UCSF researchers have genetically encoded mouse cells to respond to light, creating cells that can be trained to follow a light beam or stop on command like microscopic robots.

This is the first time researchers have been able to import a light controlled “on-off switch” from plants into a mammalian cell to instantly control a variety of cell functions, the researchers said. As such, it offers both a powerful new tool in cancer and cardiovascular research, as well as the potential to ultimately control complex processes such as nerve growth.

The findings appear in the September 13 advanced online publication of the journal Nature and are available at http://www.nature.com. They are reported alongside a paper on similar research led by Klaus Hahn, Ph.D., and his colleagues at the University of North Carolina, Chapel Hill.

Together, the papers are the first to demonstrate that plant light-switches can be imported into mammalian cells to control complex regulatory processes. The UCSF research is unique in developing a generic plug-and-play switch, based on protein recruitment, which can be wired to control diverse processes in many types of cells and organisms, the researchers said.

The findings could have various therapeutic applications down the road, such as the ability to guide nerve cells to reconnect across a broken spinal pathway in a spinal cord injury, according to Wendell Lim, PhD, one of three senior authors on the paper and the director of the Cell Propulsion Laboratory, a National Institutes of Health Nanomedicine Development Center at UCSF and UC Berkeley.

More immediately, the findings offer a new approach for scientific research into the complex regulatory processes involved in diseases like cancer and inflammation, he said.

“This is a powerful tool for cell biology and cancer research,” said Lim, who is a professor in the UCSF Department of Cellular and Molecular Pharmacology. “If you have a controllable ‘light switch’ that is generic enough to use in multiple cell functions, it gives you the ability to control where and when a cell moves, using a simple beam of light, and control what it does when it gets there.”

Many cell processes are governed by where and when proteins appear in the cell, Lim explained. When those processes are based on an extremely complex network of signals, such as in diseases like cancer, he added, it’s helpful to have an on-off switch to insert into that process.

The research was carried out by Anselm Levskaya, a graduate student in both Lim’s laboratory and in the laboratory of Chris Voigt, PhD, a synthetic biologist and assistant professor of pharmaceutical chemistry in the UCSF School of Pharmacy who was also a senior author on the paper.

Levskaya initially looked to plants for proteins that might serve as the light sensor. Plants are known to rely upon phytochromes, or light-sensing signaling proteins, to control a variety of processes, such as a plant’s growth toward sunlight and seed germination.

He proposed that these phytochromes could be genetically engineered into mammalian cells and tied to a specific function, in this case, cell movement.

Levskaya identified a pair of interacting proteins from plants, known as the PhyB-PIF interaction, that could be turned on and off like a switch, and then imported that cellular signaling system into live mouse cells in a cellular pathway that controls cell motion. The resulting cells can be pulled by an external beam of dilute red light, or pushed away by an external infrared beam.

“We’ve been able to use similar light sensors to program bacteria and yeast cells to follow a chain of if-then commands,” Voigt said. “What’s remarkable here is the ability to, first, do this in mammalian cells, and secondly, find a method to turn them off again after they’ve performed the function we selected.”

The reversible aspect of Levskaya’s work is significant, Voigt said. While many methods are aimed at disrupting cellular pathways, most are fairly simple and only work in one direction: they shut a process down, or prevent two proteins from interacting, but they are limited to that one action.

This approach, by contrast, enables researchers to control precisely when the disruption occurs and for how long, then stop it at will.

The work involved a collaboration between three UCSF laboratories: the Voigt Laboratory, which uses synthetic biology to create light switches and sensors in bacteria; the Lim Lab, which studies how complex networks of signaling proteins cause cells to move, grow and differentiate; and the Weiner Lab, led by Orion Weiner, PhD, which uses microscopy to study guided cell movement.

All three labs are affiliated with the National Institutes of Health Nanomedicine Development Center at UCSF, known as the Cell Propulsion Laboratory, whose goal is to engineer “smart cells” that are programmed to carry out novel therapeutic functions in cancer and regenerative medicine. The labs are also affiliated with the California Institute for Quantitative Biosciences (QB3) at UCSF.

Levskaya is studying in the UCSF Graduate Program in Biophysics and in the Department of Pharmaceutical Chemistry, in the UCSF School of Pharmacy. Voigt is a faculty member of the Department of Pharmaceutical Chemistry. Weiner is in the UCSF Cardiovascular Research Institute. Lim is a member of the Department of Cellular and Molecular Pharmacology, and the Howard Hughes Medical Institute.

Source:
Kristen Bole

University of California - San Francisco

Johns Hopkins’ Center for the Epigenetics of Common Human Disease has been chosen as one of four recipients of a $45 million National Institutes of Health (NIH) grant for Centers of Excellence to advance genomics research. The Hopkins Center will receive $16.8 million over five years.

“We’re grateful for such generous support to continue our work in understanding how epigenetic control affects disease,” says the center’s director, Andrew Feinberg, M.D., M.P.H.

Over the past five years, Feinberg, professor of molecular medicine at the Johns Hopkins University School of Medicine, has led a team of researchers at the center to study the epigenetic basis of common health problems, including autism and psychiatric illnesses. Epigenetics, or “above the genome,” refers to changes in genes other than the DNA sequence itself. The changes affect which genes are turned on or off and therefore which proteins are produced in cells. Feinberg says that because epigenetic variation may be at least as great between individuals as variations in the DNA sequences themselves, understanding the epigenome may help explain how errors occur in normal development and how environmental factors lead to cancer, autism and other disorders.

The center has already developed novel statistical and analytical tools to identify epigenetic modifications across the human genome. With the new funds, awarded by two NIH institutes - the National Human Genome Research Institute (NHGRI) and the National Institute of Mental Health - Feinberg and his colleagues plan to refine these tools so they can be used efficiently and cost effectively in large studies. The team will focus their efforts on studying the epigenetics of bipolar disorder, aging and autism. They will also explore how other factors, such as a person’s genetic makeup, lifestyle choices and environmental exposures, interact with epigenetic factors to cause disease.

The Johns Hopkins Center for the Epigenetics of Common Human Disease has been recognized since 2004 as one of NHGRI’s Centers for Excellence in Genomic Science.

Source:
Christen Brownlee

Johns Hopkins Medical Institutions

While little is known about the causes of glioma, researchers at the National Cancer Institute have found that this rare but often deadly form of brain cancer may be linked to early life physical activity and height.

“Our findings suggest that biological factors related to energy expenditure and growth during childhood may play a role in glioma etiology. This clue could help researchers better understand important features of glioma biology and the potentially modifiable lifestyle factors that could be important in preventing this disease,” said Steven C. Moore, Ph.D., research fellow in the Nutritional Epidemiology Branch, NCI. Moore also added that “engaging in regular physical activity throughout the lifespan conveys many benefits.” Results of this prospective study are published online first in Cancer Research , a journal of the American Association for Cancer Research.

Gliomas are the most common type of brain cancer, accounting for nearly 80 percent of brain and central nervous system cancers. Though little is known about the causes of glioma, some evidence suggests that early life exposures may play a role in disease etiology. Because the brain develops rapidly during childhood and adolescence, it may be more susceptible to environmental influences during this time.

Moore and colleagues examined whether markers of early life energy expenditure and intake (physical activity, body mass index and height) are related to glioma risk. Between 1995 and 1996, researchers distributed a baseline questionnaire about dietary intake and other lifestyle exposures to participants in the National Institutes of Health-AARP Diet and Health Study. Nearly 500,000 men and women answered questions about physical activity, body weight and height. The researchers then followed study participants for eight years, during which time 480 glioma cases occurred.

Participants who were physically active during adolescence had a decreased risk of glioma; their risk was about 36 percent lower than those who were inactive, according to the study. The researchers also found that those who were obese during adolescence had an increased risk of glioma; their risk was approximately three to four times that of individuals who were normal weight during adolescence. However, Moore cautioned that “we did not have many people in the study who were obese during adolescence.” Moore and colleagues additionally confirmed results of previous studies linking height to increased glioma risk; risk among taller participants was twice that of those considered shorter.

“Aside from our finding for height, which had been previously reported, these results were surprising,” he said. “But, to our knowledge, no one has looked at glioma risk as related to energy balance in childhood and adolescence before.”

The researchers found that the association between physical activity and glioma risk was not consistent across the lifespan. Neither physical activity nor obesity in adulthood were associated with glioma risk. Since the data were collected before the participants were diagnosed with cancer, it is unlikely that the participants would respond to the questionnaire differently because of their diagnosis, according to Christine B. Ambrosone, Ph.D., professor of oncology and chair of the Department of Cancer Prevention and Control at Roswell Park Cancer Institute. However, both Ambrosone and Moore commented that additional prospective studies are needed to confirm these findings, especially the association with obesity, which was in small numbers.

“These results highlight the potential importance of habits during childhood and adolescence for risk of brain cancer later in life. Additional research is needed to understand the biologic mechanisms that underlie these relationships,” added Ambrosone, who is an editorial board member of Cancer Research and was not associated with this study.

Source
American Association for Cancer Research

A common weed and human cancer cells could provide some very uncommon details about DNA structure and its relationship with telomeres and how they affect cellular aging and cancer, according to a team led by scientists from Texas A&M University and the University of Cincinnati (UC).

For the study, the multi-institutional team examined the telomeres of Arabidopsis, a plant found throughout the world, and discovered a new set of essential telomere proteins. The team then identified the human counterpart, a discovery that could be beneficial in understanding human cancers and cellular aging. Their work is published in the current issue of the journal Molecular Cell and was funded by the National Institutes of Health.

Dorothy Shippen, professor of biophysics and biochemistry at Texas A&M, and Carolyn Price, professor of cancer and cell biology at the UC College of Medicine, served as co-corresponding authors of the study.

Telomeres are located at each end of a chromosome and are composed of DNA and protein. Their main function is to protect the ends of the chromosome, but they also play a key role in cell division. Researchers also believe they play a key role in cellular lifespan.

“We found that removal of the plant telomere proteins caused rampant end-to-end joining of chromosomes and dramatic defects in plant development,” explains Shippen.

“The Cincinnati team then showed that removal of one of the human proteins from human cancer cells caused wide-spread DNA damage and complete loss of some telomeres.”

Price adds, “We know that telomeres act as a protective cap for chromosomes and these caps are needed to stop chromosome fusions. We also know that telomere length determines how many times a cell can divide.

“However, we still don’t fully understand how the cap structure prevents chromosome joining or regulates telomere length. This is important because problems in telomere maintenance lead to diseases such as cancer, premature aging syndromes, aplastic anemia and pulmonary fibrosis. The discovery of a new protein complex that is required to maintain the protective telomere cap is very exciting and should open up new research avenues related to human disease.”

The Arabidopsis plant is found worldwide and is related to the cabbage, radish and mustard plant family. Because of its genetic makeup, it has been used for decades as a model organism for studies in the cellular and molecular biology of flowering plants.

The multi-institutional research team says these findings open up new doors on several fronts, leading to an “evolutionary bridge” in current work on telomeres.

“At the very least, it will give us a better understanding of the fundamental composition of telomeres and how they function,” Shippen notes.

“This could give us a new window in defining the role or roles telomeres play in safeguarding our DNA.”

“It could also give us new insight into how damaged telomeres block cell division,” Price adds. “These new proteins seem to function in replication of DNA at the chromosome end, so further study may also give clues into how the protective caps work when a cell divides.

“These are all questions that we need to be answered if we are to fully understand the role of telomeres in human health.”

Source:
Dorothy Shippen

Texas A&M University

The National Institutes of Health (NIH) has awarded researchers in Rice University’s new BioScience Research Collaborative (BRC) a $2 million Grand Opportunity (GO) grant to develop a fast, inexpensive test for oral cancer that a dentist could perform simply by using a brush to collect a small sample of cells from a patient’s mouth.

“We want to provide an accurate diagnosis for oral cancer in less than 30 minutes using a minimally invasive test that requires no scalpels or off-site lab tests,” said principal investigator John McDevitt, Rice’s Brown-Wiess Professor in Bioengineering and Chemistry. “The payoff for this could be tremendous because oral cancers today are typically diagnosed much too late in their development.”

NIH established the GO grant program to support projects that address large, specific research endeavors that are likely to deliver near-term growth and investment in biomedical research and development, public health and health care delivery. GO grant funding was provided by the American Recovery and Reinvestment Act.

If oral cancer is detected early, the prognosis for patients is excellent, with a five-year survival rate of more than 90 percent. Unfortunately, the actual five-year survival rate for oral squamous cell carcinoma is only about 50 percent, among the lowest rates for all major cancers. Oral squamous cell carcinoma affects about 300,000 people per year worldwide, and most cases are diagnosed in their late stages.

The new test is possible because of a novel microchip invented in McDevitt’s lab. This “lab-on-a-chip” uses the latest techniques in microchip design, nanotechnology, microfluidics, image analysis, pattern recognition and biotechnology to shrink many of the main functions of a state-of-the-art clinical pathology laboratory onto a microchip the size of a postage stamp.

The microchips are mounted on disposable, plastic cards that are slotted into a battery-powered analyzer. A brush-biopsy sample is placed on the card and microfluidic circuits wash cells from the sample into a reaction chamber. The cells pass through mini-fluidic channels about the size of small veins and come in contact with “biomarkers” that react only with specific types of diseased cells. The machine uses two LEDs, or light-emitting diodes, to light up various regions of the cells and cell compartments. Healthy and diseased cells can be distinguished from one another by the way they glow in response to the LEDs.

The oral-cancer test will be developed in collaboration with scientists at the University of Texas M.D. Anderson Cancer Center, the University of Texas Health Science Center at Houston, the University of Texas Health Science Center at San Antonio and the University of Sheffield in the United Kingdom. In addition to cancer, McDevitt’s lab is developing tests for heart attacks and HIV, and it is developing a process to produce the disposable cards for pennies apiece.

“An affordable oral-cancer test that can be performed painlessly and quickly in either a regular visit at the doctor or dentist’s office benefits patients and clinicians by detecting cancer earlier and lowering health care costs,” McDevitt said.

The analyzers used in the test are made by Austin-based startup LabNow, a company McDevitt launched while at the University of Texas at Austin. McDevitt moved his lab from UT-Austin to Rice in July 2009 to be in the BRC, a state-of-the-art research facility that’s within walking distance of the major research institutions of the Texas Medical Center (TMC). McDevitt’s lab is slated to begin trials of a lab-on-a-chip saliva test for heart attacks with the TMC’s Baylor College of Medicine in January. In addition, LabNow is preparing for tests next spring in Africa of a lab-on-a-chip test for HIV immune function.

Source: Jade Boyd

Rice University

The decision to use expensive cancer therapies that typically produce only a relatively short extension of survival is a serious ethical dilemma in the U.S. that needs to be addressed by the oncology community, according to a commentary published online June 29 in the Journal of the National Cancer Institute.

Tito Fojo, M.D., Ph.D., of the Medical Oncology Branch, Center of Cancer Research at the National Cancer Institute, in Bethesda, Md., and Christine Grady, Ph.D., of the Department of Bioethics, the Clinical Center at the National Institutes of Health, tackle the controversy concerning the life-extending benefits of certain cancer drugs and the extent to which their cost should factor in deliberations.

The authors illustrate cost-benefit relationships for several cancer drugs, including cetuximab for treatment of non-small cell lung cancer, touted as “practice changing” and new standards of care by professional societies, including the American Society of Clinical Oncology.

They ask, “Is an additional 1.7 months [the additional overall survival for colorectal cancer patients treated with cetuximab] a benefit regardless of costs and side effects?”

According to Fojo and Grady, in the U.S., 18 weeks of cetuximab treatment for non-small cell lung cancer, which was found to extend life by 1.2 months, costs an average of $80,000, which translates into an expenditure of $800,000 to prolong the life of one patient by 1 year. At this rate, it would cost $440 billion annually, an amount 100 times NCI’s budget, to extend the lives of 550,000 Americans who die of cancer annually by 1 year.

To address the issue, the commentators recommend that studies powered to detect a survival advantage of two months or less should test only interventions that can be marketed at a cost of less than $20,000 for a course of treatment.

Every life is of infinite value, the authors say, but spiraling costs of cancer care makes this dilemma inescapable.

“The current situation cannot continue. We cannot ignore the cumulative costs of the tests and treatments we recommend and prescribe. As the agents of change, professional societies, including their academic and practicing oncologist members, must lead the way,” the authors write. “The time to start is now.”

Citation: Fojo T. and Grady C. How Much Is Life Worth: Cetuximab, Non - Small Cell Lung Cancer, and the $440 Billion Question J Natl Cancer Inst 2009, 101: 1-5.

Source:
Steve Graff

Journal of the National Cancer Institute