfortunately, the drugs often have fleeting impact and horrendous side effects.

In his 2004 book Blindsided: Lifting a Life Above Illness, Richard M. Cohen, a former senior producer for CBS News and CNN, wrote about living with MS. “Dr. Frankenstein dreamed up this therapy,” Cohen says about receiving steroid injections for his condition. “Anyone who is not a mess going into the hospital for intensive steroid treatment is a maniac on departure. . . . Steroids made me fat and crazy. My mood swings were wild.”

MS is fundamentally a disease of myelin, a tough sheath which insulates nerve cells in the brain and throughout the body. Thanks to myelin, this cell network normally hums with electrical and chemical signals that in sum comprise the experience of a healthy human being moving through the world. In MS, the cause of which is still a mystery, the body’s own immune system attacks myelin. Stripped of their insulation, the nerve cells slow down or stop firing altogether. Think sugar in the gas tank and sand in the gears. The resulting symptoms can be devastating: blindness, hearing loss, loss of balance, weakness, memory loss, and cognitive impairment. On an MRI scan, demyelination shows up as malevolent lesions on the brain, not unlike dead patches of coral on a reef that should be teeming with life.

The conundrum of MS is that—at least in theory—the brain can deploy a counterweapon. In recent years, scientists have learned that when lesions start occurring, the brain cranks up production of oligodendrocytes, cells that build new myelin. Eventually, however, something shuts down this production line, which, if left to run at full steam, might reverse the course of the disease.

Larry’s research suggests the culprit flipping the stop switch is an enzyme known as PH20, which happens to be produced by the same cells that trigger creation of new oligodendrocytes. In other words, when it comes to MS, the seeds of salvation and suffering are bound up together. It turns out that PH20 breaks apart a certain largish sugar molecule, hyaluronic acid, that builds up at the lesions and is thought to be part of the body’s anti-inflammatory response. The smaller, broken-up remnants of what used to be hyaluronic acid are what seem to gum up the works.

The situation is sort of like a fire department sending trucks to fight a fire in a skyscraper (an MS attack causes demyelination). Trucks show up and douse the flames for a while (oligodendrocytes build new myelin). But the trucks’ noisy sirens and flashing lights cause such panic that people flee haphazardly into the streets around the building, preventing new trucks from arriving (the PH20 enzyme breaks up hyaluronic acid, and the resulting bits of brain chemistry prevent new oligodendrocytes from forming).

This research suggests that if a drug could be developed to target PH20—to shut off the siren and lights, as it were—then the restorative process of resheathing nerve cells in protective myelin might proceed unabated.

Based on earlier studies, some MS researchers had concluded the most promising approach might be a drug that silences PH20 and a whole family of related enzymes. But this broad-brush approach was problematic since these other enzymes are key to healthy joints and even to proper functioning of the heart.

“The side effects would probably be much worse than MS,” Larry says. 

By contrast, PH20 plays a significant role in only one other area of the body, one that’s only important in certain contexts—sperm cells. This means one side effect of a drug aimed solely at PH20 might be what Sherman calls transient male infertility.

“I think most people would be okay with that; women certainly will be,” he says wryly. “And men probably will be, too. They’d rather have their myelin back than worry about reproducing.”

“We’re very early on and any treatment realistically is many years away,” says Bruce Bebo, associate vice president of discovery research for the National Multiple Sclerosis Society. “But Dr. Sherman’s recent finding is a milestone. He and his colleagues have identified a specific target for drug treatment that might eventually lead to an ability to repair damage to myelin. There’s hope.”

Larry’s skills go far beyond science. He is a talented piano player and a natural on stage. His talks on the effects of music and love in the brain have attracted international attention and have made him something of a star in the OMSI Science Pub series, which sends local scientists out into Portland’s vibrant bar scene to give informal talks. As part of the series, he appears a couple times each year at the Bagdad Theater on Hawthorne Boulevard, which is routinely sold out when he performs.

This ability to bridge science and the arts was honed at Reed, where he paired his longstanding fascination with biology with classes in theatre. His scientific aptitude was apparent growing up in San Diego where, yes, he did win his middle school science fair. (No big deal, he says—he just plugged in all the relevant information from the several-thousand-page Merck diagnostic manual and built a database that could predict whether a given set of symptoms might add up to chronic lung disease.) He assumed he would be headed to a big research university, like Berkeley or Cornell. Then a high school math teacher mentioned that her son, a Reedie, had done a thesis on medieval garbage.

“I thought, ‘That sounds really cool,’ and I started to look into Reed more and more,” he says. “I found out they had this fantastic biology program and an opportunity to do research for students during their entire time on campus, but they also had this great emphasis on humanities.”

Naming professors he remembers, Sherman lists faculty from science and the humanities in roughly equal numbers. He talks of a lifelong bond with thesis adviser Larry Ruben [biology 1955–92], who’s closing down his lab in May after a career at Reed that started in the 1950s. Maryanne McClellan [biology 1981–] and Steve Arch [biology 1972–2012] were “amazing mentors.” But don’t leave out John Kenney [religion 1980–95], who taught the iconic Hum 110 when Sherman was a freshman: “He taught me how to write.” And Craig Clinton [theatre 1978–2010]: “I learned so much more than theatre from him.”

He learned from his fellow Reedies, too, even after graduation. In the late 1980s, while earning his PhD at OHSU, he teamed up with several alumni to put on shows as part of Portland-area theatre troupe, Oracle Theatre. Several of his fellow performers went on to success in the entertainment industry, including Mark Worthington ’83, who later worked as a production designer on the television series Ugly Betty, and playwright and novelist Gordon Dahlquist ’83, perhaps best known for his 2006 book, The Glass Books of the Dream Eaters.

Collaboration with these creative heavyweights helps explain how Larry got his start as a sort of vaudevillian scientist, a genre that’s unique even by Portland’s quirky standards. It all started a few years ago when he was playing piano at a department party. A colleague, who didn’t know of his talents, approached with a question. Would Larry be willing to give a talk on music and the brain for a local philanthropic group?

Drawing on his theatre training at Reed, Larry put together a show quoting everyone from great neuroscientists to Mel Brooks, and also displaying his own prodigious piano skills. (He has been playing since he was four and, to the chagrin of any music student who has ever struggled through hours of rote practice just to play a passable version of “Für Elise,” can hear a song a few times and then generally play it by ear.)  

The talk was an immediate hit and word quickly spread through both the science and music communities. Larry has since given popular lectures on the neuroscience of music, love, and creativity at least 50 times in the last few years, in venues ranging from elementary schools and senior centers to Severance Hall in Cleveland. In 2009, he collaborated with vocalist Valerie Day (former lead singer of the ’80s band Nu Shooz) for a show called “Brain Chemistry for Lovers,” which nearly sold out Portland’s 800-seat Newmark Theatre. The Oregonian described it as “science lecture as cabaret,” adding that “the show’s great strength might be how its microscopic perspective on emotions shows us just why these particular expressions of love’s joys and travails have endured.”

Larry, who’s not hard to find on YouTube, obviously has fun in front of a crowd. But mainly he takes to the stage to make the case for neuroscience to nonscientists.

“I have a huge concern that we in this country are abandoning science,” he says, adding that when he was an assistant professor at the University of Cincinnati in the late 1990s, the NIH funded about the top quarter of all grant proposals. Now it’s just the top 7%. “I feel like it’s my duty to go out and get the public engaged in this.”

At the moment, he’s preparing for another show on nature versus nurture. Larry, as it happens, was adopted as a child. Never one to shy away from risks as a performer, he will take to the stage at the Newmark Theatre in May and reveal what he’s learned in his efforts to track down his birth parents and biological siblings—along with illustrations and graphics from an accomplished artist, a live orchestra, singing by Day, and original music composed by Day’s husband, John Smith, inspired by a DNA sequence.  

In the meantime, there is more work to be done in his lab. Drug development is a tortuous process fraught with more failure than success. Any compounds that show promise will have to be tested on mice and macaques before human trials can begin.

When his research hits a brick wall, Larry turns to a piano and plays the blues—improvising sometimes in a major key, sometimes in a minor key, but always building towards a cadence that rings true.

Geoff Koch works at a software company in the Portland area, is a father to two faultless daughters, and obsessively reads the poetry and fiction of Jim Harrison.

Tags: Health/Wellness, Research