A LESSON FROM THE BEARS | WRITING CONTEST | COMING OF AGE
FOR MEMBERS OF THE ALUMNI ASSOCIATION OF THE UNIVERSITY OF NEBRASKA–LINCOLN
I M BB II N N GG C LC LI M
T T H E H
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“Mountain of Hope” “Mountain Hope” D r. W illia m C. M obl ey, B.S. ’70
Dr. William C. Mobley, B.S. ’70
FALL 2010
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By Tom Nugent
hen ursine expert Thomas J. Spady set out to study reproductive physiology in the American black bear a few years ago, he had “no idea” how smart his subjects actually were. Imagine his surprise when a remarkably clever Ursinus americanus began to train him to supply her with more fish and honey than the daily feeding schedule required. “I could hardly believe my eyes,” said the still-awestruck molecular biologist. “But there was no denying the fact that Honey was using her smarts to manipulate me into feeding her more than I wanted to. “Are these creatures amazing, or what?” One bright and sunny morning back in June of 2006, a youthful molecular biologist who was studying bears in the rugged Black Hills of South Dakota got the surprise of a lifetime. The biologist’s name was Tom Spady (B.S. ’94) and the name of the black bear that startled him was “Honey.” The surprise took place during a bear-training session in which Spady was attempting to teach a group of five black bears to urinate on command. Spady’s challenge, on that recent morning at the Bear Country USA refuge and study center in the remote upper Midwest, was a daunting one: find a way to get the lumbering animals to pee in specially designed containers at the same time each day. NEBRASKAMAGAZINE 15
Amazing Bear Facts!
Did you know that a full-grown black bear can cover ground almost twice as fast as a full-grown human? Ever wondered how many pounds of oozy-ripe blueberries a hungry bear can consume in a day, as he (or she) builds up fat reserves for winter hibernation? Fascinating stuff? You bet. With thanks to nationally recognized bear expert Tom Spady and his colleagues in the world of ursine research, here are ten amazing facts from the Annals of American Bear-ology:
Most bears give birth while asleep (more or less) in their den, to tiny under-developed cubs (eyes and ears closed, sparse hair, etc.). For most species, cubs are less than .002 the weight of their mom. Giant panda cubs are about .001 the weight of mom at birth. This equates to about the size of a stick of butter. Black and brown bears can have up to six cubs in a litter, although this is rare. Most times it’s only two to three cubs in a litter. Interestingly, different cubs in the same litter can be sired by different males. This may in fact, be common in wild bears. Specifically how this happens is one of the questions Spady is pursuing, as it may be a vital key to improving conservation of bears. The American black bear, scientific name Ursus americanus, comes in many different colors in addition to black. Why? This animal’s coat can be different colors just like people have different-colored hair, and the trait is genetic in bears just as it is in humans. These different coat colors, known as “color phases,” include black, brown, blond, red (known as “cinnamon phase”) and, rarely, white or bluish-grey. The color of a bear’s coat will also change during its life, with age, exposure to sunlight, and as they shed each year. Black bears from the eastern United States are almost all solid black, whereas lighter colors (mostly brown and blond) are more common in black bears from the western U.S. The theory behind this is that the dark coat color is most adaptive as camouflage in the dense forests and wooded mountains of the East Coast while the lighter brownish coat color is possibly adaptive in the West because it makes the black bear look more like a brown bear, and the historic habitat of the brown bear is the more open plains, hills and sparsely wooded mountains of the western U.S. In spite of their massive size and clumsy-looking body language, your typical black or brown bear can reach speeds up to 35 miles an hour when going at full throttle. (The fastest human can only manage 20 mph.)
16 fall2010
As a specialist in the reproductive physiology of black bears, Spady needed the urine in order to measure its estrogen content – so he could better understand the natural biological cycle regulating fertility in bears. The bottom line: by pinpointing the hormonal cycles of black bear reproduction, the dedicated researcher would be much better equipped to help improve reproduction rates in several bear species (such as polar bears and sun bears) which now face the looming threat of extinction. The scientific concept behind Spady’s work was simple: Use the tools of modern molecular biology to achieve the “animal conservationist” goal of helping survivalthreatened bears produce more offspring. So far, so good. But there was a problem. He needed daily samples to answer his question properly. The hormones are present in blood, urine and feces. He couldn’t bleed the bears every day, they wouldn’t much care for that. Urine and feces could be collected without harming the bears (a big plus), but would be impractical to collect because he would have to hope that he was close at hand when they decided to “go”. The problem was further compounded because several bears lived together in the pen. Black bears are very large, very powerful creatures … and your typical female Ursus americanus can easily stand five feet tall and tip the scales at 400 pounds. They’re also extremely agile animals outfitted with dagger-like claws and enough strength to drop a bull moose in its tracks with a single paw swipe. Given these impressive facts, Spady was understandably struggling with a vexing question: How do you get a 400-pound black bear to pee in a cup on command? The solution at first seemed obvious: Reward them with food each and every time they urinate in the receptacle provided for it. With the help of a professional animal trainer, Spady spent a couple of weeks teaching the bears to participate in the same precise ritual of urination each day.
First, the five females were led from their holding pens to the urination and feeding area, where the former UNL biology major was stationed with his buckets of food and his honey-sweetened water. As soon as each bear did her business in the container, Spady leapt forward to dispense a savory treat for the cooperative animal, along with cheerful words of praise and encouragement. (He also used a specialized “training clicker” as an auditory signal to reinforce the key message: Thanks for your urine.) The system worked beautifully at first … but then the bear they had named “Honey” introduced a new and startling wrinkle. “One morning I gave Honey her foodreward,” the 39-year-old Spady recalled during a recent interview at the California State University San Marcos, where he now teaches molecular biology and other science courses, “only to discover that she’d left an insufficient amount of urine in the container. I also noticed that she was maintaining eye contact with me. She waited for a minute or two … and then returned to the container and peed some more. “Because of the way the training works, you have to reward the bears with food each and every time they urinate for you. And Honey had obviously figured that out. By holding back some of her urine, she was gaming the system – she was manipulating me in order to get me to feed her twice.” With a sudden and disorienting shock, Spady came to a new realization about the intelligence of black bears. “All at once, I realized that the bear was
training me,” he said with a look of astonishment. “She had learned to manipulate me in order to get as much food as possible. What does that tell you about the intelligence level of these animals?” Deeply rattled, the Hastings-born scientist began to look more closely at the behavior patterns of the great bruins at Bear Country USA, a privately operated ursine wildlife park where the animals range freely over 300 acres of wilderness each day. How smart were these bears? Within a few weeks, the shaken investigator made another key discovery … a dramatic finding also related to feedingtime and the disbursement of honey-water and succulent salmon. What he noticed was that many of the resident bears were being rewarded with food by the mini-bus drivers who brought park visitors to the animals’ feeding and swimming area on a regularly scheduled basis, several times a day. “Each time the bus pulled up, the driver could hit a lever and release food into their enclosure,” explained the deeply impressed bear-ologist. “But the drivers didn’t always do this – it was entirely up to their discretion – and I soon noticed that the women drivers were much more likely to feed the bears than the men drivers. “Well, the bears had noticed it, too! As the bus climbed the hill to the enclosure, the driver would be talking on a little loudspeaker to the visitors, describing the habits of the bears and so on. And if the driver was a woman, the bears would usually stop swimming or sunbathing and run down to the fence in order to be fed. “But if it was a male driver, they’d usually ignore the arrival of the bus and keep on swimming or dozing.” For Spady, the implications were crystal-clear. “The black bears were listening to the drivers on the bus, in order to identify their gender, and they were reacting accordingly,” he said with a note of awe rising through his voice. “Pretty smart, huh? “Can you see why I find these animals so fascinating? They really are quite remarkably intelligent, and I’m also pretty convinced by now that they have emotions. “Really, these bears are the masters of their habitat … and I think we often fail to understand how intelligent they are, due to
our own human bias. I’ve spent hundreds of hours observing black bears – and I still learn something new every time I go out in the field and resume my research as a bear reproductive physiologist.”
Surviving A Brutal Struggle With Organic Chem
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orn and raised in the central Nebraska city of Hastings – “way out in the middle of corn country” – Thomas Spady was touched by history in two very interesting ways. First, his great-uncle on his father’s side, Edwin Perkins, gained international fame about 75 years ago as the supremely innovative inventor and distributor of Kool-Aid, the powdered soft drink for kids that soon took the world by storm. (“I kinda grew up with that in the family history,” Spady said. Hastings is the official birthplace of Kool-Aid.) A bright and studious high-schooler, the youthful Spady did especially well in science … and eventually decided to follow his two older brothers (John, ’89; Stephen, ’93) to UNL. After arriving on campus in the fall of 1990, he quickly joined the Farmhouse Fraternity and then signed up for all of the science courses he could get. “The Farmhouse Frat had a strong academic emphasis,” he recalled, “and I wound up taking some very challenging courses. At one point, I found myself putting in a lot of hours in a genetics lab, where I was doing research with Professor Paul Blum [now the director of the UNL’s Nebraska Bioenergy Facility]. He was studying a microorganism known as an ‘Archaeon’ – a microbe that lives in hot sulfur springs – and my job was to expose it to radiation and then look for mutants. “That was a great learning experience. Dr. Blum was very patient with me, and the lab work gave me a taste of what science is really like.” Although Spady enjoyed most of his course work, he struggled mightily with the dreaded organic chemistry. “I got through it somehow,” he remembers with a pained wince, “but as soon as the semester was over, I got my revenge. I took the six-inchthick textbook out in the backyard and
burned it to a crisp.” After earning his UNL degree (biology with an emphasis on genetics) in 1994, Spady headed for Omaha and the University of Nebraska Medical Center, where he hoped to earn a doctorate in biochemistry and molecular biology in order to become a researcher on human breast cancer. “My mother was struggling with the disease during that period,” he recalled, “so I was very motivated.” But his plans for becoming a world-class investigator of the pituitary gland and how it can sometimes trigger breast cancer were interrupted in a way he could not have predicted: “I worked with rats a great deal of the time, and I found that I really enjoyed that aspect of the research. But later, after they’d been sacrificed in our experiments, I found that I was less interested in applying the genetic data we had obtained to human cancer research.” For Spady, the Ph.D. work in Omaha opened the door to a scientific career very different from the one he’d imagined. Fascinated by his studies of how hormones work to help control reproduction in rat populations, he realized that he actually wanted to become a reproductive physiologist – a molecular biologist who could specialize in the biochemistry of reproduction in large mammals, such as bears.
Learning Humility … By Watching Bears
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y 2003, Spady’s growing interest in the reproductive cycles and birth rates of bears had led him to sign on as a researcher at the famed San Diego Zoo … where he spent the next six years studying ways to help polar bears, panda bears and other members of the ursine family to produce more cubs – thus increasing their chances of survival in a world that for many species of bear now seems increasingly threatened. After joining the science faculty at California State University San Marcos last year, Spady has continued to conduct research aimed at “helping bears to withstand the threat of extinction by helping them to improve their birth rates.” In a recent scientific study published in Mammal Review and entitled “Evolution of reproductive seasonality in bears,” he succinctly described the heart of his scientific research as seeking to provide “a context for understanding the ramifications of current environmental change on the NEBRASKAMAGAZINE 17
Can We Save The Polar Bears?
It’s a proven scientific fact: as the ice in the Arctic region (the North Pole) continues to melt under the impact of global warming, the ranks of the majestic polar bear – the world’s largest land-based carnivore – are growing smaller each year. As of 2010, the total world population of Ursus maritimus has shrunk to only 20,000-25,000 bears, according to the latest scientific estimates. “At this point, I do think the polar bear is in extreme danger of going extinct,” said bear reproduction expert Tom Spady, “and I won’t be surprised if we see a rapid decline in their numbers during the next decade or so. “As the data from many other researchers show clearly, fewer [polar bear] cubs are now being born per litter, due to altered fertility patterns linked to global warming and toxic pollutants.
reproduction of these important [bear] species” (www3.interscience.wiley.com/ journal/118520797/abstract). Like a few other international experts who specialize in ursine reproduction (such as Japan’s famed Toshio Tsubota), Tom Spady spends hundreds of hours each year watching his beloved bears do their thing. A confirmed bachelor with a monk-like dedication to his work as an ardent teacher and researcher, he said he never stops being amazed at the grace and the strength and the remarkable intelligence of the creatures that have become his great passion. “As a scientist, I have a great deal of respect for these remarkable creatures,” he told Nebraska Magazine the other day, after a brief tour of his instrument-crowded lab
about 30 miles north of San Diego. “I respect their strength and their agility, of course – but I also deeply respect their intelligence, their ability to quickly respond to any challenge in their environment and begin looking for ways to overcome it. “If the bears have a lesson for us, it’s probably a lesson about humility. You know, we think we’re pretty smart as human beings. We’ve got technology and science and engineering … and sometimes we start thinking we’re so advanced that it actually hinders us. It doesn’t allow us to fully see the wonders of nature that are all around us. “The bears can help to teach us that lesson, if only we’ll take the time to stop and really look carefully at what they’re all about.” n
“Right now I’m very concerned, because there’s no doubt that the reproduction rate has been significantly affected. Polar bears are on the brink, partly because they’re at the top of the food chain. They feed on seals for the most part, and seal fat tends to concentrate large amounts of stored chemical and industrial toxins, which appear to be affecting their birth rate.” Spady also notes that during the past 40 years, retreating sea ice in the key Hudson Bay area of Canada has greatly reduced the annual hunting period during which the bears can catch seals … leaving them increasingly vulnerable to starvation. “The Hudson Bay ice is now melting one month earlier each year than it used to,” said the California State University San Marcos researcher, “and that’s very significant. The bears can only hunt seals for about three and a half months each year, so losing a month of hunting time is taking a huge toll on their nutrition. “If that pattern continues, which now seems likely, they may not be able to maintain their numbers much longer.” Although animal lovers can easily become “discouraged and depressed” by images of struggling polar bears on shrinking ice floes, Spady said it’s important not to succumb to the polar-bear blues … since there may still be time to curb global warming enough to save them. “Find out how you can donate time or money to fight pollution and global warming, and to wildlife conservation projects, for example. Or you could look for ways to drive your car less, and maybe start recycling to cut down on your contribution to the carbon footprint. “Feeling bad about the fate of the polar bears is understandable, but action is what’s needed to start confronting the problem right here and right now.”
18 fall2010
C oming of Age By Shannon McClure
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t almost 21 years old, the Lied Center now draws bigger audiences, balances its budget and gains solid footing with new leadership. For two decades, the Lied Center for Performing Arts has ignited the spirit of the University of Nebraska community through music, theater and dance programs as well as serving as a home for the E.N. Thompson Forum on World Affairs and other significant events. Nebraska audiences have enjoyed internationally acclaimed artists through the Lied’s dynamic programs. Now heading toward its 21st birthday, the performing arts center is experiencing a renaissance due to energetic new leadership and renewed interest and involvement from the university community and Nebraskans across the state.
Bill Stephan, Executive Director
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SUCCESS IN CHALLENGING TIMES No business has been immune to the current economic crisis, least of all arts organizations like the Lied Center that rely on generous donations from corporations, foundations and individuals to subsidize affordable ticket prices. Hoping to weather whatever storm may come next, audience members throughout the country have been cautious in spending precious dollars on arts and entertainment. But even in this climate, the end of the Lied Center’s 2009-2010 season on June 30 brought good news. By operating on a shoestring budget and with a lean, devoted staff, the center achieved a balanced budget season for the first time in several years. The impressive preliminary numbers for the 2009-2010 season show higher ticket sales overall. The number of tickets sold increased by 32 percent over the 2008-2009 season and ticket sales revenue increased 42 percent. Much of this progress can be attributed to the Lied Center’s new leadership.
FRESH LEADERSHIP Executive Director Bill Stephan has been leading the charge upward at Nebraska’s “Home for the Arts.” Since he joined the staff in winter 2009, ticket sales, donations and momentum have been positive. Performances from well-known artists such as Yo-Yo Ma, Wynton Marsalis and Bernadette Peters have also helped generate renewed excitement from Nebraskans. “We are focusing on bringing the finest artists in the world to Nebraska. Good arts programs which are reasonably priced combine to make a recipe for success,” said Stephan. In addition to sterling quality arts programs, Stephan has made a renewed commitment to marketing and promotion of the season’s performances. In particular, a new pricing initiative provides lower ticket prices and a greater diversity of price points. This affordability, coupled with a mix of both mainstream performances and more niche arts programming, makes Nebraska’s Lied Center accessible to nearly anyone who has the desire to attend. Along with increasing earned ticket revenue, donations from individuals have risen. One key factor in this effort is the new “Gold Circle” program, which has established a five-year fund for fiscal sustainability to ensure that the Lied can bring the finest quality artists in the world to Nebraska. Complementing Stephan’s talents, Ann Chang, a fixture on the Lincoln arts scene, serves as the artistic director at the performing arts center. Chang provides a valuable connection with the arts programs at the university and brings a rich background of classical music expertise to the organization. The Lied Center continues to maintain and build upon its tradition of presenting virtuoso artists performing classical music. While the emphasis on incredible performances is vital to its success, the center does much more than just mainstage presenting.
This past year, more than 20,000 students participated in AdventureLied, the center’s educational outreach program. While many think of the Lied Center as only presenting programs in Lincoln, the state’s performing arts center takes artists on the road to communities from Hastings to Scottsbluff. The center’s arts in schools program, affiliated with the Kennedy Center in Washington, D.C., infuses the arts to all aspects of education for thousands of young people, including the students at the Umonhon Nation School in Macy.
THE WORK AHEAD Though much work has been done to advance the Lied Center, more work is on the horizon. Now 20 years old, the building requires ongoing maintenance and updating in order to continue providing a comfortable environment for audience members and an experience rivaling that found in newer performing arts venues. Upcoming capital improvements include a new stage floor, main hall sound system, heating and cooling systems and a new roof, to name a few. Stephan continuously works with the statewide and campus advisory boards, staff and other stakeholders to maintain a prudent long-term plan for the institution that includes cross-campus collaborations, statewide education and outreach, and infrastructure development as key objectives. In addition to the physical building plans, Stephan seeks input on the artistic future of the Lied including ideas for its 25th anniversary season in 2014-2015, arts education initiatives and new artistic collaborations.
SOMETHING FOR EVERYONE The 2010-2011 season, now underway, features “Broadway” performances of “A Chorus Line,” “Spamalot,” “Fiddler on the Roof,” “Menopause the Musical” and the ever-popular Blue Man Group. Other notable offerings include the Harlem Gospel Choir, Broadway and film star Bernadette Peters, the long-awaited return of the Alvin Ailey American Dance Theatre, GRAMMY® Awardwinning violinist Joshua Bell, a night of jazz with Branford Marsalis and Terence Blanchard, and the popular rock group Los Lonely Boys. Thanks to continued support from the university’s Committee for Fee Allocation, the Lied Center launched a new UNL student ticket program this fall that features free tickets to a myriad of events at the center, along with substantial discounts for other events. The “Arts for All” program will further enhance the richness of each student’s collegiate learning experience. Early response to the season looks promising. Season tickets have been on sale since April and by August, nearly half of the seats for the most popular shows had already sold. Remaining tickets for all events are on sale online at liedcenter.org and in person at the Lied Center Ticket Office. n Shannon McClure is the new director of marketing and public relations for the Lied Center.
BEYOND THE STAGE The Lied Center exists to educate, inspire and entertain the people of Nebraska through the performing arts. In addition to performances, the center presents extensive educational outreach programs for university students and Nebraskans at large. NEBRASKAMAGAZINE 29
After more than 20 years of arduous medical research on the neuroscience of Down syndrome, pioneering neurologist William Mobley two years ago achieved a stunning breakthrough at Stanford University. By coming up with a discovery that promises to make life better both for people with Down syndrome and Alzheimer’s Disease, the internationally renowned neuroscientist has brought new hope to millions of suffering patients in this country and all around the globe. By Tom Nugent, Photos by Nick Abadilla
30 fall2010
c l i m b i n g
t h e
“Mountain of Hope” Dr. W illia m C. M obley, B.S. ’70
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hen the breakthrough came in a neuroscience lab at Stanford University about two years ago, Dr. William C. Mobley (B.S. ’70) was far too busy taking notes and planning new experiments to think about celebrating.
Instead of ordering in a bottle of French bubbly, Mobley (he has an M.D. and a Ph.D in neurology from Stanford) immediately redoubled his efforts to pinpoint the healing effects of a biochemical compound that his research team had just identified as “apparently very effective in reversing some of the brain deficits caused by Down syndrome.” Mobley’s 2008 discovery has the potential to start making life better for millions of people with DS around the world in the future. But it may also have a dramatic impact on 10-20 million Americans who are expected to be struggling with Alzheimer’s Disease in the next few decades, as 75 million members of the “baby boom generation” confront the health problems associated with aging. (Says the Chicago-based Alzheimer’s Association, which recently gave the former UNL chemistry-zoology major a $239,000 grant to continue his research: “The results of Mobley’s study could lead to new therapies for both Alzheimer’s Disease and Down syndrome.”) What Mobley (pronounced MOB-lee) found in his Stanford lab on that morning could very well mark a turning point in the continuing struggle to tame two chronic degenerative diseases of the brain – by treating both people with Down syndrome and Alzheimer’s with a drug compound that replaces a key substance (norepinephrine) required for effective signaling between neurons.
The bottom line: Neurons (the information transmitting cells in the brain and nervous system) are connected quite closely to one another at a physical structure called a synapse. Each synapse is activated by a small neurotransmitter molecule that is released from one neuron to act upon its partner. All brain functions are made possible by the action of synapses, each of which serves a specific purpose. All losses of brain function are due to the failure of specific types of synapses. When neurons are damaged in degenerative diseases, synapses fail and the neurotransmitters used to communicate between neurons are unable to work. Mobley and his colleagues discovered that norepinephrine, a neurotransmitter required for helping the brain to learn and remember information, was deficient in a mouse model of DS. Deprived of this essential substance, the neurons could not communicate and cognition was compromised. The model organism mimicked what happens in elderly people with Down syndrome and in those with Alzheimer’s Disease who experience noticeable deficits in such basic functions as remembering and learning. For Mobley and his colleagues at Stanford’s Department of Neurology and Neurological Sciences, the challenge had long been to find a way to reverse the harmful brain deficits of degenerative nervous system disorders like DS. Their approach was to first understand the genetics behind the ailments and then to seek therapies aimed at offsetting the damage they cause. One way to do that, they reasoned, was to explore how another category of molecules might be affected in DS and AD. “Neurotrophic factors,” small proteins that normally signal to keep synapses active and healthy, might be involved in the degeneration of neurons in these disorders.
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Mobley & Co. had been working for several years with a “mouse model” in which the presence of an extra copy of a specific segment of a mouse chromosome was used to “mimic” the neurobiology of humans with DS. Their challenging task: to see if they could learn from the model whether or not and how neurons were being deprived of neurotrophic factors and to prevent, at least partially, the expected loss of neurons. For the Mobley team, the dramatic finding that neurotrophic factors were involved was announced by the clicking of a Geiger Counter-like device that was tracking a “radio-labeled” (radioactive) chemical marker in the lab test of the mouse brain cells under investigation.
“We discovered that in spite of the degeneration of the neurons that make this neurotransmitter, and the apparent decrease in the levels of this chemical at synapses, the synapses could still be activated in a culture dish if we artificially restored norepinephrine levels. My colleagues Ahmad Salehi, Alexander Kleschevnikov and Pavel Belichenko were very excited by this result. In studies in mice, we tested the idea that the same would be true in mice and found that it was. By giving the mice a drug that was converted to norepinephrine, we reversed some of the behavioral changes that affected them – changes that are similar to those in people with DS. The results suggested that we may be able to reverse cognitive problems in people with DS.”
“When I walked into the lab that day in 2002, I got a very nice surprise,” Mobley told Nebraska Magazine during a recent interview in the Department of Neuroscience at the University of California San Diego, which he now chairs. “All at once Jean Dominique, a talented ‘postdoc’ [postdoctoral researcher] hurried over and showed me the results of his assay of the neuron-signaling in the mice.
Enormously encouraged by their finding, Mobley and his Stanford crew of investigators were also heartened by the fact that the compound they were studying has been studied for years in Japan and in other ongoing clinical trials by a U.S. company. Enormously encouraging to Mobley and his colleagues is that this company is now interested in trying out the compound in people with DS.
“Those results were clear and unequivocal – they showed that neurotrophic factors were involved in the degeneration of neurons. We went on to show that a specific gene was largely responsible for the problem, and we realized that we might very well be looking at a potentially important cause for both Down syndrome and Alzheimer’s.
“The good news here is that we won’t have to wait through years of testing before moving the compound toward people with Down syndrome,” said the former UNL Phi Beta Kappa science student. “As a matter of fact, there is a strong interest in testing this compound as soon as possible. And that’s wonderful news for us in the lab – because our sole purpose right now is to help people with Down syndrome, and we’re hopeful we’re going to be able to do that sooner rather than later.”
“As it turns out, the brain chemistry in DS that causes the deficits is in many ways identical to the chemistry in Alzheimer’s, which is why virtually all people with Down syndrome also develop the brain changes of Alzheimer’s by the age of 40 or so. “Because of the similarity, it was reasonable to expect that what we discovered about Down syndrome will also work to help Alzheimer’s patients.” The next big breakthrough was in 2008. “We reasoned that the failure to communicate at synapses might be reversed by simply supplying the missing neurotransmitter,” Mobley explained. “Our focus was a population of neurons in the brain stem – i.e. those lying at the base of the brain – whose neurotransmitter is norepinephrine. The synapses that are activated by this neurotransmitter are very important for learning and memory, perhaps the most important ones of all in the brain.
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So what was it like for Dr. M and his colleagues, when these breakthroughs occurred? “You do get a warm feeling inside,” said the 61-year-old scientist with a cheerful smile. “But really, there’s no time to waste to follow up on the finding. What happens is that you immediately start asking yourself: How can we write this [experiment] up, in order to show exactly what we’ve found here? What are the scientific implications, and what further experiments can we conduct in order to better document the results? “These moments of discovery are very nice, of course, but they don’t suddenly change everything. For me, scientific research is about working day in and day out in a really rewarding process with lots of joy in it. “I don’t see the process as one in which
you do ‘years of grueling work’ and then enjoy a sudden breakthrough. I see it more as a matter of fully enjoying each and every day at work – and then also enjoying some special times [during breakthroughs] that are even better.”
STUDYING 120 HOURS FOR AN EXAM? Born in Lincoln to parents who were the descendants of English-German-Irish immigrants to Nebraska, Bill Mobley likes to joke that “my mother claims she was born [at what later became] the 50-yard line [of Memorial Stadium], a few years before it was built [in 1923]. I’m not sure that the 50-yard line claim is quite correct, but she was born in her parents house very close to the where the stadium would be built. Whenever I go to a game I try to think about what that spot must have looked like so many years ago. “Anyway, we were dyed-in-the-wool Nebraskans, for sure. My dad delivered milk for Roberts Dairy for several years, and then he spent the rest of his career selling Butternut Coffee around Lincoln and all across southeastern Nebraska. He had grown up during the Depression, when money was extremely tight, so he hadn’t been able to realize his dream of going to medical school. But he was a very kind, thoughtful man who took good care of his five children and never complained. It was a deeply rewarding experience when I eventually completed my Ph.D and M.D. and become a neuroscientist.” As a student at Lincoln’s Pius X Catholic High School, in the early 1960s, Mobley worked part-time as an orderly at Lincoln General ... and by the time he landed on the UNL campus in 1966, he was already determined to launch a medical career. After signing on as a member of the Sigma Phi Epsilon Fraternity (“One of my best memories of UNL is the camaraderie we enjoyed in the frat house”), he buckled down to some “very serious academics” ... and excelled in his coursework. He remembers working very hard in preparation for post-holiday final exams, sometimes studying for 120 hours or more for exams in organic chemistry.
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One of his most powerful UNL memories is of the “wonderful hours” he spent in a “mysterious and magical” chemistry lab under the tutelage of Professor Lawrence J. Parkhurst (now Hewit University Professor). “He took me under his wing, and he made physical chemistry a real adventure,” Mobley recalled. “I can remember sitting in Avery Hall working on experiments where I applied various purified gases to understand the biochemistry of a hemoglobin taken from a sea cucumber, Thyonella gemmata. When I added a certain clear gas, the hemoglobin would change to a certain specific and beautiful color. “For me, it was absolutely riveting, the experience of watching a chemical reaction take place and realizing that this was probably the first time anybody had ever conducted this particular experiment. Larry was extremely supportive and enthusiastic – the kind of professor who treated me to lunch at a nearby Mexican restaurant where he taught me about the world of discovery and the life that a scientist is privileged to lead. “What a great guy, and what a terrific teacher!” After earning his UNL B.S. in 1970, Mobley was struggling to find a way to pay for medical school, when he discovered that he could benefit from free tuition and even get paid a little if he also worked on a Ph.D. while studying to be a doctor. Accepted at high-powered Stanford University in Palo Alto, he sailed through several years of round-the-clock research with Eric Shooter, classroom-based studies and clinical clerkships to emerge in the mid-1970s as both a budding physician and researcher. After completing a pediatric residency at Stanford in 1979 and a neurology residency at The Johns Hopkins University in 1982, Mobley worked at the Walter Reed Army Institute of Research for three years before moving to the Department of Neurology at the University of California San Francisco. He returned to Stanford (in 1997) to launch what became a 12-year quest to understand the genetic basis of Down syndrome and also identify therapeutic approaches that could help reduce the cognitive deficits caused by the disorder. After identifying the gene on human chromosome number 21 that’s responsible for many of those deficits, Mobley began to zero in on the biochemical scenario which unfolds when neurons are deprived of vitally important substances, such as norepinephrine.
LEADING THE WAY UP THE ‘MOUNTAIN OF HOPE’ By November of 2009, when he published his groundbreaking study for neuronal signaling in Scientific Translational Medicine (“Restoration of Norepinephrine-Modulated Contextual Memory in a Mouse Model of Down Syndrome,” http://stm.sciencemag. org/content/1/7/7ra17.abstract), the relentlessly focused and apparently tireless researcher was convinced that the compound represented a “huge opportunity” to improve the lives of people with Down syndrome ... and perhaps also the lives of Alzheimer’s patients in the years ahead. “If you ask me what we’re hoping to accomplish here at UCSD [in the Department of Neuroscience, which he began chairing last year],” he will tell you with a smile of quiet determination, “I would simply say that if we can help to make things better for a single person with Down syndrome, then all of our years of hard work will be fully justified.” Optimistic and resolutely cheerful, Mobley said he’s convinced that medical research is well on the way to more breakthroughs in finding help for patients with degenerative diseases of the central nervous system. Still, he often frets over what he sees as the toughest problem now facing medical researchers in this country: “Finding ways to more effectively translate the discoveries of medical science to the clinic, where they can benefit patients, quickly and directly. “This is an extremely difficult problem right now,” said the father of three now-adult sons (his wife of 38 years, Gretchen, is a retired nurse), “and it’s quite troubling that we can’t do a better job of getting new drugs and new therapies from the science lab out to the medical community in a reasonable amount of time. “The obstacles in the way of translating great science to great medicine are so formidable that some of us have taken to calling the process the ‘Valley of Death.’ Right now the system is simply broken,
that’s all. There are regulatory problems involved, and funding problems, and commitment of interest problems ... and the communications that go on between academia and industry simply do not work well. In the end, I believe that patients are suffering unnecessarily. We must get our act together – and now.” Then, with a look of rock-solid determination and an enthusiastic nod of his elegantly groomed, silver-haired head: “What we have to do is to find a way to transform the Valley of Death into the Mountain of Hope, so that great science can more easily become great medicine!” n
Understanding Down Syndrome A Q&A With Pioneering DS Researcher William Mobley, M.D., Ph.D.
Q. What is Down syndrome and why is it called that? A. Down syndrome is a developmental disorder that occurs because of a genetic mistake that takes place at the time of conception – i.e. when the sperm fertilizes the egg.. The disorder causes an interruption in normal physical and intellectual development, and this leads to impairments of one kind or another after birth. The condition is named after Dr. John Langdon Down, the first physician to formally identify the disorder, back in 1866. Q. What happens, exactly, to cause the disorder? A. In essence, the genetic mistake is a failure to properly distribute the 21st chromosome to the egg (usually) or the sperm. This results in the presence in the fertilized egg of an extra copy of the 21st chromosome. All the problems that then are experienced by the embryo, the fetus, the child and the adult are due in one way or another to the presence of the genes on the extra copy of the 21st chromosome. These extra genes interfere with normal development of cells and tissues throughout the body and the nervous system. The interference leads to physiological abnormalities that produce both physical and mental deficits in people with Down syndrome. Q. How many Americans are affected by Down syndrome? A. The most recent estimates indicate that about one American infant in 800 is born with DS. About 5,000 children born in this country each year will have the disorder. At present, more than 400,000 people are living with Down syndrome in the United States. NEBRASKAMAGAZINE
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Q. What are the physical symptoms? A. Babies born with DS are often of small stature, hypotonic (i.e. with reduced muscle tone) and possess an unusual facial appearance with an upward slant to the eyes. They will often display a single crease in the palm of the hand, as well. Also, more than a third will struggle with DS-related heart defects of varying severity. But these symptoms vary a great deal. Most important, people with DS are nevertheless unique individuals and, like all humans, of inestimable value. A. What are the intellectual and learning deficits that can accompany DS? A. Children with DS often struggle to keep up with their peers. They are slower than normal in learning to walk, talk and take care of themselves. The mental deficits they face can make it difficult to learn, but many do succeed in an ordinary school setting and go on to live rich and rewarding lives; they hold jobs and often live independently. Still, nearly half will require some level of assistance in their daily functioning while growing up, and some will need to live in a structured environment as adults. Q. Are babies born with Down syndrome at greater risk for other diseases or physical disorders?
A. Yes. Children with DS are more susceptible to childhood leukemia and thyroid conditions, along with hearing and respiratory ailments. In addition, all will develop the brain changes of Alzheimer’s disease by age 40 and many will go on to show cognitive decline by the age of 60. Most of the medical issues can be treated with today’s powerful medications and therapies. It is the neurological issues, those involving the brain, that are the biggest concern at present. But even with these concerns, people with DS lead healthy lives with life spans that now average 60 years Q. Does the disorder strike babies regardless of race, ethnic background or economic class? A. Yes. People of all races and economic status are affected equally. It’s also important to remember that Down syndrome is not caused by the behavior or lifestyle habits of the mother or father. Q. Can people with Down syndrome learn to function successfully as adults contributing to their communities? A. Absolutely. The majority of them will go on to lead rewarding, productive lives. But to accomplish that, they need what the rest of us need – warm, loving families and lots of support from parents, teachers,
counselors and friends. It’s important to remember that people with Down syndrome aren’t really very different from those without DS. They want to get a good education and a good job. They want to date and enjoy an active social life. They face some special challenges, but none of us is without challenges in our lives. Q. Is medical science helping to make life better for people with Down syndrome, and is there hope for an eventual cure? A. I would rather speak of treatments than a cure. But there’s no doubt that bringing people with DS into the mainstream of society and advances in medical science have improved their lives enormously in recent years. Their life span has more than doubled in the past few decades. At my lab at the University of California San Diego, we’re very hopeful about the prospective treatments that could improve mental function. A major pharmaceutical company will soon began clinical trials of one such drug, and it is possible that it will be of significant benefit for people with DS. I’ve never been more optimistic about the future of DS research than I am right now. My colleagues and I are energized as never before to make a positive contribution to the well being of people with DS and their families. n
> STarTing kiDS off aT 1ST anD goal.
Character. Courage. Leadership. Respect. These are the principles former Husker Matt Davison is instilling in today’s young athletes so they reach their goals, both on the playing field, and in life. To make a donation, or find out how to bring Matt’s foundation to your community, visit www.creatingcaptains.org or call 402.672.1787.
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