From Scripps: “BIOMEDICAL ADVANCES”

Scripps

Scripps Research Institute

December 2015

Scientists at The Scripps Research Institute (TSRI) pursue the quest to understand the fundamental processes of life and advance human health. Here is a small sampling of highlights of their findings from 2015.

1

A NEW APPROACH TO ALZHEIMER’S

Most people with Alzheimer’s disease have a smattering of brain cells with an abnormally high number of copies of a gene linked to the dangerous amyloid plaques, according to a new study. The research provides a completely new understanding of brain disease and could lead to new treatments and better diagnostics.

“Our findings open a new window into the normal and diseased brain by providing the first evidence that DNA variation in individual neurons could be related to brain function and Alzheimer’s disease,” said Jerold Chun, professor at TSRI and its Dorris Neuroscience Center, whose research was also supported in part by the Shaffer Family Foundation.

At Scripps Florida, while studying prion diseases that include “mad cow,” Professor Corinne Lasmésas discovered a killing mechanism that could underpin a range of intractable neurodegenerative diseases, including Alzheimer’s Parkinson’s and ALS.

PROJECT FIGHTS OSTEOPOROSIS WITH BONE-FORMING CELLS

The possibility of a broken hip can be a real concern – but researchers on TSRI’s Florida campus are bringing hope to those at risk. Their therapeutic approach, while still preliminary, could promote the development of new bone-forming cells in patients suffering from bone loss.

In basic lab tests, treatments with the compound (called SR2595) led to a significant increase in osteoblast formation, a cell type known to form bone. Interestingly, the protein targeted by this potential treatment is involved in many diseases, including diabetes.

“The next step is to perform an in-depth analysis of the drug’s efficacy in animal models of bone loss, aging, obesity and diabetes,” said Patrick Griffin, chair of the Department of Molecular Therapeutics.

FOUND: NEW TOOLS AGAINST HIV

A team at Scripps Florida has found a powerful anti-HIV agent that attacks all viral strains tested, including the hardest-to-stop variants.

“Our compound is the broadest and most potent entry inhibitor described so far,” said Professor Michael Farzan, who has won a grant from the Bill and Melinda Gates Foundation to continue his investigations. “This is the culmination of more than a decade’s worth of work on the biochemistry of how HIV enters cells.”

In other work, virologist Professor Susana Valente and colleagues showed a natural compound called Cortistatin A greatly reduces residual HIV in the body, potentially offering a “functional cure.”

On the California campus, Professors Dennis Burton, William Schief and David Nemazee designed an effective way to “prime” the immune system to fight off HIV that could become part of a series of anti-HIV vaccines and booster shots.

FINDINGS POINT TO ROOT CAUSE OF CYSTIC FIBROSIS – AND POTENTIAL NEW THERAPIES

Scientists uncovered a clue that could lead to new treatments for cystic fibrosis – a mutant protein present in most cases of the disease is so busy “talking” to the wrong cellular neighbors that it cannot function normally.

The team, supported in part by the National Institutes of Health and the Cystic Fibrosis Foundation, found a way to disrupt this unhelpful chatter, partially restoring the protein’s normal function under laboratory conditions. Therapies like this could one day treat the root cause of cystic fibrosis, not just the symptoms.

“The proteins and the interactions we’ve identified really fuel the pipeline for new drug targets to treat cystic fibrosis,” said Casimir Bamberger, a research associate in the lab of TSRI Professor John R. Yates and co-first author of the new study with TSRI Staff Scientist Sandra Pankow.

TEAM TAKES AIM AT AGE-RELATED DISEASES

A TSRI collaboration with the Mayo Clinic and other institutions identified a new class of drugs that dramatically slows the aging process in animal models. The drugs, dubbed “senolytics,” target senescent cells (cells that have stopped dividing) that accumulate and damage tissues as we age.

Animal models of aging showed improvements in heart function and osteoporosis after a single course of treatment.

“We view this study as a big, first step toward developing treatments that can be given safely to patients to extend healthspan or to treat age-related diseases and disorders,” said Professor Paul Robbins, who led the portion of the work at Scripps Florida with Associate Professor Laura Niedernhofer. Their labs are funded in part by the Glenn Foundation.

The Petrascheck lab also showed in worms that one antidepressant, mianserin, reduces transcriptonal drift and increases longevity.

BACTERIAL BUILDUP LINKED TO COLON CANCER

Scientists made a surprising link between bacterial “biofilms” in the colon and the development of life-threatening colon cancer. Their research suggests a vicious cycle in which cancerous changes in colon cells promote the growth of bacterial conglomerations called biofilms, and biofilms in turn promote cancer development.

The work, led by Professor Gary Siuzdak and supported in part by the California Institute for Regenerative Medicine (CIRM), suggests that removing biofilms could be a key strategy for preventing and treating colon cancers, which currently kill about 50,000 Americans per year.

In other cancer research, chemist Ben Shen, vice chair of the Department of Chemistry at Scripps Florida, demonstrated how a natural antibiotic adds sulfur atoms to its structure, boosting its tumor-fighting abilities.

CHEMISTS PRODUCE BRAIN-PROTECTING COMPOUND

Chemists devised an efficient way to create large quantities of a molecule with brain-protecting potential. The plant-derived molecule, called jiadifenolide, might be useful in conditions such as Alzheimer’s, stroke and traumatic brain injury.

Until now, chemists had found it difficult to synthesize useful amounts of the compound. “With our new method, someone could make the gram to kilogram quantities needed for tests in animals and humans,” said chemist Ryan A. Shenvi, whose work was funded by the National Science Foundation, as well as Amgen, Boehringer Ingelheim, the Baxter Foundation, Bristol-Myers Squibb, Eli Lilly, Novartis and the Sloan Foundation.

In other remarkable organic chemistry work, Phil Baran, the Darlene Shiley Chair of Chemistry at TSRI, discovered a broad and strikingly inexpensive method for synthesizing “amines,” organic compounds prominent in drugs and other modern products.

STEPS TOWARD A LIFE-LONG FLU VACCINE

Seasonal flu typically causes more than 200,000 hospitalizations and 36,000 deaths every year in the United States, according to the U.S. Centers for Disease Control and Prevention. While a yearly flu shot provides some protection, strains not covered by the vaccine can emerge rapidly.

Now scientists from TSRI and the Janssen Pharmaceutical Companies of Johnson & Johnson have found a way to induce the body to make rare but powerful antibodies that fight a wide range of influenza subtypes – work that could one day provide broader protection and eliminate the need for repeated seasonal flu shots.

“This was the proof of principle,” said Ian Wilson, Hansen Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology. “These tests showed that antibodies elicited against one influenza subtype could protect against a different subtype.”

RESEARCHERS TARGET MEMORIES TO PREVENT METH RELAPSE

Recovering addicts often grapple with the ghosts of their addiction – memories that tempt them to relapse even after rehabilitation and months of drug-free living. Now, scientists have made a discovery that brings them closer to a new therapy based on selectively erasing these dangerous and tenacious drug-associated memories.

The new research, led by Scripps Florida Associate Professor Courtney Miller, demonstrates the effectiveness of a single injection of an early drug candidate called blebbistatin in preventing relapse in animal models of methamphetamine addiction.

“We now have a viable target and by blocking that target, we can disrupt, and potentially erase, drug memories, leaving other memories intact,” said Miller. “The hope is that, when combined with traditional rehabilitation and abstinence therapies, we can reduce or eliminate relapse for meth users after a single treatment by taking away the power of an individual’s triggers.”

LEUKEMIA CELLS MADE TO KILL EACH OTHER

Researchers found a way to use antibodies to transform leukemia cells into leukemia-killing immune cells. The surprise finding could lead to a powerful new therapy for leukemia and possibly other cancers.

“It’s a totally new approach to cancer, and we’re working to test it in human patients as soon as possible,” said Richard A. Lerner, Institute Professor and the Lita Annenberg Hazen Professor of Immunochemistry at TSRI whose study was supported by the JPB Foundation and Zebra Biologics. “We’re in discussions with pharmaceutical companies to take this straight into humans after the appropriate preclinical toxicity studies.”

In other research related to leukemia, a study from the Reed lab showed that too much of a key protein, called cyclin E, slows down DNA replication and introduces potentially harmful cancer-linked mutations when cells divide.

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The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.