In discovering the genes responsible for storing fat in cells, scientists at the Albert Einstein College of Medicine of Yeshiva University, New York, have answered one of biology’s most fundamental questions.
Their findings, which appear in the 17 to 21 December online issue of the Proceedings of the National Academy of Sciences, could lead to new strategies for treating obesity and the diseases associated with it.
Scientists had previously identified the genes responsible for synthesising fat within cells. But the genes governing the next step – packaging the fat inside a layer of phospholipids and proteins to form lipid droplets – have long been sought, and for good reason.
“Storing fat in lipid droplets appears crucially important for enabling cells to use fat as an energy source,” says Dr David Silver, assistant professor of biochemistry at Einstein and senior author of the article. “From yeast to humans, partitioning fat into droplets is a universal feature among animals. And in humans, of course, acquiring excessive amounts of these fat droplets in our fat tissue leads to obesity.”
Dr Silver and his colleagues identified two genes that are crucial for packaging fat into lipid droplets. They called the genes FIT1 and FIT2 (for Fat- Inducing Transcripts 1 and 2). Both genes code for proteins that are more than 200 amino acids in length, and the two genes are 50% similar to each other. The amino acid sequences of the FIT proteins do not resemble any other known proteins found in any species, indicating that the FIT genes comprise a novel gene family.
“Now that we’ve identified the genes and the proteins they code for, it should be possible to develop drugs that can regulate their expression or activity. Such drugs could prove extremely valuable, not only for treating the main result of excess lipid droplet accumulation – obesity – but for alleviating the serious disorders that arise from obesity including Type 2 diabetes and heart disease,” said Dr Silver.
Other Einstein scientists involved in the research were lead author Bert Kadereit, Pradeep Kumar, Wen-Jun Wang, Diego Miranda, Erik L. Snapp, Nadia Severina, Ingrid Torregroza and Todd Evans.
The US National Institutes of Health (NIH) launched the Human Microbiome Project on 19 December with the awarding of US$115 million to researchers over the next five years. The aim of the project is to explore the collective genomes of all the microorganisms present in or on the human body to better understand the role this astounding assortment of bacteria, fungi and other microbes play in human health and disease.
The human body contains trillions of microorganisms, living together with human cells, usually in harmony. However, while many maintain our health others cause illness. “The human microbiome is largely unexplored,” said Elias A. Zerhouni, MD, NIH director.
“It is essential that we understand how microorganisms interact with the human body to affect health and disease. This project has the potential to transform the ways we understand human health and prevent, diagnose and treat a wide range of conditions.”
Initially, researchers will sequence 600 microbial genomes, completing a collection that will total some 1,000 microbial genomes and providing a resource for investigators interested in exploring the human microbiome. Other microbial genomes are being contributed to the collection by individual NIH institutes and internationally funded projects. Researchers will then use new, comprehensive laboratory technologies to characterise the microbial communities present in samples taken from healthy human volunteers, even for microbes that cannot be grown in the laboratory.
The samples will be collected from five body regions known to be inhabited by microbial communities: the digestive tract, the mouth, the skin, the nose, and the female urogenital tract. Demonstration projects will subsequently be funded to sample the microbiomes from volunteers with specific diseases. This will allow researchers to correlate the relationship between changes in a microbiome present at a particular body site to a specific illness.
Traditionally, microbiology has focused on the study of individual species as isolated units, making it difficult to develop an inventory of all the microbes in and on the human body. Because their growth is dependent upon a specific natural environment, it’s difficult to recreate microbe-host interactions in the laboratory.
Advances in next generation DNA sequencing technologies relying on a process called metagenomic sequencing will be used. Instead of isolating each microbe, all of the DNA within the collected samples will be sequenced. “Our goal is to discover what microbial communities exist in different parts of the human body and to explore how these communities change in the presence of health or disease,” said National Human Genome Research Institute director, Francis S. Collins, MD, PhD, co-chair of the Human Microbiome Project Implementation Group. Data from the Human Microbiome Project will be deposited in National Center for Biotechnology Information NCBI Map Viewer www.ncbi.nlm.nih.gov/mapview/
Researchers at the Stanford University School of Medicine have taken a small but significant step, in mouse studies, toward the goal of transplanting adult stem cells to create a new immune system for people with autoimmune or genetic blood diseases.
The researchers found a way to transplant new blood-forming stem cells into the bone marrow of mice, effectively replacing their immune systems. However, many aspects of the technique would need to be adapted before it can be tested in humans, said Irving Weissman, MD, a cosenior author of the study and director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine.
The work was done on a particular group of mice that are a poor mimic for the human immune system. Still, Weissman suggested the remaining hurdles could eventually be overcome. When those barriers are surmounted, the benefits are potentially big.
The study was published in the 23 November issue of Science. A person with an autoimmune disease such as multiple sclerosis has a defective immune system in which immune cells attack the person’s own body. An immune system transplant, much like a liver or heart transplant, would give the person a new system that might not attack the body. The way to get a new immune system is to transplant new blood-forming stem cells into the bone marrow, where they generate all the cells of the blood.
But before transplanting new stem cells, the old ones first must be removed, which is currently done by intensive chemotherapy or radiation. Those processes eliminate the cells of the bone marrow, but also damage other tissue and can cause lasting effects including infertility, brain damage and an increased risk of cancer. A treatment for M.S. at the expense of brain function is hardly an ideal therapy.
An international team of scientists, supported in part by the US National Human Genome Research Institute (NHGRI), announced early November that its effort to map genomic changes underlying lung cancer has uncovered a critical gene alteration not previously linked to any form of cancer.
The research, published in the journal Nature, also revealed more than 50 genomic regions that are frequently gained or lost in lung adenocarcinoma, the most common type of lung cancer in the United States.
“This view of the lung cancer genome is unprecedented, both in its breadth and depth,” said senior author Matthew Meyerson, MD, PhD, a senior associate member of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, and an associate professor at Dana- Farber Cancer Institute and Harvard Medical School in Boston. “It lays an essential foundation, and has already pinpointed an important gene that controls the growth of lung cells.
This information offers crucial inroads to the biology of lung cancer and will help shape new strategies for cancer diagnosis and therapy.” Each year more than 1 million people worldwide die of lung cancer.
The new study focused on lung adenocarcinoma, the most frequently diagnosed form of lung cancer in the United States, accounting for approximately 30% of cases. New approaches to cancer treatment rely on a deeper understanding of what goes wrong in tumour cells to spur uncontrolled growth. Through decades of research, it has become clear that lung cancer – like most human cancers – stems mainly from DNA changes that accrue in cells throughout a person's life.
But the nature of these changes and their biological consequences remain largely unknown, which has inspired the recent formation of multi-disciplinary teams that are using new genomic tools and technologies to study cancer in a more systematic, comprehensive manner. The latest study was conducted as part of the Tumor Sequencing Project (TSP), an ongoing effort to apply large-scale approaches to the identification of genomic changes in lung adenocarcinoma.
Specifically, the TSP researchers uncovered a total of 57 genomic changes that occur frequently in lung cancer patients. Of these changes, more than 40 appear to be associated with genes not previously known to be involved in lung adenocarcinoma. More research is needed to precisely identify and characterise these genes, but researchers are excited by the possibility that their findings may suggest new ways of attacking this deadly cancer.
The most common abnormality identified by the TSP team involves a region on chromosome 14 that encompasses two known genes, neither of which had been previously associated with cancer. Through additional studies in cancer cells, the researchers discovered that one of the genes, “NKX2.1”, influences cancer cell growth. “NKX2.1” normally acts as a master regulator that controls the activity of other key genes in cells lining the lungs’ alveoli.
The discovery that a gene functioning in a select group of cells – rather than in all cells – can promote cancer growth may have broad implications for the design of drugs for a wide range of cancers. All data generated by the TSP are being made available to the scientific community in public databases. For information on how to access the databases, go to: www.genome.gov/cancersequencing
A specific variation in the glucocorticoid receptor gene is associated with lung disease progression in cystic fibrosis, research published in November in the online open access journal Respiratory Research reveals. This finding adds weight to previous research suggesting that specific subgroups of patients with cystic fibrosis may benefit from glucocorticoid treatment.
Patients with cystic fibrosis show wide variability both in terms of the inflammatory burden of the lung and in their response to inhaled glucocorticoids. As such, the effectiveness of this therapy in patients with cystic fibrosis remains uncertain.
However, previous research has suggested that specific subgroups of patients may benefit from treatment with inhaled glucocorticoids. In several inflammatory diseases, variations in sensitivity to glucocorticoids have been found to be associated with single nucleotide polymorphisms in the glucocorticoid receptor gene.
So, a team from Hôpital Trousseau, Assistance Publique Hôpitaux de Paris, Inserm and Université Pierre et Marie Curie (all based in Paris, France) set out to investigate the effect of four polymorphisms (TthIII, ER22/23EK, N363S and BclI) in the glucocorticoid receptor gene on disease progression in 255 young people with cystic fibrosis.
The BclI glucocorticoid receptor gene polymorphism was found to be significantly associated with a decline in lung function, as measured by the forced expiratory volume in 1 second and the forced vital capacity.
The deterioration in lung function was more pronounced in patients with the BclI GG genotype than in those with the CG and CC genotypes. The authors write: “The association of BclI polymorphism and lung disease progression in cystic fibrosis gives support to the concept that specific subgroups of patients with cystic fibrosis may benefit from the use of glucocorticoids preferably by the inhaled route. If true, this should allow discriminatory prescribing which is of tremendous importance.”
Until recently, only one of the approximately 30,000 genes in the human genome has been linked to risk of late-onset Alzheimer’s disease (AD). Now, a new study in the 19 November 2007 issue of NeuroReport used a publicly shared genome dataset to strongly support findings that variation in the sequence of the SORL1 gene may be a second risk factor gene for late-onset disease.
Identifying the genes involved in AD ultimately may help determine who may be at greater risk and enable researchers to zero in on pathways to develop new treatments. Three mutated genes – amyloid precursor protein (APP) and the presenilins (PS1 and PS2) – have been shown to cause rare, earlyonset, familial forms of the disease which mostly occur in middle age.
A gene variant – apolipoprotein e4 (APO-e4) – was the first confirmed risk factor for the common form of late-onset AD, which typically occurs after age 65. Earlier this year, researchers first linked variations in the gene SORL1 to late-onset AD.
The analysis involved 14 collaborating institutions in North America, Europe and Asia, and 6,600 people who donated blood and tissue for genetic typing. This new study confirms those findings and in a novel way. Lindsay A. Farrer, PhD, of the Boston University School of Medicine and colleagues accessed data from a genome-wide association study (GWAS) recently made publicly available online by the Translational Genomics Research Institute (TGen), a nonprofit research institute promoting genomics research. GWAS involves rapidly scanning for markers across the complete set of DNA of many people to find genetic variations related to a particular disease.
By analysng TGen’s data on the DNA of 1,408 cases and controls, Dr Farrer’s study replicated the findings of the earlier studies that linked SORL1 data to late-onset AD. “These results are especially remarkable since this gene was not a focus of the original TGen study which generated the data used to test our hypothesis,” Dr Farrer said.
Lung cancer target
One of the deadliest forms of cancer appears to carry a specific weakness. When a key gene called 14-3-3zeta is silenced, lung cancer cells can’t survive on their own, researchers have found.
“The gene is a potential target for selective anticancer drugs,” says Haian Fu, PhD, professor of pharmacology, haematology & oncology at Emory University School of Medicine and Emory Winship Cancer Institute in the United States.
The research results were published in the Proceedings of the National Academy of Sciences (PNAS). Treatment options for lung cancer are limited, Dr Fu says. “The recent trend towards targeted therapies requires us to understand the altered signaling pathways in the cell that allow cancer to develop,” he says.
Dr Fu and his collaborator, Fadlo Khuri, MD, deputy director of clinical and translational research at Emory Winship Cancer Institute, chose to focus on the gene 14-3-3zeta because it is activated in many lung tumours. In addition, recent research elsewhere shows that survival of lung cancer patients is worse if the gene is on overdrive in their tumours, Dr Fu says.
In the PNAS study, the authors used a technique called RNA interference to selectively silence the 14-3- 3zeta gene.
They found that when 14-3-3zeta is turned off, lung cancer cells become less able to form new tumour colonies in a laboratory test. The finding has implications beyond lung cancer, in that 14-3-3zeta is also activated in other forms of cancer such as breast and oral.
Since 14-3-3zeta was identified as a promising target for drugs, Dr Fu and his coworkers are making use of a robot-driven screening programme at the Emory Chemical Biology Discovery Center to sort through thousands of chemicals that may disrupt its interactions.
They hope to identify these compounds rapidly and move them from bench into clinical testing.
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