2011-06-23 / Top News

Five projects at Scripps Research Institute in Jupiter create buzz about potential breakthroughs


HARRY ORF, PH.D., has something he wants to say, but the vice president of scientific operations at Scripps Florida does not know how much he’s allowed to say about it.

“There’s something coming out,” he pauses, eyeglasses down, eyebrows up in emphasis, “But I’m not sure how much I can tell you.”

He exhales a, “Hmmm,” and turns to his computer. Click, click, click on his keyboard. “Well,” his shoulders drop down, he minimizes his screen. “There’s a breakthrough in the area of diagnostics that will be stunning,” he says, drawing out the “-ing” and the scope of everything such an adjective might mean, “Let me just leave it that general.”

This is the Scripps Research Institute — this is BIG — this could be Alzheimer’s big, Parkinson’s big, this could be cancer big, but Dr. Orf can only say ambiguous words about it, so he resorts to what he can say.

CLEVELAND CLEVELAND Scripps is the largest independent biomedical research facility in the nation. Awarded more than $80 million by the National Institutes of Health, Scripps was the first of four screening centers to channel this grant money into a clinical trial — one with the potential to halt the progression of multiple sclerosis.

Dr. Orf is quick to clear a misconception, “We are not a drug company,” says the Scripps professor of chemistry. “We make basic discoveries, we do not treat patients. But all the breakthrough discoveries made in medicine, all the treatments, all the new drugs, they don’t start in hospitals. It all starts here. This is where innovation begins.”

Beyond a nonprofit biomedical research facility, Scripps has earned national acclaim as a graduate school, the Kellogg School of Science and Technology ranking it 7th in the nation in biology, 4th in biochemistry, 3rd in organic chemistry and 7th in chemistry by the U. S. News and World Report. The white coats you see in the hallways are not scientists backed by Ph.D.’s, they’re undergraduates and high-school interns.

BOHN BOHN The ones in the Converse T-shirts and Adidas sneakers, the ones you might not make eye contact with at Publix, are the doctors studying worms to influence human lifespan, doctors discovering Hepatitis C inhibitors, doctors watching lifeless proteins evolve without DNA, doctors linking obesity to addiction, doctors who do get ideas in the shower and watch mindless television to make the science go away.

As Dr. Orf exhibits, the doctors are cautious in speaking about “breakthroughs.” “Is there anything I can potentially say about … ” again Dr. Orf cuts off and turns to his computer. He lets out a “bbbb …” breath over his lip. “Let me just see here.” Minutes, maybe seconds, feels like minutes. “Um, so I don’t know what I can say or not, just again, there’s a breakthrough in early disease diagnostics.” He crosses his legs and folds his hands in his lap, “That’s as specific as I can be at this point.”

KENNY KENNY This is Scripps. This is Jupiter. This is big. Here are five findings, findings involving cancer and addiction and robots, findings stunning enough for Dr. Orf to allude to, findings deserving of anticipation.

¦ Scripps news release: Scientists identify novel use for old compound in cancer treatment

Scripps scientists took an old drug off the shelf — a drug developed in the 1970s, abandoned in the ’80s — to find the drug may prevent the progression of prostate and colon cancer, maybe even neuroblastoma, a childhood cancer affecting the nervous system.

GILL GILL “We were able to prove in mice treated with the drug, the drug tripled their lifespan,” says John Cleveland, Ph.D., professor and chair of cancer biology. “It essentially cured them of cancer, because they never died from the cancer they were diagnosed to die from.”

The drug — difluoromethylornithine (DFMO) — works as an inhibitor of a metabolic enzyme, and in blocking the function of said enzyme, blocks tumor cell growth.

The Scripps study was published in a January 2009 issue of the journal Cancer Research. Clinical trials underway show DFMO has prevented the progression of colon and prostate cancer in 90 percent of participants who took it. “That’s better than tamoxifen, the gold standard of cancer drugs,” says Dr. Cleveland, adding DFMO patients took the drug for one year only and reported no side effects, implying DFMO to be a safe agent.

HODDER HODDER In circles of scientists who dedicate their entire lifetimes to the study to one enzyme, one protein, Dr. Cleveland has somewhere tangible to look and see how his studies are impacting human lives. “It’s in clinical trials right now. It’s actually happening,” says Dr. Cleveland, who attests cancer touches us all.

Dr. Cleveland’s nephew is a leukemia survivor. He lost his grandmother to the disease. He lost his mother to the disease two years ago. Yes, he finds his work satisfying, but he finds it frustrating. He can’t move faster. He can’t help but think the drugs he’s working on now may have prevented the progression of his mother’s disease.

Working at St. Jude’s Children’s Research Hospital, Dr. Cleveland ate lunch side-by-side with children who were given bleak diagnoses. “You would know some would make it, and some would not,” he says. “It really lights a fire under you to do something about it.”

Scientists work from this building at The Scripps Research Institute in Jupiter. 
COURTESY PHOTO Scientists work from this building at The Scripps Research Institute in Jupiter. COURTESY PHOTO Five empty water bottles sit on the windowsill behind him. An etching of mahimahi is carved on the glass. Most days Dr. Cleveland rides his bike to work, 14 miles round trip, keeping him tan and fit. He plays tennis, he kayaks, he snorkels, then he goes back to his laptop, because when it comes to a disease claiming more than half a million American lives each year, Dr. Cleveland says, “I don’t stop thinking about it.”

Dr. Cleveland has his sights set on new targets and cancer therapeutics. “You have to know how cancer cells have been able to resist a drug and how to take care of that problem.” In one of his current collaborations with a colleague, Dr. Cleveland says, “We’ve done that.”

When asked to describe the high of such success, strides the layman might deem inconceivable, there are no metaphors, no multisyllablistic words, the scientist simply says, “Yeah, it’s really fun.”

Besides DMFO, Dr. Cleveland has an anti-malarial drug in 15 clinical trials. Given in combination with conventional anti-cancer agents, chloroquine has been found to kill tumors otherwise resistant to therapy, including pancreatic cancer.

“I’ve been fortunate to be involved in these two studies, to have it happen,” Dr. Cleveland says. “It shows we can accelerate the pace, moving agents further into clinics, up to the point where pharmaceutical companies improve the drug-like properties and make it orally available. … Hopefully, there will be another.”

¦ Scripps news release: Team discovers plant has potent pain-killing properties

A chemist did not mean to find a plant as powerful as morphine, but at Scripps, chemists and pharmacologists eat lunch at the same table. When one sits by the other, they chat findings. Ergo, a compound derived from the bark of the crepe jasmine emerges as a painkiller, one as effective as morphine, showing fewer side effects, meaning maybe, no addiction.

“Let me tell you the story of it,” starts Laura Bohn, Ph.D., associate professor of molecular therapeutics and neuroscience. Chemist Glenn Micalizio, Ph.D., was creating chemical structures, spending a couple of years breaking down a particular synthesis strategy into nine steps. He stumbles upon a new compound. “For a chemist, this could be the end. They publish their work in a journal and move on to the next structure,” continues Dr. Bohn. “But we’re unique at Scripps. Pharmacologists and chemists work in the same building. We talk. We synergize. We can be more creative.”

Literature suggested other compounds taken from the crepe jasmine (Tabernaemontana divaricate) could be opioid in nature, but such suggestions were never proven. As a pharmacologist, studying morphine and drugs like morphine, Dr. Bohn would know if the compound was an opiate. She ran a number of assays. The compound — conolidine — was not an opiate.

Next step mice, standard pain tests similar to a bee sting in a paw. When given morphine, mice would not react to the sting. When given conolidine, the mice did not react. “This was very encouraging, to see conolidine produce the same amount of pain relief as morphine, that’s why we’re excited,” says Dr. Bohn, taking almost 15 minutes in explaining the science to a point where the non-science minded could appreciate her joy.

She can speak to the science endlessly, but when asked for emotion, not what the science means, but what the science means to her, “how did this finding make you feel,” another scientist answers in one syllable, “Oh, cool.”

“It keeps you going through the lull,” Dr. Bohn expands. “You have to divide the thrill from the research. You have to have another project on the side, one that you can look at and say, ‘Neat, neat, interesting.’ Twice now, the one on the side has been the really cool thing. Actually, three times.”

Conolidine was found to pass easily through the blood-brain barrier, still present four hours after injection. Dr. Bohn was surprised by the pain-relieving properties, “How could we have it so good?” Her studies were published May 23, in an advanced online edition of Nature Chemistry. Dr. Bohn cannot yet call the compound non-addictive. Animals must be given the choice to choose it. But tests measuring an animal’s running behavior have been promising.

When given morphine, animals run more. When given cocaine, animals run more. When given conolidine, animals ran as if they had been given nothing, implying no addiction.

Dr. Bohn now aims to figure out how the compound acts, what protein it targets, what receptor it hits. Pursuing more than 50 probable cellular targets, she has found what it doesn’t hit. She has never had this happen.

Ordinarily, she identifies the target, then improves the drug. This one’s backward, she has the drug, but no target.

She checks her email, nervous because she’s had three good things in a row. “Why couldn’t you wait another month,” she says to her piling good luck. “One, after another, after another, we’ll be dry for months and months and months.”

She sits at her desk wearing sandals, a scientist with toes exposed. Her white coat hangs on the back of her office door. She will work a little more on a paper she’s trying to get published, then she will go down to the lab, look at the data.

She loves to see the data at the end of each day, gives her a morsel to think about all evening. When it’s time to turn off her thoughts, she will turn on her TV, watch a half-hour of mindless television, so she can fall asleep.

“I don’t know what I’d be if I didn’t do this,” says the scientist. “I like problem solving. I like puzzles. I like that we have the chance to find truth. What we find is not just going to be some perception of reality, it’s actually going to be reality, I like that.”

¦ Scripps news release: Study shows compulsive eating shares addictive biochemical mechanism with cocaine, heroin abuse

Besides receiving the accolades of scientific journals, Paul Kenny, Ph.D., made the Colbert Report on Comedy Central for his study showing the same molecular mechanisms driving people to drug addiction steer the compulsion to overeat, making an addiction an addiction, whether it’s cocaine or cupcakes.

Rats binged on junk food — bacon, sausage, pound cake, cheesecake, Hostess Ding Dongs, candy bars, food served in cafeterias — even when the rats knew their fatty “fix” came at the cost of an electric shock, they didn’t care, they ate.

As the rats grew more and more obese, the pleasure centers in their brains became less and less responsive. They constantly required the “pleasure,” the stimulation of the food, to avoid the “crash.”

When the junk food was cut off and “salad bar” served, the rats refused to eat, literally starving themselves for two weeks. “Food is not as innocuous as it may seem,” says Dr. Kenny, associate professor of behavioral and molecular neuroscience, his study published in Nature Neuroscience in March 2010.

The scientist from Dublin sees the social reach of his study in the “golden arches” on every corner of every street. “McDonalds, supermarkets have very tasty, very cheap food,” Dr. Kenny says. “Low budget families eat what they can, they buy what they can, and that can be very, very dangerous.”

Dr. Kenny describes how food does not change your genes, but it does genetically alter how your genes work. “This can transfer to your progeny. It’s stunning and it’s scary, and it’s just the tip of the iceberg in our obesity epidemic.”

Two dry-erase boards shape an L in the corner of his office, numbers crowding symbols in green, red, black and blue, though most of his more forward-moving insights present themselves when he puts down the marker. “The absolute best place is in the shower, it always clicks there.”

Dr. Kenny investigates the connection between molecular biology and complex questions, the bridge between, “How do I feel?” and “What do I do?” He studies depression, schizophrenia and addiction. And yes, during the clammy palms and turbulence of an airplane, he’s thought of his research on anxiety, telling himself, “There goes my amygdala being activated.”

“Sounds very nerdy,” says the scientist, in an Irish accent, who has model good looks. He knows overeating fatty foods changes how his brain works, he has seen the brain flooded by dopamine, receptors overstimulated. Sometimes he thinks about this when he eats, but jokes it’s too late for him, his brain already damaged by unhealthy food. He thinks of more when he feeds his two children.

To think of all the headlines heralding his three years dedicated to rats and addiction and obesity, he is incredibly gratified, but typically headlines make him nervous. He has seen headlines oversell findings, and he has seen the public lose faith. “Sometimes, good science, you don’t publish immediately. You sit back and understand it, understand what it means. You develop the story, so it has greater impact,” says Dr. Kenny, leaving one to wonder, what will come out of his lab next?

¦ Scripps news release: Scientist identifies new pathway affecting lifespan

His colleagues say he’s the best thing to come out of Manchester since Joe Cocker — Matthew Gill, Ph.D. — the man who works with worms.

When people hear worms, they find it odd, many asking Dr. Gill, “Whatever could you find that’s useful from a worm?” Published in Nature on May 12, Dr. Gill found a group of molecules in nematodes, molecules never identified in these worms before. He found that the lower the levels of these molecules, the longer the lifespan of the worms.

“We were able to see something somebody has not seen before,” says Dr. Gill, associate professor of metabolism and aging. “We were able to detect molecules in worms, and we were the first to assign any function to these molecules.”

In this function, lies the gravity of the study. These molecules, N-acylethanolamines (NAEs), signal nutrient availability, ultimately influencing lifespan. By feeding the worms less, by watering down their worm food, scientists were nearly doubling the worm’s lifespan. Worms that typically live 20 days, were on the cusp of 40.

These molecules, these NAEs, are not just present in nematodes (Caenorhabditis elegans), they’re present in humans.

“It’s not about trying to live to be 150 or 200 years old,” Dr. Gill says. “It’s really about finding ways to combat age-related diseases. Parkinson’s, Alzheimer’s, cancer, the incidence of these diseases increase as we get older. If we can understand aging, we can simultaneously learn how to prevent the onset of these diseases.”

While a fundamental discovery, Dr. Gill defines his study as a basic discovery. But even in his modesty, you can nearly hear the wheels turning between his sideburns, as if the scientist were saying, “If we can understand the molecular mechanisms, the biological pathways in worms, we can translate the effects of dietary restriction to a drug, effecting human health and aging without having to stop eating.”

At any given time, Dr. Gill could have several hundred thousand worms in his laboratory, each barely the size of a fingernail shaving. These worms are transparent. Under a microscope, you can see eggs in their hermaphrodite bodies, you can see muscles move food through their intestines. “We know crazy things,” says Dr. Gill, who knows all 959 cells of a nematode, knows where all cell divisions take place, where every cell made will go, what every cell made will become.

Each worm can lay 300 eggs, and in the course of three days, baby nematodes have matured into adults. Dr. Gill grows worms as he needs them, though he sometimes waits for a particular strain to come in the mail, centimeter-sized nematodes stuck to the bacteria solution of a petri dish and shipped through the general post.

Day-to-day, Dr. Gill must make sure his worms are fed and make sure their population does not grow out of control. His little girl attests to his dedication to his lab: when she hears of other grownups working, the 4-year-old asks, “Do you work with worms or flies?”

Working with lifespan, Dr. Gill says sometimes his science is no more sophisticated than poking a worm, “If it moves, it’s alive. If it doesn’t, it’s dead.” The world of worms can be insular, hence Dr. Gill’s attraction to Scripps. He sees a production line of discovery in his corridor, moving from flies to worms to fish to mice.

“As scientists, we each need our own personal conviction, to know what it is you’re doing and why it’s important,” Dr. Gill says. “I work with worms to improve human health.”

¦ Scripps news release: New treatment halts multiple sclerosis

Scripps scientists can stop multiple sclerosis in mice. Scientists cannot yet call it a cure, but they can stop the progression of the autoimmune disease.

Led by Tom Burris, Ph.D., professor of molecular therapeutics, scientists developed a compound to shut down a particular white blood cell. Blocking the blood cell’s signals, MS symptoms disappear.

Current treatments for MS suppress the entire immune system, tricking the body into attacking itself. The new compound solely attacks white blood cell TH17, sparing other disease-killing cells. The study ran in an April issue of Nature. Behind this science is a robot, and behind the robot is Peter Hodder, Ph.D., senior director and head of lead identification of the translational research institute. Dr. Hodder pulls up a PowerPointlike slide to illustrate the path of drug discovery.

First circle, “Discovery Biology,” identify the target for drug discovery. Arrow down to, “Lead Identification,” identify drug-like leads for the target through High Throughput Screening (HTS). Arrow over to “Medicinal Chemistry,” improve pharmacologic properties of leads. Arrow ultimately arcs through animal testing, to clinical trials.

Dr. Hodder clicks through his 13-page presentation, illuminating how robotics, biology and chemistry combine to discover new drugs, but when asked to elaborate on how discovery feels when arrows may point to the cure for MS, he halts, “I know what you’re trying to get at. I’m not very much for talking about my emotions.” Then, the scientist turns his emotion to fact, “It’s why I’m here.”

He may not think he’s good at emotion, but he’s good at metaphors, giving a tour through his lab, where he screens roughly 40 campaigns against millions of compounds each year. He compares one device to acupuncture needles, dipping tiny bits of compound into an assay plate with 1,536 wells, much more efficient than a hand pipette. He compares a camera to the Hubble telescope, picking up the faint lights of data that cells exude when they’re still alive and happy. A cell dispenser to an inkjet printer, dispensing living cells like droplets of ink.

Then, the robot platform. The robot has no name, but looks like the yellow arm of an automobile assembly line. Dr. Hodder says the robot communicates to peripheral machines, as if they say to one another, “Please put a plate on me. OK. Don’t touch me now. OK. Please pick me up. OK. Thank you.”

The robot tests activity against a library of 625,000 compounds, the largest drug-discovery HTS library in academia. Shelves of compounds behind a glass front, the vault looks like a jukebox full of blank CDs, where essentially, scientists put in their dollar, and pray it plays that one song, that one Willie Nelson ditty.

Dr. Hodder laughs. Thinks back to how just one discovery feels, and says what he said to some robotics engineers in his lab, “Well, now you can say, when you’re up there in front of St. Peter, you can be like, ‘OK, there may be some bad things, but I actually did something really good here, something good for health.’”

Saints are at the gates in Jupiter. And the gates are at Scripps. ¦

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