The Scripps Research Institute

FALL 2006 VOLUME NINE / NUMBER TWO

NON-PROFIT U.S. POSTAGE PAID PERMIT 751 SAN DIEGO, CA THE SCRIPPS RESEARCH INSTITUTE

A PUBLICATION OF THE SCRIPPS RESEARCH INSTITUTE

Ofﬁce of Communications—TPC30 ENDEAVOR 10550 North Torrey Pines Road La Jolla, California 92037 www.scripps.edu

PUBLISHER: Keith McKeown

EDITOR: Mika Ono Benedyk

DESIGN: Miriello Grafico

PRODUCTION: Miriello Grafico Kevin Fung

COVER ILLUSTRATION: Carey Sookocheff

PORTRAIT PHOTOGRAPHY: Dana Neibert Bruce Hibbs

PRINTING: Precision Litho

HELEN DORRIS

Donor Profle: Helen Dorris THE SCRIPPS RESEARCH INSTITUTE

Helen Dorris is part of the Scripps Research family. Busy researchers greet her in the hallway and stop to discuss current projects. More than a sup- ENDEAVOR porter, she is their friend. Helen takes a keen interest in the neurosciences and has helped bring several researchers to Scripps Research to explore the mysteries of Alzheim- er’s, schizophrenia, and other brain disorders. VOLUME NINE / NUMBER TWO FALL 2006 She is proud of the research she supports but shies away from taking any credit. “What’s important is the work these people are doing,” she says. “They should have the glory.” 17 Helen Dorris has made several gifts of real estate to Scripps Research to establish a fellowship to study schizophrenia and to create both the Helen L.

FEATURES: ALSO: Dorris Child and Adolescent Neuro-Psychiatric Disorder Institute and the

Harold L. Dorris Neurological Research Institute. SCENES THE BEHIND The institutes, now the home of some of the world’s top brain researchers, uncover the pathological basis of neurological and psychiatric disorders and expedite the discovery of promising new therapeutic approaches. 02 THE POWER OF SUGAR AND FAT: 01 AT THE FOREFRONT ERIC ZORRILLA EXPLORES 16 BEHIND THE SCENES EVOLUTION GONE WRONG

BENEFIT FROM A GIFT ANNUITY Join The Scripps Legacy Society by establishing a gift annuity. You’ll qualify for an immediate tax 08 A MATTER OF BALANCE: deduction, receive a fixed income for the rest of your life, and support Scripps Research scientists’ LAYTON SMITH PROBES FAT AT THE present and future research. MOLECULAR LEVEL

LIFE RATES FOR AN INDIVIDUAL:

Age Rate

75 7.1% For example, if you are 75 years old and establish a $100,000 gift annuity with Scripps 80 8.0% Research, you will receive $7,100 per year for the rest of your life, some of it tax-free, while 12 WHAT LIES BENEATH: 85 9.5% also receiving an immediate tax deduction of $46,264. Deferred gift annuities are available NATASHA KRALLI EXAMINES 90 11.3% for younger individuals. THE INTRICACIES OF METABOLISM

Find out how you can receive fixed annual income for life, now or as part of your retirement planning, while also providing a gift to Scripps Research. Please contact Cheryl Dean, at (858) 784-2380 or [email protected], to learn about joining the many members of the Scripps Legacy Society and making the future discoveries of Scripps Research scientists part of your legacy.

ENDEAVOR IS A PUBLICATION OF THE SCRIPPS RESEARCH INSTITUTE

This issue of Endeavor magazine features Scripps Research investigators working to understand obesity—an increasingly common condition that now puts almost one third of all Americans at increased risk of developing diabetes, heart disease, stroke, and some types of cancer. At the Forefront

Minor Mutations in “Bird Flu” Virus Increase New Class of Enzyme Inhibitors Blocks Chances of Human Infection Replication of SARS Virus Scientists at The Scripps Research Institute, the Centers Scientists have discovered a class of compounds that blocks for Disease Control, and the Armed Forces Institute of the SARS virus from replicating, a finding that may open Pathology have identified what the researchers described the door to new drug targets against the deadly disease. as a possible pathway for a particularly virulent strain The study was conducted by researchers from Scripps of the avian flu virus, H5N1, “to gain a foothold in the Research; the Genomics Research Center; Academia Si- human population.” nica, Taiwan; and the National Taiwan University. The H5N1 avian influenza virus, commonly known Chi-Huey Wong, Ph.D., who is the Ernest W. Hahn 01 as “bird flu,” is a highly contagious and deadly disease in Chair in Chemistry at Scripps Research and a member of poultry. So far, its spread to humans has been limited, with The Skaggs Institute of Chemical Biology, said the new 177 documented severe infections, and nearly 100 deaths finding is an important step in developing a possible drug AT THE FOREFRONT THE AT in Asia, according to the World Health Organization. treatment against SARS. “This new class of inhibitors, Using a recently developed microarray technolo- called benzotriazole esters, represents the most potent gy—hundreds of microscopic assay sites on a single small SARS virus protease inhibitors known today,” he said. surface—the study, led by Scripps Research Professor Ian REFERENCE: Chemistry and Biology, 13 (3), 261-268 Wilson, D. Phil., showed that relatively small mutations (March 24, 2006). can result in switching the binding site preference of the Immune Response to HIV in the Brain avian virus from receptors in the intestinal tract of birds a “Double-Edged Sword” to the respiratory tract of humans. A team at Scripps Research has shed new light on the REFERENCE: Science, 312, 404-410 (April 21, 2006). molecular basis of problems with brain function in mod- Lack of a Key Enzyme Increases Resistance to Sepsis els chronically infected with an immune deficiency virus Scientists at Scripps Research, The La Jolla Institute of similar to human immunodeficiency virus (HIV). Allergy and Immunology, and Merck Research Laborato- Using multi-disciplinary analysis, the team found ries have uncovered a “fundamentally new role” for an en- both a low-level viral infection in the brain and immune zyme that, when present in vivo in certain forms, impedes cells that had infiltrated the brain in order to protect the immune response to bacterial infection. against the virus. According to the new study, the presence of caspase- “Over the long-term, this immune response may 12, which appears to modulate inflammation and innate act as a double-edged sword,” said Howard Fox, associ- immunity in humans, increases the body’s vulnerability ate professor at Scripps Research and director of Scripps to bacterial infection and septic shock, while a deficiency NeuroAIDS Preclinical Studies center, “protecting against confers strong resistance to sepsis. This new discovery rampant viral replication in the brain, but leading to suggests potential treatments for sepsis and other inflam- brain dysfunction.” matory and immune disorders. The publication coincides with an $11.2 million “It’s known that the presence of caspase-12 as a full- award for a five-year renewal of the center called Scripps length protein occurs in a small percentage of people of NeuroAIDS Preclinical Studies (SNAPS), which works African descent,” said Richard Ulevitch, Ph.D., chair of with Scripps Research and local, national, and interna- the Scripps Research Immunology Department. “As a tional investigators to understand, treat, and prevent neu- result, some of these individuals are far more susceptible rological complications of HIV infection. to severe sepsis and have a significantly increased risk of REFERENCE: Journal of Neuroscience, 26 (17), 4577-4585 dying from it.” (April 26, 2006). REFERENCE: Nature, 440, 1064-1068 (April 20, 2006).

“Sugar tastes good because our brains are tuned to detect sugar; fat tastes good because our brains are tuned to detect fat …Under conditions like those in which humans evolved, when food was scarce, the ability to identify these foods as preferred fuels, seek them out, and eat them promoted survival. Unfortunately, in our current environment of plenty, the excess of such foods is making us sick.”

ERIC ZORRILLA, PH.D.

The Power of Sugar and Fat 03

ERIC ZORRILLA EXPLORES EVOLUTION GONE WRONG ERIC ZORRILLA ERIC

Blame it on taste. If so much food on the market whether or not a person is overweight) of 25 or didn’t taste so good, America might not be experi- greater. About 32 percent of adults—more than 60 encing its current obesity epidemic. Scripps Research million people—are clinically obese with BMIs of 30 Institute scientist Eric Zorrilla, Ph.D., says highly or higher. Among children and teens aged six to 19 palatable foods, which are often fat and sugar-lad- years old, 17 percent—more than nine million young en—and are available to a greater degree today than people—are considered overweight. Being over- ever before in human history—can be addictive and weight or obese increases the risk of many diseases lead to obesity and sickness. and health conditions, such as hypertension, dys- “Evolution favored those genes that allowed lipidemia, Type 2 diabetes, coronary heart disease, individuals to readily detect and be motivated by stroke, and certain cancers. energy-containing foods,” says Zorrilla, an assistant DRUG-LIKE EFFECTS professor in Scripps Research’s Molecular and Inte- grative Neurosciences Department, who has been Zorrilla, who has previously studied the relation- studying the relationship between palatability and ship between drug abuse and stress, says the brain weight gain for several years. “Sugar tastes good be- mechanisms that drive a susceptible person to eat cause our brains are tuned to detect sugar; fat tastes ever-greater amounts of palatable food are similar to good because our brains are tuned to detect fat. those that compel certain individuals to abuse drugs. Things that contain lots of sugar and fat are energy “Certain highly palatable foods can indeed act dense. Under conditions like those in which humans like drugs,” Zorrilla says. “Changes occur in the evolved, when food was scarce, the ability to identify brain as a result of drug-taking that may cause an in- these foods as preferred fuels, seek them out and eat creased vulnerability for subsequent drug abuse. We them promoted survival. Unfortunately, in our cur- believe the same thing happens in binge-type eating rent environment of plenty, the excess of such foods that is driven by highly desired fatty or sugary foods. is making us sick. It’s evolution gone wrong.” The compulsive aspect of binge eating, like drug Evolution is going wrong for vast numbers of abuse, is not a weakness of morals or will. It cannot people. U.S. government data from 2003-2004 esti- be overcome simply by going on the right diet. To mate that two out of every three adults 20 years of stop binge-eating you have to treat the motivational age and older are overweight, defined as having a processes and underlying brain chemicals that over- Body Mass Index (BMI—a method used to gauge ride the body’s energy homeostasis—the normal bal- 04 ERIC ZORRILLA brain chemistry. binging. It’s the reason most diets, which generally which diets, most reason th the It’s binging. food preferred highly the and food preferred less the between contrast a cycle, a creates restriction “The Zorrilla. says excess,” to in give us of many cream, ice or cake find to refrigerator the open day one then and foods ‘forbidden’ or desired highly eating from ourselves restrict we “When ets. sweet food.” survive; they’re eating because they crave the hits of to eating aren’t animals the model, this In animals. has been limited makes it extremely attractive to the it after food sugary the to access “Having says. rilla Zor hours,” two in eat will hours 24 for all at food any to access had haven’t that rats than minutes 10 not available. is food sugary their withdrawal,when drug of mark hall behavior,a anxious more show also Rats sion. half ses 10-minute single that during calories daily their about consume to begin dramatically—they that within a week the rats’ eating behavior changes chow, which is healthy but bland. Zorrilla has found sug rat only eat can chocolaty,they time the of rest The foods. ary day—to per minutes access—10 disordered from results overeating that theory the test to models developedanimal group, his in fellow postdoctoral a Ph.D., Sabino, Valentina and dent, you needfoodandtostopeatingoncefueledup.” when eat to you tell that mechanisms between ance n hi “ig” oe, nml hv limited have animals model, “binge” their In This is similar to what h what to similar is This “These sweet-deprived rats will eat more in those stu graduate a Cottone, Pietro with Zorrilla, 40 % MEN 31 28 % % < < 2 % 29 appens to people on di on people to appens % WOMEN 37 33 % % t ed to leads at < < 2 % ------

Association ( are obese. or women of overweight percent 62 about and men two three than every more of out older, or years 20 Americans for Of States 2003-2004. United the in women and men adult overweight, obese weight, and normal underweight, of prevalence The blander food.

y h bd a ft oe agesvl” than “aggressively” more fat as body stored the is food by binge restriction, after that found also have scientists the Interestingly, work.” don’t eaten, is what also but much, how only not restrict and finickiness. binging both heroin, in involved is including alcohol, and morphine, drugs, abused several of erties prop rewarding mediates and pleasure with ciated asso strongly is which system, receptor opioid the brain, the in that found have team his and Zorrilla BALANCE OF OUT BRAIN less likelytochooseasaladwithleanchicken. bacon cheeseburger and a soda for lunch, he or she is a of taste the to accustomed becomes someone once pealing. Translated to humans, this might mean that ap less become suddenly eaten be might normally having access to tasty foods, other healthy foods that of result a as that shows it because important is ness finicki The finickiness. and then—binging havior for fivedaysorlonger, despitelosingweight. tomed rats will continue to reject less-preferred food sugar-accus that found has team Zorrilla’s model, different hungry.a being chow,In despite the reject a history of access to the chocolaty, sugary foods will with rats chow—those food—rat preferred less their with presented then are say,and time, hours, of two period short a for food any to access given not are ior.model binge the in rats if that found has Zorrilla The flip side of binge behavior is “finicky” behav There are two sides to the disordered eating be eating disordered the to sides two are There obese overweight normal underweight , 2006, 295, 1549-1555) 295, 2006, ,

Journal of the American Medical Medical American the of Journal ------

“Certain highly palatable foods can indeed act like drugs.”

ERIC ZORRILLA, PH.D.

“If comparisons between pleasurable aspects of Zorrilla has found that unlike ghrelin, a stom- foods are what drives both binging and finickiness, ach hormone that initiates meals but does not dic- then both behaviors should be reduced with an opi- tate how much or how fast someone will eat within ZORRILLA ERIC oid receptor antagonist,” Zorrilla says. In fact, this is the meal, palatable food expands meal size, causing what happened when they administered the drugs faster eating, especially at the start of the meal. Be- nalmefene or naltrexone, opioid receptor antagonists ing deprived of food has identical effects. that slightly dull the pleasurable smell and taste of “When we’re hungry, our brains adapt so that food in people. Both nalmefene and naltrexone have food tastes better,” Zorrilla says. “However, palat- been tested against alcohol addiction by another able food seems to activate some of the same brain Scripps Research scientist, Barbara Mason, Ph.D., reward circuits primed by food deprivation so we eat and found to lessen relapse in particular episodes of as if we were very hungry, even though we may have binge drinking. just eaten. To counter this behavior, it makes sense to “These and related drugs could potentially be look for molecules that have anti-palatability effects, used to treat people with binge eating disorder, clini- such as nalmefene and naltrexone, which reduce the cal obesity, or bulimia by allowing the body’s natu- amount eaten in a meal and also slow down how fast ral energy homeostasis mechanisms to exert them- we eat at the start of the meal.” selves,” Zorrilla says. “Food still tastes pleasurable, a AN OBESITY VACCINE person still wants to eat if hungry, but the desire for food becomes less compulsive and overriding. The In addition to his work on the relationship between brain is better able to say ‘enough is enough.’” palatability and obesity, Dr. Zorrilla and a scientist An individual’s proclivity toward binge/finicky visiting his lab, Shinichi Iwasaki, M.D., Ph.D., in eating also may turn out to be genetically deter- collaboration with investigators Kim Janda, Ph.D., mined, Zorrilla says. and Michael Meijler, Ph.D., faculty in the Depart- “We’ve found that some rats are more sensitive to ment of Chemistry at Scripps Research, are seeking relative palatability than others. They’ll binge con- to develop an obesity vaccine. The scientists have sistently and become finicky consistently. Scientists targeted ghrelin, which stimulates appetite and always talk about the genetic aspect to obesity and alters metabolism to promote fat storage. Ghrelin we agree completely that in some people, for reasons is secreted when a person hasn’t eaten for several we don’t yet completely understand, palatability is a hours, signaling that it’s time to eat and to conserve bigger determinant of how they eat than in others.” the resulting fuel. After eating sufficiently, ghrelin To better understand what drives food intake, levels drop off and the urge to eat, as well as metabo- Zorrilla is also studying how palatability controls lism, normalize. > eating behavior from meal to meal. 06 ERIC ZORRILLA on pleasure and pain perception that has been found to play a role in food intake. Magnification: x80 at 6x7cm size. size. 6x7cm at x80 Magnification: intake. food in role a play to found been has that perception pain and pleasure on actions morphine-like its for named peptide occurring naturally a beta-endorphin, of crystals of micrograph light polarized A “Our research suggests that once people grow accustomed to highly sweetened food—such as high fructose corn syrup, which is present in so many foods now—their reference point about what food should taste like changes.”

ERIC ZORRILLA, PH.D.

Mice designed to lack ghrelin or its receptor are less “Our research suggests that once people grow likely to become obese when high-fat food is avail- accustomed to highly sweetened food—such as high able. Ghrelin receptor antagonists decrease appetite fructose corn syrup, which is present in so many ZORRILLA ERIC and increase energy expenditure. In people, ghrelin foods now—their reference point about what food levels increase when we diet, stimulating appetite should taste like changes,” Zorrilla says. and slowing down metabolism, thereby making it Fueling the desire for highly palatable food to- difficult to maintain weight loss. For these reasons, day is an industry with legions of people working to an anti-ghrelin treatment potentially could help peo- make food taste better—a situation that didn’t exist ple lose weight and keep it off and also might help just a couple of decades ago. prevent weight gain. Zorrilla cites diet drinks as an example of how The vaccine, which only would be administered the ante on sweetness has been upped. It used to be to obese people with a BMI of 30 or above, would that diet sodas had an unpleasant taste, but now that stimulate the production of antibodies against ghre- many are sweetened with tasty artificial sweeteners, lin. So far, the team has overcome biochemical ob- they are arguably as good as regular soda. So even stacles and identified “proof of principle” modified though the soda itself may not promote weight gain, ghrelin haptens—substances that led rats to produce drinking it raises the expectation of what other foods should taste like. This leads a heavy diet soda drinker antibodies against ghrelin. Rats with the greatest to demand the same sweetness from other foods and specific antibody response against the active form avoid less pleasing, albeit healthier, alternatives. of ghrelin, which exists in both active and inactive Even though it’s clear that obesity is related forms, gained the least weight and body fat. to what people are eating, it’s difficult to trace the Research on the vaccine is in the early stages problem directly back to palatability and to the food and several safety issues need to be studied before industry. ”It’s analogous to what happened with human testing. But Zorrilla says such active im- smoking,” Zorrilla says. “It was only when lung munization holds promise because it circumvents cancer rates began to rise dramatically that things the problem of compliance that often arises with started to change. As a society we now have to ask prescribed medications. ourselves—have we reached the point where there

A QUESTION OF PUBLIC HEALTH should be more regulation of the food industry? Should there be warning labels on certain foods? Individuals make personal choices about what to More public education programs? There’s going to eat, but they make those choices in the context of have to be a cultural sea change to have an effect the societies in which they live. That’s why the easy on the obesity problem. But if something doesn’t availability of fatty and sugary foods cannot be sepa- change, the number of people struggling with obesity rated from the rise of obesity. will keep rising.” ANNA SOBKOWSKI “New therapies that target apelin …might enhance the body’s checks and balances and bring something that is dysfunctional back into line with the rest of the body.”

LAYTON SMITH, PH.D.

08 A Matter of Balance

LAYTON SMITH PROBES FAT AT THE MOLECULAR LEVEL

A FLORIDA BOY COMES HOME Layton Harris Smith sees science as something that So how does a Florida boy—born and raised in LAYTON SMITH must be relevant to society. And with nearly one-third Tampa—return to study the biology of obesity in the of the U.S. population defined as obese, according to Sunshine State? Credit his mother. government figures, there’s perhaps nothing more “When I finished my postdoc at Vanderbilt, relevant than understanding how obesity works. I was looking at positions and I had a conversation Smith, associate director of pharmacology at with my mom,” he recalls. “I said there’s no science Scripps Florida’s Department of Drug Discovery, in Florida. Within six months they announced the is leading an effort to figure out how obesity throws Scripps deal. She called me up and said, ‘well there the body’s normal regulatory system out of balance. is now.’” He’s also probing the series of events triggered by fat That tip from mom led to a recruiting trip, and cells that lead to cardiovascular disease and diabetes a return to a state he calls home. Smith said he’s in obese people. excited about the pioneer spirit at Scripps Research’s “Everybody knows that being fat and having new biomedical campus. diabetes are bad for you, but nobody understands “It’s very much a start-up mentality here,” he the exact reasons why,” says Smith. “When someone notes. “We have a good group of young scientists and is obese, it’s not that they are just a bigger person. everyone seems to understand we are doing some- They are a normal sized person wearing a 150-pound thing new.” coat of fat.” Smith has just to look at former generations of Smith’s research probes fat at the molecular his own family for examples of entrepreneurship. level. Using tools at Scripps Florida’s Advanced His mother’s family owned one of Florida’s largest Technologies group, he’s searching for drug targets cigar companies—Corral, Wodiska Y Ca.—from that may prevent or control obesity, keenly focusing its founding in 1905 until it was sold in the late on the real-world benefits of the sometimes abstract 1980s. The family also ran a successful agricultural world of basic biomedical research. business, raising oranges, grapefruit, and blooming “When it comes to pharmacology, we have an flowers in the same area. eye toward the human condition,” he says. “We ask When it got time to pick a career, however, if what we are doing in the lab is moving us closer Smith’s father, an attorney, wasn’t keen on Layton to making a better therapy or identifying a way to following in his footsteps. So as a pre-med under- prevent disease.” graduate at Tulane University, Smith instead found

10 LAYTON SMITH which he received the postdoctoral rese postdoctoral the received he which during fellowship postdoctoral productive a and to led 2002, in completed he which thesis, doctoral more thanadoublewhammy.” was “It says. Smith cholesterol,” decreasing beyond health vascular improves that statins of dividend from buildingup. platelets prevent and walls arterial relax helps that body the in chemical occurring naturally a tacyclin, pros of production promote could statins lesterol, remove cholesterolfromarterialwalls. that drugs powerful and popular highly the statins, of effects the at looking was team The Medicine. lar Cardiovascu of Division Vanderbilt’s in Vaughan Douglas of laboratory the to him led This disease. affect drugs how body,consequently the and affects disease how of mechanisms the was him interested Vanderbilt.What at program pharmacology the for opted he Instead, school. medical against decided Smith 1996, in biology molecular and of cell in science bachelor a with Tulane from graduating After PEOPLE REMEMBERING discovering somethingnew?” and lab a to going than work different. to way better completely What something was This thing. same the did grandfather “My day,”says. ery Smith genetics lab. the joy of discovery while studying frog embryos in a This work on statins became the basis of Smith’s abiological we identified time, first the “For that, found Smith ev work to went and suit a on put father “My in addition to reducing cho reducing to addition in arch award arch - - - - collagen around the vessel. vessel. the around collagen for staining increased by indicated as fibrosis vascular of signs show panel) (right II angiotensin with infused aortae Here, hypertension. to contribute that fat by produced angiotensins as known molecules of series a are there that rather but weight, more carrying is body the because harder work to has heart the that just not It’s hypertensive. also are patients obese Most

tor Award in2004. of Study the for Xenobiotics in2003andthePfizer Young Investiga Society International the from fat cells. by produced hormone a in imbalance an by caused projects are identifying drug targets for hypertension arriving at Scripps Florida in April 2005. His current of cardiovasculardisease. developmentto contributes obesity how and obesity with associated proteins the at looking project a gan be Smith stomach. the and brain the to messengers chemical and hormones own its producing organ an fact, scientists now believe that fat behaves more like that fatisn’tjustastoragedepotforextraenergy. In showing published being was research new as different way a in obesity about think to began Smith HORMONES OF YANG AND YIN THE all obese. derbilt University Medical Center. They were nearly patients suffering from hypertension and diabetes with at the Van contact face-to-face got Smith tion, advantage.” an him gives world… clinical the in foot a “Having Vaughanpeople,” in death and disability cause says. that problems address to motivated is “He diseases. same these from suffering are who people the about forgets he that wizardry high-tech by dazzled so not is but problems, research basic tackle to arrays gene standing of how to use modern research tools such as According to Vaughan, Smith has a good under mt hs otne wrig n bst since obesity on working continued has Smith investiga clinical in master’s a pursuing While

- - - - -

“If we know how a disease works, we know where to interrupt pathology of that disease to mitigate symptoms or cure the disease. It becomes important to understand what is being produced by the fat that has deleterious effects on cardiovascular disease, particularly hypertension.”

LAYTON SMITH, PH.D.

“If we know how a disease works, we know where apelin works. Apelin also plays a role in regulating to interrupt pathology of that disease to mitigate food intake, but early research in animal models symptoms or cure the disease,” he says. “It becomes shows contradictory findings: some animals eat more SMITH LAYTON important to understand what is being produced by when exposed to apelin in the cortex, others eat less. the fat that has deleterious effects on cardiovascular “We’ve been interested in apelin from the disease, particularly hypertension.” standpoint of the brain,” Reyes says. “Layton has It turns out that most obese patients are also hy- been interested in its role in cardiovascular disease pertensive. It’s not just that the heart has to work and obesity.” harder because the body is carrying more weight, Smith is taking advantage of the cell-based but rather that there are a series of molecules known screening technologies available at Scripps Florida as angiotensins produced by fat that contribute to do analyses on a genome-wide scale. It’s one of to hypertension. only a handful of places in the country where that Angiotensin is part of the larger renin-angioten- kind of technology is available. In collaboration with sin-aldosterone system (RAAS) that is responsible for the Advanced Technologies group, he’s using robots the long-term regulation of blood pressure. In nor- to screen 15,000 mammalian genes—about half the mal patients, angiotensin is believed to be balanced expected genome of humans—to identify regulators by another signaling molecule called apelin. We be- of apelin signaling. Until recently, this would have lieve that in obese patients, angiotensin takes over been impossible because it would take years just to and apelin can’t keep the system in check, Smith ex- test the effects of a few genes. plains. This yin and yang of the two hormones is the “We’re looking to identify genes that affect the central focus of Smith’s work at Scripps Florida. apelin system,” Smith said, “and then to find chemi- “Clearly, the RAAS system is out of balance in cals to exploit the aplin pathway. That way we can obese people,” he says. “New therapies that target see if this system is meaningful and can eventually apelin might be better than current drugs that sim- be targeted therapeutically.” ply knock down the aberrant RAAS system. It might While Smith is looking for new approaches to enhance the body’s checks and balances and bring obesity on a molecular level, he would still like to something that is dysfunctional back into line with see stronger prevention efforts—especially when it the rest of the body.” comes to young people. “Here in Florida, I see most adults are fairly fit CREATIVE COLLABORATIONS and thin, but their children are overweight or even Smith has been working with Teresa Reyes, formerly obese,” Smith says. “I’m already looking at the next assistant professor at Scripps Florida, Department generation of patients.” of Neurobiology, on finding out more about how ERIC NIILER

“We have all been taught metabolism in college, but once you get deeper into the subject you find out that there’s a lot we still do not understand, particularly on how metabolism is regulated.”

NATASHA KRALLI, PH.D.

What Lies Beneath 13

NATASHA KRALLI EXAMINES THE INTRICACIES OF METABOLISM NATASHA KRALLI NATASHA

There are those who believe in the magic bullet After completing her Ph.D. work, she went on to theory of science, the single discovery or treatment postdoctoral training in the laboratory of Keith that suddenly and forever solves a particularly knot- Yamamoto at the University of California, San Fran- ty problem. cisco (UCSF), where she worked on genetic screens Natasha Kralli, Ph.D., an associate professor in for steroid hormone receptor activity. The Scripps Research Institute Department of Cell When she left UCSF in 1997, she took her Biology, isn’t one of them. She believes in finding knowledge of yeast genetics and different modula- what lies beneath the surface of things—in this case, tors of steroid hormone receptors to start her own of metabolic activity, how it’s regulated, and how to research group—this time in Switzerland, a neutral keep it from going haywire, twisting itself into disor- choice for Kralli and her husband, Ulrich Mueller, ders like obesity, diabetes, or Parkinson’s disease. Ph.D., who is from Germany (and is now a Scripps Research faculty member). GLOBAL SCIENTIFIC TRAINING In her lab in Switzerland, Kralli pursued a grow- Born and raised in Greece, Kralli has spent the last ing interest in the intricacies of steroid hormone re- 20 years moving around the globe, turning up in un- ceptors, also known as nuclear receptors, using yeast expected places and doing unexpected things in her as a model system. scientific life. Nuclear receptors are a large family of tran- Her parents, who traveled a lot because of their scription factors that control cellular metabolism business, encouraged their children to go abroad for including things like growth, inflammation, and their education. Kralli chose England, namely Sussex glucose, and lipid homeostasis. They are loved by University. She started out with an interest in marine pharmaceutical companies because they are bound biology but soon found that she liked molecular biol- and regulated by small molecules, such as natural ogy and biochemistry better. steroids, retinoids, or synthetic compounds—making At the end of her undergraduate work, she them prime drug candidates. moved to the United States for a doctoral program, A BIG QUESTION which offered the opportunity to try different labs, as well as experience a new country where “science The big question Kralli had (and still has) was this: was happening.” Following a phone interview, she How can one nuclear receptor do different things in arrived at the University of Pennsylvania in 1986. different cells at different times? This entails a more 14 NATASHA KRALLI

“Exercise isoneofthebestwaystoimprove musclemitochondrial stand, particularly on how metabolism is regulated.” under not do still we lot a there’s that out find you subject the into deeper get you once “but says, she been studied for a long time, many mysteries remain. have metabolism and physiology while that found drial function. mitochon on receptors these of effects broader the explore to necessary was change the believes ever, how Kralli, mammal. a unicellular of complexity the simple, for yeast leave to switch a quite was It system. model a as mice use to decided she 2003, in California, Jolla, La in Research Scripps joined and she says. co-activator toregulatemitochondrialfunction. transcriptional the enable that factors key are tors ferent roles). look similar to estrogen receptors, they have very dif evenbecause Kralli they to though according nomer These were named estrogen-related receptors (a mis molecules. regulator as-yet-unknown with but tors recep hormone steroid resemble that receptors tors, fascinated by a small family of orphan nuclear recep became be—she should dance the what dancer the pathways—telling molecular new create could ners to have new functions inthesecells. receptors the enabling thereby cells, some only in present is coactivator The jobs. specific to them directing receptors, nuclear to partner a as acts that multitask. can it how words, other function—in one than more perform can protein one how of question, general PH.D. KRALLI, NATASHA exercise thesameway.” and generalhealth.However, notallindividualsrespondto function, andthereisnoquestionthatexercisehelpsweightloss “We have all been taught metabolism in college,” Entering the field with fresh eyes, Kralli soon Kralli eyes, fresh with field the Entering Switzerland left Kralli When work. her did So shifted,” interest our of lot a moment, that “At Kralli found that these particular orphan recep part in change a how studying was she While coactivator a transcriptional identified Kralli ------

MODERN-DAY PATHOLOGIES MODERN-DAY evolutionary advantages. They take up nearly a quarter of the cell cytoplasm cell the of quarter energy.a nearly up take They usable into material organic convert that cells the within organelles stations, power cellular partners in the regulation of mitochondrial function. their and receptors estrogen-related orphan these by played roles the on her—is with working searchers re five has now—she laboratory her of work The galaxy makes it virtually impossible to come up with metabolism-driven this in stars ill-fated the all and For Kralli, the innate complexity of obesity, diabetes, SUSPECT USUAL THE chondrial function.” w work to excited we’re So, good. very that’s percent, few a just by it increase can you “If says. she improvements,” big hope peutic applications. the now—with right that her findings can one day lead to practical thera address to trying is Kralli what of part is That established. from far is link a such but mitochondrial factor, causative a be decreased can function that suggests evidence function inmusclecells. and density mitochondrial reduced have diabetes to studies have shown that people who are predisposed example, For diseases. neurodegenerative or athies, our modern-day pathologies, such as diabetes, myop certain provided they because cell the incorpo into were rated that bacteria specialized of kind a were goes, theory the organisms, These organisms. as out started to theory, according endosymbiotic and, the DNA, own their have cyto entire plasm), the fill they cells specialized some (in

iohnra r, s a be s otn noted, often so been has as are, Mitochondria “With mitochondrial activity you don’t look for look don’t you activity mitochondrial “With Is this a corollary function or is it a cause? Some Mitochond il yfnto udris ay of many underlies dysfunction rial ith molecules that can boost mito boost can that molecules ith

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High magnification electron microscopy images of sections of adipose (fat) cells, showing lipid droplets (in red) next to mitochondria (in green). Mitochondria burn the lipids stored in the droplets to generate usable energy. Cells with more mitochondria have a higher capacity for burning fat and generating energy.

a single cure, a magic bullet. It’s multifactorial, she an enormous benefit—say, a booster pill that may help says, which makes it difficult to put everyone in the those who, for a variety of reasons, do not benefit as same basket or to point to a simple cause. In terms of they should from exercise.” obesity, which has been very much in the news lately, There might be other benefits as well. For example, 15 Kralli, like nearly everyone else, puts part of the onus it’s known that mitochondrial function decreases with on the usual suspect—a general lack of exercise in the age, the reason diabetes is so often associated with ag- modern American lifestyle. ing. Neurodegenerative diseases, such as Parkinson’s NATASHA KRALLI NATASHA “I don’t think Europeans are necessarily better at and Alzheimer’s disease, are also associated with ag- sports per se but certain aspects of their lifestyle en- ing and with impaired mitochondrial function. courage daily physical activity,” she notes. “In Switzer- A DELICATE BALANCE land, we would often go to work biking or using public transportation, which meant walking twice a day two But it isn’t an easy or risk-free equation: “In the pro- to three blocks to catch the bus. Here in San Diego, cess of converting what we eat to ATP—the usable en- people get in their cars and drive door-to-door.” ergy—mitochondria produce free radicals that damage One can counteract decreased physical activity by cells. The big question is how to boost mitochondrial eating less, but of course that is not always easy. activity without increasing the associated damage. But that’s not all. Because, as Kralli points out, Ideally, you want to boost your defense mechanisms there are genetic components that render people sus- that deal with this damage, right along with increas- ceptible to obesity or diabetes. ing mitochondrial function. Science tells us that will “Exercise is one of the best ways to improve muscle be feasible.” mitochondrial function,” she says, “and there is no ques- So this is where it takes you, back towards an un- tion that exercise helps weight loss and general health. derstanding of so many things that lie below the sur- However, not all individuals respond to exercise the face of what at first seems so simple, deceptively so. same way. There are studies showing that the benefits of “I like working in a field where new knowledge exercise, in particularly the increase in oxidative ca- can translate to the treatment of human disease,” she pacity induced by endurance training, depend on ge- says. “A good drug not only has to target the right netic factors.” pathway to fix what’s broken, but also to spare other In other words, a person who is diabetic and obese pathways so as not to cause side effects. This is not might do the same exercise regimen as a healthy, lean trivial. Understanding the underlying intricacies of the person, and the healthy person might benefit more. system, all the little details that make it work, provides “We do not understand exactly what kinds of an essential basis for others, biotech or ‘big pharma,’ switches have been turned around inside the cells and to search for better drugs.” account for these differences,” she says. “Because our Is she ever just purely amazed by all those under- orphan receptors respond to exercise—their levels go lying intricacies? up—and have an impact on mitochondrial function, “Oh,” she says, her voice rising like effervescence, we believe they are part of the ‘control board.’ Finding “constantly.” ways to modify these regulator networks could provide ERIC SAUTER 1. Donors Kim and Barbara Doren, and Dan and LaJuan Fenn at the Frontiers inaugural lecture at the Estancia La Jolla Hotel and Spa, California. 2. Donors Gwen Marinos and Van Blackie Cooke at the second 1 2 California event in the series.

3. Nicky Lerner, M.D., Ph.D., wife of Scripps Research President Richard A. Lerner, M.D.; Richard M. Krasno, Ph.D., of The William R. Kenan, Jr. Charitable Trust; and his wife, Carin Krasno, at the first Frontiers lecture in Florida, held at the Kravis Center for Performing Arts in West Palm Beach. 4. Charles Weissmann, M.D., Ph.D. (left), professor and chairman of the Scripps Research Department of Infectology, and Professor A. Donny Strosberg, Ph.D. (right), who spoke on “Frontiers in Infectology” at an event held at The Lifelong Learning Society auditorium, Florida Atlantic University, Boca Raton. They are pictured with Paul Mauer, Ph.D., one of 3 4 the institute’s five founding scientists.

Behind the Scenes

16 NEW FRONTIERS FOR SCRIPPS RESEARCH

Those interested in attending future lectures What is the relationship between ozone and heart disease? How does a pioneering by Scripps Research scientists should new therapy save infants with a deadly lung disease? What are the hot topics in contact Ginny Deary, at (858) 784-9367 or infectious disease research? These are some of the questions that leading scientists [email protected] from The Scripps Research Institute are addressing for friends and supporters of the institute in a new bi-coastal lecture series, “Frontiers in Science.”

“Our goal is to provide our donors and the public with solid scientific information presented by world-class scientists,” says Denise M. Scalzo, vice president of BEHIND THE SCENES Development, “and to underline the importance and value of biomedical research in a changing world.”

The information-packed lectures, which feature scientists from both the Califor- nia and Florida campuses of Scripps Research, are followed by a reception, where participants can mingle and ask further questions of the researchers.

In the inaugural event in January, Professor Paul Wentworth, Ph.D., and Assis- tant Professor Jorge Nieva, M.D., shared their perspective on the inflammatory response, the body’s first-line defense against microbial pathogens. The inflammatory response may—according to a growing body of evidence—also play a cru- cial role in some of the most devastating afflictions of modern life, including heart disease, Alzheimer’s, and cancer. Studies by the Wentworth lab are suggesting a link between ozone produced by our own bodies during inflammation and toxic compounds in the blood, which Wentworth has dubbed “atheronals.”

In another lecture, Charles G. Cochrane, M.D., professor emeritus of immunology and one of the institute’s five founding scientists, spoke on his discovery having world-wide implications—the successful synthesis of pulmonary surfactant, a product which will save the lives of severely premature babies and extend the life of adults afflicted with acute respiratory distress syndrome, or lethal, active lung injury.

“The speakers were not only knowledgeable, but engaging and entertaining,” said Ruth Graul, who supports Scripps Research with her husband, Bill Graul. “Their presentation was very informative and their research can certainly make a difference in the lives of people.” “What’s important is the work these people are doing. They should have the glory.”

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