Fall 2009

The Brain Institute :: Thinking Beyond the Box :: Cancer Breakthroughs

THE MAGAZINE OF THE MOUNT SINAI MEDICAL CENTER

MOUNT MOUNT SINAISINAISCIENCE & MEDICINESCIENCE & MEDICINE

16 Mount Sinai Science & Medicine

What makes an addict?

Dr. Yasmin Hurd has some surprising answers.

Addiction Margaret W. Crane

THE BRAIN

FALL 2009 17

Genetics + Developmental exposure to marijuana + Molecular receptivity = Addiction

‘‘There’s a huge debate going on about the legislation of marijuana use in the United States,” says Dr. Yasmin Hurd, Director of the Center of Excellence in Mood and Motivation Disorders at Mount Sinai’s Brain Institute. “Many people consider marijuana a ‘nice little drug’ that is safe for recreational use, while others see it as the main gateway to heavier drugs, like heroin and methamphetamines.

“At the Brain Institute, we’re approaching the question a little differently.”

For years, Dr. Hurd has been studying the genetic, developmental, and environmental factors that put people at risk for drug addiction. A scientist with

a mission, she and her interdisciplinary team are uncovering neurobiological changes that take place when a person is fi rst exposed to a drug and at later points as addiction takes hold.

Adolescent vulnerabilityAt a neurobiological level, according to Dr. Hurd, two major conditions are necessary—though not necessarily suffi cient—for a person to become an addict:

> Genetic mutations predisposing someone to addictive forms of behavior

> Exposure to environmental insults such as psychoactive drugs during the prenatal or adolescent period of development.

These factors loom large in Dr. Hurd’s work. Her recent research into the effects of marijuana provides a vivid illustration of how the addiction process works.

Dr. Hurd and her interdisciplinary team across Mount Sinai are looking at the relationship between marijuana and what she calls “the neurobiological gateway” to addiction: They are tracking the actual molecular processes that play out in the brains of genetically vulnerable teens during and after exposure to marijuana.

“We need to be clear: addiction is a true mental disorder,” says Dr. Hurd. “While marijuana appears to be safe in adults, it wreaks havoc in the developing brain.” She points to a 25-year prospective study carried out in New Zealand, indicating that early exposure to the drug, when combined with a genetic abnormality, notably increased a child’s risk of developing a serious mental illness later in life.

Formula for risk Genetics + developmental exposure

to marijuana + molecular receptivity = addiction.

This, then, is the working formula that underpins Dr. Hurd’s visionary research. In deepening our understanding of who is at risk for an addiction disorder, the Hurd lab

is simultaneously reshaping the debate on marijuana legalization at a time of rapid policy change. What’s at stake, she believes, is no less than the health of the next generation.

“Simply put,” she says, “we need to use science-based evidence to improve mental health care for those affl icted with addiction disorders.”

Early exposure to marijuana notably

increased a child’s risk of developing a

serious mental illness later in life.

18 Mount Sinai Science & Medicine

The Brain Institute:

New VisionMargaret W. Crane

Dr. Eric Nestler has a scaled-up, collaborative

model for neuroscience research.

THE BRAIN

Mount Sinai Science & Medicine18

FALL 2009 19

Dr. Eric Nestler has a dual role—as Director of the Brain Institute and Nash Family Professor of Neuroscience—and he makes it all sound easy. Gather enough talent and resources and put them to work in the right research environment, he says, and you’ll get results—big results in the form of diagnostics, treatments, and cures for diseases of the brain and spinal cord.

But Dr. Nestler left out one vital ingredient: himself. He’s the exceptional leader who is galvanizing neuroscience talent and resources across Mount Sinai and infusing the Brain Institute with all the elements it needs to succeed.

“What we’re building here is no less than the best neuroscience research institute in the world,” says Dr. Nestler.

Found in TranslationIn recent years, the entire relationship between basic and clinical research has been redefi ned to allow for the rapid translation of scientifi c discoveries from the laboratory to the patient’s bedside. But the path of translational research is anything but linear.

In the case of neurodegenerative diseases such as Alzheimer’s and Parkinson’s, one researcher might look at complicit genes and molecular pathways in mice whil e another might focus on how the disease affects the individual neuron, and yet another might analyze how circuits of nerve cells function in healthy versus disease-stricken animals.

With translational research at the core of its mission, the Brain Institute will rapidly channel basic research fi ndings toward the clinical testing of new diagnostics and drug candidates. In turn, clinical researchers strive to bring new diagnostics and treatments into routine clinical practice, but along the way they often make discoveries that double back into basic research. Thus, translational research is actually a complex series of feedback loops, with the lines between basic and clinical research becoming less and less distinct.

Personal VisionDr. Nestler’s vision for Mount Sinai’s fl edgling Brain Institute is all about tomorrow’s personalized medicine.

“Today,” he says, “if we suspect a relative has Alzheimer’s disease, the process begins with a visit to our family doctor or geriatrician. Our doctor may have strong reasons for making a diagnosis of Alzheimer’s, frontotemporal dementia (FTD), or another disease that affects cognition, but there’s no way to confi rm that diagnosis, much less tailor the treatment to our relative’s precise condition.

“Soon—I have no doubt—we will develop tests that will allow us to distinguish between many diseases and their subtypes,” he explains. “That’s when the era of truly personalized medicine will begin, and the Brain Institute is uniquely equipped to get us there.”

What we’re building here is no less than the

best neuroscience research institute in the world.

20 Mount Sinai Science & Medicine

Myelin, an insulating membrane that allows nerve impulses to travel throughout the body quickly and effi ciently, isn’t something you tend to notice—until it’s gone.

This protective sheath can become damaged in young adults with diseases such as multiple sclerosis. Not all myelin disorders begin in adulthood; some infants are unable to form myelin, and this leads to early onset of neurological defi cits comparable to those seen in adults.

For decades, myelin disorders ranked among the most impenetrable of conditions, and among the most diffi cult to treat. Now, stem-cell research and advanced biomedical technologies are speeding the pace of progress.

Dr. Patrizia Casaccia

offers new hope for

repair in myelin

disorders.

Repair Replace, Cure

Margaret W. Crane

THE BRAIN

FALL 2009 21

Dr. Patrizia Casaccia, Chief of the Center of Excellence in Myelin Disorders: Mechanisms and Repair at Mount Sinai’s Brain Institute, has been mounting an interdisciplinary effort to understand how neurons can be protected in multiple sclerosis and how cells can repair their own myelin when it’s damaged or improperly formed. A neurologist with expertise in molecular and cell biology, Dr. Casaccia has one overriding concern: to help and heal people with myelin disorders through science.

Myelin lost—and regainedThe symptoms of myelin loss or damage—called demyelination—depend on the specifi c nature of

the affected nerve cell. If the neuron handles motor information, demyelination will lead to a loss of motor control that tends to worsen over time. If demyelination occurs along a sensory pathway, it can cause tingling, pain, numbness, or a combination of the three. The disease process may affect a cognitive neuronal circuit, with deeply distressing symptoms such as memory loss, speech impairment, and diffi culties processing information.

According to Dr. Casaccia, there are two possible ways to regain lost myelin:

> Foster its regrowth and repair by stimulating the cells that are still there; or

> Replace lost myelin via stem-cell-based therapy and related technologies.

The Casaccia lab has been emphasizing repair-oriented research, identifying and testing pharmacological compounds capable of generating new myelin production. Dr. Casaccia is also directing a complementary research effort on the damage and repair to the axon, which is the portion of a neuron conducting electrical impulses.

Hope through stem cells In some patients, the myelin along particular circuits of neurons has been completely destroyed. Is there is hope for people affl icted with such severe myelin loss? Recent strides in stem-cell therapy promise to replace myelin from scratch. “Stem cells can now be created from a little piece of skin. In collaboration with the Black Family Stem Cell Institute and the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai, we shall implement this ‘tailored’ stem cell technology for repairing damaged myelin and nerves,” Dr. Casaccia says.

“We’re currently working towards methods to direct these skin-derived stem cells to choose the ‘right’ path so that they become myelin-forming cells or new neurons.

“It is the collaborative spirit at Mount Sinai that allows the integration of basic science with the Neuroimaging group, the expert clinical team at the Corinne Goldsmith Dickinson Center for Multiple Sclerosis and the Neuropsychology group. The development of interdisciplinary areas of research, the availability of resources such as patients’ samples deposited at the Biobank, and bioactive compounds that are newly synthesized by chemical engineers at the Institute for Experimental Therapeutics are tangible proofs of the current effort towards the development of new therapies to cure demyelinating disorders.”

Recent strides in stem-cell therapy

promise to replace myelin from scratch.

IA

O F T H EG R A P E

NI S EP R

Margaret W. Crane

22 Mount Sinai Science & Medicine

THE BRAIN

FALL 2009 23

E rnest Hemingway considered wine to be the most civilized thing in the world. In recent years, we’ve learned it can also be one of the healthiest—especially if it’s made from red grapes and consumed in moderation.

Studies show that a daily glass of red wine improves cardiovascular health, eases stress, and even cuts the risk of developing some types of cancer. The positive effects of red wine on memory and cognition also have been reported widely in the pages of leading scientifi c journals, such as the British Journal of Medicine, The Lancet and Science.

For Dr. Giulio Pasinetti, a Mount Sinai neuroscientist at the forefront of Alzheimer’s research, the question is: Why? What component of the grape acts to prevent our brain cells from deteriorating? What, exactly, is in that glass of red?

Dr. Pasinetti heads up the Center of Excellence for Research in Complementary and Alternative Medicine in Alzheimer’s Disease, one of the Mount

Sinai Brain Institute’s nine multidisciplinary centers focused on translational research. He is championing the science that will, it is hoped, unleash the power of grapes—and other natural substances—to prevent, treat, and even cure Alzheimer’s, the dementia-causing disease that affl icts approximately 18 million people worldwide.

An epidemic waiting to happenOver the next 30 to 40 years, our society is expected to undergo a huge demographic change.

“It used to be easy to depict the U.S. population by age as a pyramid, with large numbers of young people on the bottom and a tiny group of the very old at the top,” says Dr. Pasinetti. “By the year 2050, however, we’ll have approximately 23 million nonagenarians and centenarians, compared with fewer than 5 million today. We’ll also have about 23 million teenagers. That means the age pyramid will look more like a four-sided box.”

A visionary neuroscientist probes

the ability of natural substances

to curb Alzheimer’s disease

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24 Mount Sinai Science & Medicine

While good health will be a factor in prolonging so many lives, age itself will still make the elderly vulnerable to a range of health problems.

“Age is a major risk factor for neurodegenerative disorders,” he continues, “so the anticipated demographic shift could be seen as an epidemic waiting to happen.”

Lifestyle changes alone—a healthy diet, regular exercise, and that daily glass of wine—can go far toward reducing a person’s risk of developing a neurodegenerative disease. But a more aggressive preventive strategy will be needed to curtail these diseases in skyrocketing numbers of elderly people.

Polyphenols: the natural solution?

Preventing cognitive disorders at a population level, then, is both the overarching goal and the day-to-day agenda of the Pasinetti lab, where a dedicated team has been studying polyphenols: the plant compounds most closely associated with the protective effects of a daily glass of Cabernet or Pinot Noir.

The process that governs complementary biomedical research is not unlike conventional pharmaceutical R&D. It’s about identifying promising molecular candidates, testing them rigorously, and, ultimately, using them to develop new treatments. But here’s the difference: Compared to conventional drugs, remedies based on the active component of a natural substance promise to be far safer, less toxic, easier to study, and easier for patients to tolerate, even over long periods.

Polyphenols: the natural solution?

Grape seed–derived polyphenolic extracts (GSPE), discovered in the Pasinetti lab, sailed through preclinical testing, during which they were seen to prevent the formation of beta-amyloid plaques—a leading suspected cause of Alzheimer’s disease. GSPE is currently in a Phase II clinical trial, in which clinical investigators are assessing its effi cacy in preventing Alzheimer’s.

The next step will be to study the effects of GSPE when cognitive deterioration is already advanced. That, says Dr. Pasinetti, would extend its potential reach beyond prevention into the realm of treatment.

Longer term, Dr. Pasinetti will bring his time, talent, resources, and creativity to the task of unveiling the underlying links among obesity, hypertension, diabetes, and neurodegenerative disease.

Worth a toast, we’d say.