NEW YORK - Scientists for the first time have mapped out the molecular "switches" that can turn on or silence individual genes in the DNA in more than 100 types of human cells, an accomplishment that reveals the complexity of genetic information and the challenges of interpreting it.
Researchers unveiled the map of the "epigenome" in the journal Nature on Wednesday, alongside nearly two dozen related papers. The mapping effort is being carried out under a 10-year, $240 million U.S. government research program, the Roadmap Epigenomics Program, which was launched in 2008.
The human genome is the blueprint for building an individual person. The epigenome can be thought of as the cross-outs and underlinings of that blueprint: if someone's genome contains DNA associated with cancer but that DNA is "crossed out" by molecules in the epigenome, for instance, the DNA is unlikely to lead to cancer.
As sequencing individuals' genomes to infer the risk of disease becomes more common, it will become all the more important to figure out how the epigenome is influencing that risk as well as other aspects of health. Sequencing genomes is the centerpiece of the "precision medicine" initiative that U.S. President Barack Obama announced this month.
"The only way you can deliver on the promise of precision medicine is by including the epigenome," said Manolis Kellis of the Massachusetts Institute of Technology, who led the mapping that involved scientists in labs from Croatia to Canada and the United States.
Drug makers including Merck & Co Inc., the Genentech unit of Roche Holding and GlaxoSmithKline Plc are conducting epigenetics research related to cancer, said Joseph Costello of the University of California, San Francisco, director of one of four main labs that contributed data to the epigenome map.
Epigenetic differences are one reason identical twins, who have identical DNA, do not always develop the same genetic diseases, including cancer.
But incorporating the epigenome in precision medicine is daunting.
"A lifetime of environmental factors and lifestyle factors" influence the epigenome, including smoking, exercising, diet, exposure to toxic chemicals and even parental nurturing, Kellis said in an interview. Not only will scientists have to decipher how the epigenome affects genes, they will also have to determine how the lives people lead affect their epigenome.
BOOK OF LIFE
The human genome is the sequence of all the DNA on chromosomes. The DNA is identical in every cell, from neurons to hearts to skin.
It falls to the epigenome to differentiate the cells: as a result of epigenetic marks, heart muscle cells do not make brain chemicals, for instance, and neurons do not make muscle fibers.
The epigenome map published on Wednesday shows how each of 127 tissue and cell types differs from every other at the level of DNA. Because scientists involved in the Roadmap project have been depositing their findings in a public database as they went along, other researchers have been analyzing the information before the map was formally published.
One of the resulting studies show, for instance, that brain cells from people who died with Alzheimer's disease had epigenetic changes in DNA involved in immune response. Alzheimer's has never been seen as an immune-system disorder, so the discovery opens up another possible avenue to understand and treat it.
Other researchers found that because the epigenetic signature of different kinds of cells is unique, they could predict with nearly 90% accuracy where metastatic cancer originated, something that is unknown in 2% to 5% of patients.
As a result, epigenetic information might offer a life-saving clue for oncologists trying to determine treatment, said co-senior author Shamil Sunyaev, a research geneticist at Brigham and Women's Hospital in Boston.
There is much more to come. Instead of the epigenome map being the end, said Kellis, "I very much see (it) as beginning a decade of epigenomics."
This is a microscopic view of lab-grown human muscle bundles stained to show patterns made by basic muscle units and their associated proteins (red), which are a hallmark of human muscle.
Credit: Nenad Bursac, Duke University
Date:January 13, 2015
Researchers have grown human skeletal muscle in the laboratory that, for the first time, contracts and responds just like native tissue to external stimuli such as electrical pulses, biochemical signals and pharmaceuticals. The development should soon allow researchers to test new drugs and study diseases in functioning human muscle outside of the human body.
In a laboratory first, Duke researchers have grown human skeletal muscle that contracts and responds just like native tissue to external stimuli such as electrical pulses, biochemical signals and pharmaceuticals.
The lab-grown tissue should soon allow researchers to test new drugs and study diseases in functioning human muscle outside of the human body.
The study was led by Nenad Bursac, associate professor of biomedical engineering at Duke University, and Lauran Madden, a postdoctoral researcher in Bursac's laboratory. It appears January 13 in the open-access journal eLife
"The beauty of this work is that it can serve as a test bed for clinical trials in a dish," said Bursac. "We are working to test drugs' efficacy and safety without jeopardizing a patient's health and also to reproduce the functional and biochemical signals of diseases -- especially rare ones and those that make taking muscle biopsies difficult."
Bursac and Madden started with a small sample of human cells that had already progressed beyond stem cells but hadn't yet become muscle tissue. They expanded these "myogenic precursors" by more than a 1000-fold, and then put them into a supportive, 3D scaffolding filled with a nourishing gel that allowed them to form aligned and functioning muscle fibers.
"We have a lot of experience making bioartifical muscles from animal cells in the laboratory, and it still took us a year of adjusting variables like cell and gel density and optimizing the culture matrix and media to make this work with human muscle cells," said Madden.
Madden subjected the new muscle to a barrage of tests to determine how closely it resembled native tissue inside a human body. She found that the muscles robustly contracted in response to electrical stimuli -- a first for human muscle grown in a laboratory. She also showed that the signaling pathways allowing nerves to activate the muscle were intact and functional.
To see if the muscle could be used as a proxy for medical tests, Bursac and Madden studied its response to a variety of drugs, including statins used to lower cholesterol and clenbuterol, a drug known to be used off-label as a performance enhancer for athletes.
The effects of the drugs matched those seen in human patients. The statins had a dose-dependent response, causing abnormal fat accumulation at high concentrations. Clenbuterol showed a narrow beneficial window for increased contraction. Both of these effects have been documented in humans. Clenbuterol does not harm muscle tissue in rodents at those doses, showing the lab-grown muscle was giving a truly human response.
"One of our goals is to use this method to provide personalized medicine to patients," said Bursac. "We can take a biopsy from each patient, grow many new muscles to use as test samples and experiment to see which drugs would work best for each person."
This goal may not be far away; Bursac is already working on a study with clinicians at Duke Medicine -- including Dwight Koeberl, associate professor of pediatrics -- to try to correlate efficacy of drugs in patients with the effects on lab-grown muscles. Bursac's group is also trying to grow contracting human muscles using induced pluripotent stem cells instead of biopsied cells.
"There are a some diseases, like Duchenne Muscular Dystrophy for example, that make taking muscle biopsies difficult," said Bursac. "If we could grow working, testable muscles from induced pluripotent stem cells, we could take one skin or blood sample and never have to bother the patient again."
Other investigators involved in this study include George Truskey, the R. Eugene and Susie E. Goodson Professor of Biomedical Engineering and senior associate dean for research for the Pratt School of Engineering, and William Krauss, professor of biomedical engineering, medicine and nursing at Duke University.
The research was supported by NIH Grants R01AR055226 and R01AR065873 from the National Institute of Arthritis and Musculoskeletal and Skin Disease and UH2TR000505 from the NIH Common Fund for the Microphysiological Systems Initiative.
Not quite the Biblical Noah’s Ark, but possibly the next best thing. Moscow State University has secured Russia’s largest-ever scientific grant to collect the DNA of every living and extinct creature for the world’s first database of its kind.
“I call the project ‘Noah’s Ark.’ It will involve the creation of a depository – a databank for the storing of every living thing on Earth, including not only living, but disappearing and extinct organisms. This is the challenge we have set for ourselves,” MSU rector Viktor Sadivnichy told journalists.
The gigantic ‘ark’, set to be completed by 2018, will be 430 sq km in size, built at one of the university’s central campuses.
“It will enable us to cryogenically freeze and store various cellular materials, which can then reproduce. It will also contain information systems. Not everything needs to be kept in a petri dish,” Sadivnichy added.
The university’s press office has confirmed that the resulting database will contain collected biomaterials from all of MSU’s branches, including the Botanical Garden, the Anthropological Museum, the Zoological Museum and others. All of the university’s departments will be involved in research and collation of materials. The program, which has received a record injection of 1 billion rubles (US$194 million), will promote participation by the university’s younger generation of scientists.
Sadovnichy also said that the bank will have a link-up to other such facilities at home, perhaps even abroad.
“If it’s realized, this will be a leap in Russian history as the first nation to create an actual Noah’s Ark of sorts,” the rector said.
Russia is of course not the first to attempt something of this general scale - the quest to preserve biological life forms is one everyone should be engaged in. Britain has done just that with its Frozen Ark project, its venture into preserving all endangered life forms, also the first of its kind. They say it’s "the animal equivalent of the 'Millennium Seed Bank'," a project that encompasses all of the world's seeds.
In Austen Heinz’s vision of the future, customers tinker with the genetic codes of plants and animals and even design new creatures on a computer. Then his startup, Cambrian Genomics, prints that DNA quickly, accurately and cheaply.
“Anyone in the world that has a few dollars can make a creature, and that changes the game,” Heinz said. “And that creates a whole new world.”
The 31-year-old CEO has a deadpan demeanor that can be hard to read, but he is not kidding. In a makeshift laboratory in San Francisco, his synthetic biology company uses lasers to create custom DNA for major pharmaceutical companies. Its mission, to “democratize creation” with minimal to no regulation, frightens bioethicists as deeply as it thrills Silicon Valley venture capitalists.
With the latest technology and generous funding, a growing number of startups are taking science and medicine to the edge of science fiction. In the works or on the market are color-changing flowers, cow-free milk, animal-free meat, tests that detect diseases from one drop of blood and pills that tell doctors whether you have taken your medicine.
BY IRENE KLOTZ
A new study suggests that at least two more planets are circling the sun far beyond Pluto’s orbit.
The analysis is based on calculations of bodies located well past Neptune, regions of space that include the Kuiper Belt, the scattered disk and the Oort cloud.
ANALYSIS: Kuiper Belt Was a ‘War Zone’ — A Detective Story
Instead of randomly flying through space, 12 of these so-called “extreme trans-Neptunian objects” (ETNO) show some unexpected symmetry.
“This excess of objects with unexpected orbital parameters makes us believe that some invisible forces are altering the distribution of the orbital elements of the ETNO,” Carlos de la Fuente Marcos, with the Complutense University of Madrid, said in a press release.
“We consider that the most probable explanation is that other unknown planets exist beyond Neptune and Pluto,” he said.
ANALYSIS: Strange Object Boosts Kuiper Belt Mystery
The study was based on calculations of the gravitational influences a large object would have on smaller, distant bodies.
“If it is confirmed, our results may be truly revolutionary for astronomy,” de la Fuente Marcos said.
The research is published in the Monthly Notices of the Royal Astronomical Society.
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