Christine

circadian rhythm

Scripps Research Scientists Identify New Mechanism Regulating Daily Biological Rhythms

(What goes around, comes around, and, in fact, its cycles are regulated…)

In a study published November 12 in the Journal of Biological Chemistry, scientists from the Jupiter campus of The Scripps Research Institute announced that they have identified a mechanism that regulates circadian rhythm, the master clock that controls the body’s natural 24-hour cycle. These new findings may help scientists in their search for treatments for sleep disorders, diabetes, obesity as well as some types of cancer.

“It’s well known that the “nuclear receptors” RORα and REV-ERBα, regulate expression of the gene, BMAL1, which is vital to virtually every aspect of human physiology and a core component of the circadian clock,” said Tom Burris, a professor in the Department of Molecular Therapeutics at Scripps Florida who led the study. But, he added, scientists did not how…

By way of explanation, nuclear receptors are proteins that recognize and regulate genes. They have “ports,” so to speak, that scientists can either block or send a protein to bind with, for a desired effect. As a result, the receptors control an organism’s metabolism by activating gene expression.

Gene expression is the scientific term used to describe the process where the information contained in DNA is transcribed into Messenger DNA (MRNA), and then is translated into the proteins necessary to perform critical cell functions. (DNA copies itself backwards into RNA. That process is called transcription. If a gene is not transcribed, it just sits in the cell inactive).

Now, back to the study. Here’s what the Scripps study found: The variations of the distribution of the proteins RORα and REV-ERBα not only regulate the activation of BMAL1, but also of the protein, NPAS2.

And, the scientists asked, since the expression of RORα and REV-ERBα follows a 24-hour circadian pattern, with opposing phases, and leads to the correct circadian pattern of gene expression of BMAL1 and NPAS2, what is the mechanism that governs that?

“We think it’s something of a competition between these two receptors for binding to promoters (proteins that allow expression) of these genes that triggers either the activation (RORα) or repression (REV-ERBα) of the gene,” Burris said.

Learning more about this process is important, because disorders linked to dysfunctional circadian rhythms can be severe and potentially deadly.

“When you’re dealing with circadian rhythm, the most obvious disease target is sleep – for people who do shift work, critical jobs like police work, fire fighting, and medicine,” he said. “If circadian rhythm is disrupted, you’re prone to metabolic disorders like diabetes and obesity and even breast cancer – because the core clock is closely linked to the cell cycle. If your clock goes awry, you run the risk of your cell cycle going awry as well.”

Nuclear receptors have been implicated in a number of cancers, including prostate, breast, and colon cancers, and other diseases as well, including type 2 diabetes, atherosclerosis, and metabolic syndrome.

In addition, nuclear-receptor proteins can be influenced by specific drugs, and so they can be activated by compounds such as the sex hormones, vitamins A and D, and glucocorticoids, which modulate the body’s response to stress. Actually, Scripps scientists have already identified several new drug-like molecules that can influence both of these receptor proteins.

As more is understood about the relationship between these receptors and their gene targets, researchers can consider the possibility of modulating the body’s core clock.

The first author of the study, “Characterization of the Core Mammalian Clock Component, NPAS2, as a REV-­ERBα/RORα Target Gene,” is Christine Crumbley of The Scripps Research Institute. Others authors include Yongjun Wang and Douglas J. Kojetin, also of Scripps Research. For more information, see http://www.jbc.org/content/285/46/35386.abstract

This work was funded by the National Institutes of Health.

The Scripps Research Institute, a large independent, non-profit biomedical research organization, is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular and infectious diseases, and synthetic vaccine development.

Headquartered in La Jolla, California, the institute also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter.

Christine

grease the skids, clinical trials unedited

Late October, at BioFlorida’s 13th annual conference, co-host FLCURED organized a presentation, “Greasing the Skids For Clinical Trials; Making Florida a leader in New Medical Treatments given by Dr Edith Perez, deputy director of Mayo Clinic Cancer Center; Terre McJoynt, director of Mayo Clinic Cancer Center; and Dr. Steven Ryder, president of Astellas Pharma Global Development.

Florida could potentially be a lab for clinical trials said both Russell Allen, president and CEO of BioFlorida and Mike Devine, director of FLCURED.

As part of the overall presentation, Dr. Perez spoke on “A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the National Cancer Institute’s Cooperative Group Program.”

The clinical trial component is essential to translate new knowledge into tangible results that will benefit patients with cancer,” she said.

For the past 50 years, the National Cancer Institute’s (NCI) Clinical Trials Cooperative Group Program with its Ten Cooperative Groups, which includes doctors, researchers and cancer centers, has conducted trials through networks of cancer centers and community oncology practices across the country. More than 25,000 patients and thousands of clinical investigators participate annually.

In recent years, however, “Stakeholders (people and entities that take an active roll in the clinical trials) have expressed concerns that the program is falling short of its potential to conduct timely, innovative large-scale clinical trials,” Perez said, so NCI asked the National Academy of Sciences’ Institute of Medicine to review the program.

Four goals to guide improvement were identified:
Improve the speed and efficiency of the design, launch and conduct of clinical trials.
Make optimal use of scientific innovations.
Improve selection, prioritization, support and completion of clinical trials
Foster expanded participation of both patients and physicians.

The average time required to design, improve and activate a cancer clinical trial is two years. That’s too long, since a trial concept could become outdated during that time, she said.

To improve that, the committee she served on recommended that protocol development be streamlined, coordinated and consolidated (A Clinical Trial Protocol is a document that describes the objectives, design, methodology, statistical considerations, and organization of a clinical trial).

“Processes should be streamlined for prioritizing, selecting and supporting clinical trails and for enrolling patients quickly after the trial is launched,” Perez said.

In addition, only well designed clinical trails that have the greatest possibility of improving survival and quality of life for cancer patients should be undertaken.

“A robust trial depends on the mass of physicians and patients willing to participate, but participation is not the norm,” she said.

To remedy that, clinicians should be supported and encouraged. For patients, since care costs in clinical trials by health insurers are inconsistent, consistent payment policies should be established.

“Building a Protocol Expressway: the Case of Mayo Clinic Cancer Center” was the title of Terre McJoynt’s presentation. She is the director of research operations at Mayo Clinic Cancer Center, Jacksonville.

This documented the review and revision of clinical trial protocols that was done by a team of experts from Mayo Clinic, including protocol development staff and management from three Mayo Clinic campuses, a systems and procedures analyst, a quality office analyst and two physicians.

The aim was to decrease the amount of time it takes when developing the protocol to get it to submission to an approving authority, such as the National Cancer Institute or Institutional Review Board (IRB).

“We worked on removing the inconsistencies, redundancies and errors resulting from nonstandard processes, which extended the time to get clinical trials to our patients who were waiting for them,” she said.

To study the process, they defined the problem, measured and analyzed tasks, and then made improvements. The project is now in the control phase.

“We wanted to reduce the time it took to move the new ideas through the system, without neglecting quality,” she said.

Time frames for internally authored protocols were reduced to ten weeks from 25 weeks. Externally authored protocols went from 20.61 weeks to 7.79 weeks.

Some asides here: Mayo Clinic is involved in 200 new clinical trials and oversees 1,800 trials in progress yearly.

It is reported to cost approximately $1 billion dollars for pharmaceutical companies to bring an idea to market for a new drug. A one-day delay in the development of a clinical trial for a drug that ultimately becomes successful, costs the pharmaceutical company between $800,000 and $5.4 million.

Steve Ryder, president of Astellas Parma Global presented “Clinical Trial Conduct: Issues, Challenges, and Opportunities.”

Some points he made:
At Astellas Parma Global Development, patient accrual has declined over the last ten years from 2 patients per site a month to .5 patients
3-8 percent of eligible patients in the U.S. participate in clinical trials
Oncology trials: 3-4 percent of eligible patients participate
At Astellas Parma Global Development, approximately half of oncology sites fail to enroll or complete a single study subject

He then gave an example of a successful clinical trial his company conducted with Moffitt Research Institute, a study of YN155 plus Decetaxel in subjects with Stage III Melanoma, sponsored by Astellas Pharma.

The contract process was kept at three months from the initial final signed contract.
The Institutional Review Board (IRB) approval process took 3 months from the initial to final IRB approval, despite multiple committees and one key revision that were closely managed, he said.

Enrollment exceeded expectations, because:
They used clinically sound and appropriate inclusion/ exclusion criteria, which were collaboratively selected by sponsor and primary investigators
There were no competing studies at the time of enrollment
They took strong collaborative efforts with active surveillance for appropriate melanoma patients, and
Because of the site location and reputation.