In the News: ADHD, Autism, Schizophrenia, Other Psychiatric Disorders Genetically Linked In Huge New Study

In response to ischaemia (a reduction in blood flow), the neurotransmitter glutamate is released from neurons and other brain cells (astrocytes; not shown). This induces Ca²⁺ entry (green arrows) into responsive neurons through NMDA-type glutamate receptors and Ca²⁺-permeable AMPA-type glutamate receptors. Ca²⁺ also enters through voltage-gated Ca²⁺ channels and several other types of Ca²⁺-permeable membrane channel, and is released from intracellular stores. The NCX proteins represent a primary cellular defence against Ca²⁺ overload, pumping Na⁺ ions in and Ca²⁺ ions out. But Bano et al.¹ show that in ischaemic conditions NCX is destroyed by the Ca²⁺-activated protease calpain.

by Lauran Neergaard

Washington — The largest genetic study of mental illnesses to date finds five major disorders may not look much alike but they share some gene-based risks. The surprising discovery comes in the quest to unravel what causes psychiatric disorders and how to better diagnose and treat them.

The disorders – autism, attention deficit-hyperactivity disorder or ADHD, bipolar disorder, major depressive disorder and schizophrenia – are considered distinct problems. But findings published online Wednesday suggest they're related in some way.

"These disorders that we thought of as quite different may not have such sharp boundaries," said Dr. Jordan Smoller of Massachusetts General Hospital, one of the lead researchers for the international study appearing in The Lancet.

That has implications for learning how to diagnose mental illnesses with the same precision that physical illnesses are diagnosed, said Dr. Bruce Cuthbert of the National Institute on Mental Health, which funded the research.

Consider: Just because someone has chest pain doesn't mean it's a heart attack; doctors have a variety of tests to find out. But there's no blood test for schizophrenia or other mental illnesses. Instead, doctors rely on symptoms agreed upon by experts. Learning the genetic underpinnings of mental illnesses is part of one day knowing if someone's symptoms really are schizophrenia and not something a bit different.

"If we really want to diagnose and treat people effectively, we have to get to these more fine-grained understandings of what's actually going wrong biologically," Cuthbert explained.

Added Mass General's Smoller: "We are still in the early stages of understanding what are the causes of mental illnesses, so these are clues."

The Psychiatric Genomics Consortium, a collaboration of researchers in 19 countries, analyzed the genomes of more than 61,000 people, some with one of the five disorders and some without. They found four regions of the genetic code where variation was linked to all five disorders.

Of particular interest are disruptions in two specific genes that regulate the flow of calcium in brain cells, key to how neurons signal each other. That suggests that this change in a basic brain function could be one early pathway that leaves someone vulnerable to developing these disorders, depending on what else goes wrong.

For patients and their families, the research offers no immediate benefit. These disorders are thought to be caused by a complex mix of numerous genes and other risk factors that range from exposures in the womb to the experiences of daily life.

"There may be many paths to each of these illnesses," Smoller cautioned.

But the study offers a lead in the hunt for psychiatric treatments, said NIMH's Cuthbert. Drugs that affect calcium channels in other parts of the body are used for such conditions as high blood pressure, and scientists could explore whether they'd be useful for psychiatric disorders as well.

The findings make sense, as there is some overlap in the symptoms of the different disorders, he said. People with schizophrenia can have some of the same social withdrawal that's so characteristic of autism, for example. Nor is it uncommon for people to be affected by more than one psychiatric disorder.

Online:

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)60223-8/abstract

Excerpts From: Clocks, Genes and Sleep

Core components of the circadian transcriptional clock. Brain-and muscle ARNT-like protein (BMAL1) heterodimerizes with CLOCK protein to bind E-box motifs in the promoter regions of downstream target genes, such as Period (Per 1,2) and Cryptochrome (Cry1,2) genes. PERIOD proteins (PERs) heterodimerize with CRYPTOCHROME proteins (CRYs) in order to inhibit CLOCK:BMAL1, thus closing an autoregulatory negative-feedback loop. Blocking activity of CLOCK:BMAL1 in Bmal1 knock-out mice disrupts normal circadian rhythms, and increases reactive-oxygen species (ROS), while concomitantly decreasing memory and lifespan. Circadian clock output regulates a variety of biological and physiological processes, including circadian rhythms, metabolism, learning and memory, ROS/reactive nitrogen species (RNS) homeostasis, aging and longevity, and the cell cycle.

by Malcolm von Schantz, PhD and Simon N Archer, PhD. Journal of the Royal Society of Medicine, Oct. 2003

Genes and Molecules

Information on how circadian rhythms are generated at molecular level comes mainly from studies in mice. The mechanism depends on tightly controlled concerted coexpression of specific clock genes.

Most of these genes are remarkably conserved amongst coelomates — including insects, molluscs and vertebrates — although the precise roles of specific components have drifted during evolution.

At the center of the machinery in mammals are the Period (Per1, Per2 and Per3) and Cryptochrome (Cry1 and Cry2) genes. The protein products of all these oscillate over the 24-hour cycle by inhibiting their own promoters operating in an intricate negative feedback loop.

Sleep Disorders

Sleep has famously been described as being ‘of the brain, by the brain, and for the brain’. Its relation to the circadian clock is less simple to describe. Some disorders of sleep are unrelated to circadian rhythms; others are undoubtedly related to it, particularly the advanced and delayed sleep phase syndromes. In these conditions, sleep occurs either abnormally early or abnormally late. This could theoretically be caused either by an abnormal τ or by abnormal timing of the sleep phase within a circadian cycle of normal periodicity.

Polymorphisms in clock genes can be related to circadian parameters, and the most famous finding so far is a large family where advanced sleep phase syndrome seems to be inherited as a single-gene defect. The condition manifests itself in this family with advanced melatonin, temperature, and sleep/wake rhythms co-segregating with a missense mutation in the Per2 gene. Because of the non-homologous aminoacid substitution, the resulting PER2 protein is phosphorylated less efficiently by casein kinase than the native one—an observation that offers a satisfying mechanistic explanation for the similarity between this phenotype and that of the τ hamster, whose missense mutation in casein kinase I ε results in essentially the same net effect.

Morning and Eveening Preferences

The gene associated with evening preference that has produced the most interesting results to date in humans is Per3. In a Japanese population, Ebisawa and colleagues reported that a rare single-nucleotide polymorphism causing an aminoacid substitution correlated with delayed sleep phase syndrome.

Our laboratory has studied a more dramatic genetic polymorphism, initially described but not characterized in Ebisawa's paper, encoding an 18-aminoacid tandem repeat sequence, of which humans have either four or five successive copies in each of their Per3 alleles.

By comparing HO-characterized subjects whose scores were around the mean for their gender and age group with those with extreme evening and morning preference, we were able to distinguish an excess p+revalence of the shorter repeat allele in subjects with extreme evening preference. Extending the study to a cohort of patients with delayed sleep phase syndrome, we showed that the association with the shorter allele was even stronger in this population. Thus, although no physiological studies have formally linked the extremes of evening preference and/or long τ with delayed sleep phase syndrome, it would appear from the convergence of their Per3 genotype that such a study is not only worthwhile but long overdue.

Conclusion

In man, the known human clock gene differences appear merely to predict a greater or lesser propensity.

One reason for this difference is that most of the mouse models studied so far have been engineered to abolish the function of a specific gene, rather than carrying a more or less altered form of it. Another is that laboratory rodent strains are highly inbred and thus much more homogeneous with respect to all other clock genes.

The human circadian genotype, being a polygenic trait, is more akin to a hand of cards. Most of us will have a hand containing average cards or a balanced mixture of high and low ones. Only the hands that contain predominantly low or high cards will stand out.

The great majority of us function normally with our allotted circadian phenotype and its interaction with our environment, much as we are able to deal with other aspects of our genetic inheritance.

But the minority who have been dealt a dud hand of the clock genes card game deserve more sympathy and clinical help than they are often accorded.

Our culture trends to associate early waking with virtue and industry, and late sleeping with vice and lassitude. Lack of conformity with this norm is not always a matter of choice: clearly, some people are genetically programmed for an extreme diurnal preference.

Read the whole article at:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC544627/

Lloyd I. Sederer, MD Blog Excerpt Biomarkers for Depression: Promise or Prime Time?

Complexity and networks.

Here's the tail end of an excerpt from a blog by  Lloyd I. Sederer, MD.Medical director, New York State Office of Mental Health:
Genetics and neuroscience rival the complexity of the physics of the universe. With genetic inheritance alone, there is hardly a single or simple pathway. Often, many genes are involved in complex diseases like diabetes and depression. The genes themselves actually vary in their form and expression (called genetic alleles). Those many genes, and their alleles, also are subject to highly-variable expression as a result of the physical and emotional environment they encounter in individual human beings -- with genes being turned on and off continuously by countless factors to which the person is exposed. And even within the specific cells that the genes send their messages to (via mRNA), ever-changing intracellular activity exerts further influence on what proteins are then synthesized that drive cellular functioning. As if that cascade were not complex enough, genes mutate. They change. Some changes are quite common and some rare, but our genes are constantly undergoing changes that may be adaptive or maladaptive to our everyday lives.

Yet science is remarkable, and by dint of effort, good luck and (often accidental) discovery our species enjoys vastly greater health and life prospects than our ancestors. But brain biomarkers are not what distressed patients and families should invest in right now as they seek better diagnosis and treatment of depression. Careful clinical assessment, systematically-developed and followed treatment plans created between patient and doctor, ongoing monitoring, and course corrections when needed remain the state of the art and science. That is how the predominance of people with depression today can improve and experience greater pleasure, purpose and productivity.

To read the full-blown blog post, go to:

http://www.huffingtonpost.com/lloyd-i-sederer-md/depression-biomarkers_b_2720412.html?utm_hp_ref=health-news&ir=Health%20News

In the News: Stem Cells From Cadavers? Pluripotent Cells Can Be Derived From Dead Bodies, Research Shows

by Charles Choi, LiveScience Contributor 10/16/2012   Death will come for us all one day, but life will not fade from our bodies all at once. After our lungs stop breathing, our hearts stop beating, our minds stop racing, our bodies cool, and long after our vital signs cease, little pockets of cells can live for days, even weeks. Now scientists have harvested such cells from the scalps and brain linings of human corpses and reprogrammed them into stem cells.
In other words, dead people can yield living cells that can be converted into any cell or tissue in the body.

As such, this work could help lead to novel stem cell therapies and shed light on a variety of mental disorders, such as schizophrenia, autism and bipolar disorder, which may stem from problems with development, researchers say.

Making stem cells

Mature cells can be made or induced to become immature cells, known as pluripotent stem cells, which have the ability to become any tissue in the body and potentially can replace cells destroyed by disease or injury. This discovery was honored last week with the Nobel Prize.

Past research showed this same process could be carried out with so-called fibroblasts taken from the skin of human cadavers. Fibroblasts are the most common cells of connective tissue in animals, and they synthesize the extracellular matrix, the complex scaffolding between cells.

Cadaver-collected fibroblasts can be reprogrammed into induced pluripotent stem cells using chemicals known as growth factors that are linked with stem cell activity. Reprogrammed cells could then develop into a multitude of cell types, including the neurons found in the brain and spinal cord. However, bacteria and fungi on the skin can wreak havoc on the culturing processes used to grow cells in labs, making the process tricky to successfully carry out.

Now scientists have taken fibroblasts from the scalps and the brain linings of 146 human brain donors and grown induced pluripotent stem cells from them as well.

"We were able to culture living cells from deceased individuals on a larger scale than ever done before," researcher Thomas Hyde, a neuroscientist, neurologist and chief operating officer at the Lieber Institute for Brain Development in Baltimore, told LiveScience. Previous studies had only grown fibroblasts from a total of about a half-dozen cadavers.

The bodies had been dead up to nearly two days before scientists collected tissues from them. The corpses had been kept cool in the morgue, but not frozen.

The researchers found fibroblasts taken from the brain lining, or dura mater, were 16 times more likely to grow successfully than those from the scalp. This was expected, since the scalp is prone to fungal and bacterial contamination just like any other part of the skin. These contaminants can ruin any attempt to grow fibroblasts in lab dishes.


Here, the stem cells are shown expressing various markers and differentiating into neurons.


Surprisingly, scalp cells did proliferate more and grew more rapidly than dura mater cells. "This makes sense — the skin is constantly renewing, while the turnover in dura mater is much slower," Hyde said.

Future therapies

Cells from corpses might play a key role in developing future stem cell therapies. Successfully reprogramming induced pluripotent stem cells so they behave like the cells they are meant to replace means that samples of the mimicked cells must be present for comparison. Cadavers can provide brain, heart and other tissues for study that researchers cannot safely obtain from living people.

"For instance, we can compare neurons derived from fibroblasts with actual neurons from the same individual," Hyde said. "It tells us about how reliable a given method for deriving neurons from fibroblasts is. That can be crucial if, for example, you want to create dopamine-making neurons to treat someone with Parkinson's disease."

Studying how induced pluripotent stem cells develop into various tissues could also shed light on disorders that are due to malfunctions in development.

"We're very interested in major neuropsychiatric disorders such as schizophrenia, bipolar disease, autism and mental retardation," Hyde said. "By understanding what goes wrong with the brain cells in these individuals, we could perhaps help fix that."

The scientists detailed their findings online Sept. 27 in the journal PLoS ONE.

In the News: 23andMe and Me: Personal Genomics Coming of Age, Part 1

by Paul Knoepfler, Associate Professor, UC Davis School of Medicine
A revolutionary biomedical phenomenon called "personal genomics" is poised to fundamentally change how you think about your health and your family history.

Your own unique collection of DNA contained in your genome is called a "genotype." Just as we each have a blood type, we also each have a genotype that has important, but more powerful bearing on our overall health and traits. Genomics, which you can learn more about here, is the study of our genotypes at the DNA level.

Our genotypes also contain an enormous amount of information about our family trees. The goal of personal genomics is to mine the depths of our genotypes for nuggets of information that have great bearing, quite literally, on who we are, our health, and our family history going back thousands of years. A major, but not the only, player in this relatively new field of personal genomics is a 6-year-old company called 23andMe.

Before shelling out $299 for this or a related service from another company, possible customers might ask themselves if it is worth it. From my experience, I believe it is not only worth it, but goes beyond money to see health and family history in a new way. Let me explain.

Our genotype tells three main types of important stories about us, and the only way we can understand them is through personal genomics.

Some of these stories are past tense, revealing the histories of our ancestors from whom we inherited all the parts of our DNA that collectively make up our genomes. Other stories are present tense in that they are about us, who we are and what diseases we have. Finally, a third type of story is future tense. These stories tell us about what might be. What might my kids be like? What diseases might I get?

In my mind, information is power and information about our families and ourselves is all the more crucial for us to know.

The very personal treasure trove of information in these DNA stories has for millennia been hidden from us -- ironically, tucked away right inside of us in each and every cell. Personal genomics of the kind that 23andMe conducts has the potential to reveal some of those hidden DNA stories, uncovering remarkable details about our past, present, and possible futures.

Not surprisingly, a growing number of people want to learn the stories of their DNA and to understand what their genomes have to teach them. According to Catherine Afarian, Public Relations Manager, and Dr. Joanna Mountain, Senior Director of Research at 23andMe, who I interviewed for this article, in each year of its existence 23andMe has at least doubled their business.

Over this short period of time, 23andMe has collectively analyzed the DNA of more than 150,000 people. What makes this an especially remarkable achievement is that the company, which has itself grown each year, now has only 80 employees. This team is roughly equally divided into three groups of biomedical scientists, engineers, and support staff.

I took the plunge to see what 23andMe could teach me about my family and myself. Part of my motivation was that I am a genomics researcher myself, but in addition, I was curious if I could learn anything about a major health event in my life.

I was diagnosed with a serious form of prostate cancer two years ago at the unusually young age of 42 (median diagnosis is at age 70). Could 23andMe shed any light on why this happened? I hoped so. You can read more about my experience with cancer in "Do Vulcans get prostate cancer?" and "Should Men Get PSA tests? Yes, but..."

I found the 23andMe experience illuminating in many ways, and every step was very easy. Once you place your order, they send you a small snap-cap tube, you spit into it, and then you mail it back to them.

That's it. A few weeks later, you can go onto their website to start quite literally learning the stories that your DNA has to tell you.

I think of it as a biography written in the letters of our DNA. In my case, my DNA, as translated into English for me by 23andMe, had many stories for me. The 23andMe website is very user-friendly and it divides the types of information from DNA into different categories such as diseases risk, traits, relatives, and so forth. Each area can be explored using its own handy tool.

One of the foremost things on my mind when I got my 23andMe results back was whether there was anything in my genome that could answer the important question of why I got prostate cancer and at such a young age.

Or more simply put "Why me?"

Did my genome have an answer?

I went to the 23andMe website for the very first time not realistically expecting a clear answer to the prostate cancer question. I know as a cancer biologist and genome researcher myself that almost nothing in biology is that black-and-white, but I looked at the results in the "Disease Risk" category with astonishment: Smack dab at the very top of the "increased risk" category for me was "prostate cancer"

I was surprised and impressed. Specific elements in my genome together pointed to my having an elevated risk of prostate cancer. Afarian and Mountain told me that my particular genotype put me in the top 10-20 percent of men in terms of prostate cancer risk. You might ask since I already have had prostate cancer, shouldn't my risk be 100 percent? And why only a seemingly modest 1.82x increased risk?

When it comes to disease risks, genomics in most cases is not about certainties, but rather probabilities. In other words, just as the expression goes that anatomy is not destiny, so too is it true that genotype is almost always not destiny.

Thus, 23andMe cannot tell for sure that you will or will not get a certain disease in most cases.

Instead, it estimates risk, and in my case it said there existed a relatively very high risk for prostate cancer. Often, increased risks are not that impressive in a quantitative sense either. For example, it is not uncommon for risks to be less than 2.0-fold increased or decreased. These are still meaningful in an absolute sense, but how meaningful at an actual health level?

It depends on circumstances. In the case of Stanford Genetics Professor Michael Snyder genomics studies told him he was strongly genetically predisposed to Type 2 diabetes, a disease he fairly rapidly came down with after his genome told him he was pretty likely to get it, but he was so rapidly diagnosed in part because the genome data made him and his doctors test him for blood sugar very frequently.

 In the case of prostate cancer, knowing one is in the top 10 percent risk group might make one more inclined to get PSA tests. Of course, in my unfortunate case, by the time I got my genomic data suggesting I was at high risk for prostate cancer, I had already had the cancer; but for many people the hope would be that genomics data could be obtained and be instructive before the disease manifests.

Stayed tuned for parts two and three of this story in the coming weeks, where I go more into the relative finder and family history aspects of personal genomics, other personal genomics companies, and the future of the field including 23andMe.

Disclosure: 23andMe gave me a free analysis of my genome at my request as I was researching this article on personal genomics. I have no professional/financial interest in or connection to the company.

For more by Paul Knoepfler, click here.

Understanding Mental Disorders as Circuit Disorders



Thomas R. Insel, M.D., is Director of the National Institute of Mental Health (NIMH). His tenure at NIMH has been distinguished by groundbreaking findings in the areas of practical clinical trials, autism research, and the role of genetics in mental illnesses. Prior to his appointment as NIMH Director in the Fall 2002, Dr. Insel was Professor of Psychiatry at Emory University, where he founded the Center for Behavioral Neuroscience. Dr. Insel graduated from the combined B.A.-M.D. program at Boston University in 1974.


by Thomas R. Insel, M.D., National Institute of Mental Health



When the Decade of the Brain began in 1990, scientists had developed both drug and behavioral treatments for most mental disorders, but their understanding of these disorders was primitive.

Two decades later, neuroscientists are finally uncovering the brain processes involved in mental disorders. There is great promise for development of more effective treatments in the upcoming decade.

In 1990, most theories of the causes of mental disorders were based on investigations of treatments, rather than on scientific insight about how diseases arise.

 By 2000, we had developed more treatments—including best-selling second-generation antipsychotics and antidepressants—but we were no further along in our understanding of the causes.

During the so-called Decade of the Brain, there was neither a marked increase in the rate of recovery from mental illness, nor a detectable decrease in suicide or homelessness—each of which is associated with a failure to recover from mental illness. To reduce the occurrence and death toll of mental disorders, we will need a more thorough understanding of why these mysterious illnesses occur.

People frequently cite the 1990s as the era for redefining mental disorders as brain disorders.

While this conceptual shift was important, we now realize the greater importance of developing new tools: imaging techniques for quantitative studies of brain structure, function and chemistry, as well as other comprehensive tools for mapping DNA and RNA.

What do we mean by comprehensive? Rather than focusing on four or five neurotransmitters, researchers at the turn of the 21st century were able to investigate thousands of genes to yield an unbiased survey of the biology of mental disorders. These advances ushered in a decade of discovery that brings us to 2010.

If scientists introduced mental disorders as brain disorders in the Decade of the Brain, researchers in the past ten years have demonstrated the importance of specific brain circuits.

Unlike neurological disorders, which often involve areas of tissue damage or cell loss, mental disorders have begun to appear more like circuit disorders, with abnormal conduction between brain areas rather than loss of cells.

Neuroimaging technology has revealed that specific brain pathways, mostly located in the prefrontal cortex, are involved in major mental disorders.

Deep brain stimulation, a procedure in which neurologists manipulate certain pathways via electric current, has shown promise as a treatment for depression and obsessive-compulsive disorder, on the heels of its successful use as a treatment for neurological motor disorders such as Parkinson’s.

In the past couple of years, via a new technology called optogenetics, neuroscientists have used light to manipulate circuits in experimental animals with millisecond precision and cellular resolution. Thus, for the first time, researchers can conduct specific tests of theories about brain circuits and behavior.

What causes a circuit disorder? Although this will be a major question for the next decade, we already have some intriguing ideas. Mental disorders such as schizophrenia and mood and anxiety disorders are mostly diseases of early life; their onset tends to occur during adolescence or early adulthood, when the brain is still developing.

For example, a person with schizophrenia usually experiences a psychotic break in early adulthood, which is a time when the number of cortical synapses is being pruned. The disorder might result from the excessive loss of synapses in a critical cortical pathway when the normal process overshoots.

Since 2005, scientists studying our genes, the proteins they produce and their functions have started to identify some of the key factors that increase the risk of mental disorders, from autism to schizophrenia.

The candidates include a long list of previously unknown proteins that have one thing in common: They are important for healthy brain development. Indeed, if the Decade of the Brain redefined mental disorders as brain disorders, recent research suggests that mental disorders are really developmental brain disorders, caused by disruptions in the circuitry map of the developing brain.

During this next decade, expect to see the full roster of candidates as scientists begin to describe the key variations in sequences of genes that produce altered proteins and dysfunctional circuitry.

Neuroscientists already have powerful tools to move from the study of molecules to circuits and, ultimately, to behavior. How will we translate this emerging knowledge into better treatments?

The answer for psychiatry will likely be the same as the answer in the rest of medicine: Basic discoveries regarding genes and proteins will point the way to molecular and cellular mechanisms, which in turn will yield new targets for treatment and prevention.

In some ways, psychiatry has been the victim of its early success, as medications found by accident in the 1960s delayed the search for fundamental mechanisms of disease that could yield new targets and new treatments.

After two decades of progress, clinical neuroscientists are finally beginning to understand what underlies a few mental disorders.

In the upcoming decade, which we can perhaps call the Decade of Translation, we can look forward to seeing this new understanding translate to improved treatments that will finally reduce the occurrence and death rates of these disabling illnesses.

Michael White: A Genome-Sized Media Failure

Visualizations of networked linkages between genetic components broadly across the human genome (right) and in a smaller, hierarchically arranged subset (left). Image: Gerstein et al./Nature

Last week, the large genome sciences consortium ENCODE (ENCyclopedia of DNA Elements) made a big splash by presenting its long-awaited results in a publishing extravaganza. This was a fantastic opportunity for scientists and science journalists to explain to the public some of the exciting and important research findings in genome biology that are changing how we think about health, disease, and our evolutionary past. But we blew it, in a big way.

If you read anything that emerged from the ENCODE media blitz, you were probably told some version of the "junk DNA is debunked" story. It goes like this: When scientists realized that classical, protein-encoding genes make up less than 2% of the human genome, they simply assumed, in a fit of hubris, that the rest of our DNA was useless junk. (You might have also heard this from your high school or college teacher. Your teacher was wrong.) Along came the ENCODE consortium, which found that, far from being useless, junk DNA is packed with functionality. And so everything scientists thought they knew about the genome was wrong, wrong wrong.

The Washington Post headline read, "'Junk DNA' concept debunked by new analysis of human genome." The New York Times wrote that "The human genome is packed with at least four million gene switches that reside in bits of DNA that once were dismissed as 'junk' but that turn out to play critical roles in controlling how cells, organs and other tissues behave."

Influenced by misleading press releases and statements by scientists, story after story suggested that debunking junk DNA was the main result of the ENCODE studies. These stories failed us all in three major ways: they distorted the science done before ENCODE, they obscured the real significance of the ENCODE project, and most crucially, they mislead the public on how science really works.

What you should really know about the concept of junk DNA is that, first, it was not based on what scientists didn't know, but rather on what they did know about the genome; and second, that concept has held up quite well, even in light of the ENCODE results. Among the reasons that scientists in the 1970s and '80s began to believe that much of the genome is non-functional was the observation that very similar species could have very different genome sizes. There is no reason to believe that similar species require dramatically different amounts of functional DNA, and thus something other than functional requirements must explain differences in genome size. Scientists also discovered that our genomes contain parasitic, virus-like elements called "transposons" that have the ability copy themselves within our cells. This DNA ecosystem makes our genomes more like a jungle than a precision machine. At the latest count, transposon-derived DNA makes up at least half of our genome. The transposon-derived sequences in our genomes do not have to be explained by invoking some useful function for it. There is no mystery here: this DNA is there because it can replicate.

The primary scientific task of the ENCODE group was to scope out the biochemical landscape of the genome, and put the resulting data out as a resource. The Human Genome Project gave us the text of our genome, but this text is essentially impossible to read without an interpretive guide of key biochemical landmarks. ENCODE, in what was a genuine, technological tour-de-force, measured dozens of different kinds of biochemical landmarks, which can be suggestive of important functions, but do not by themselves demonstrate that a region of the genome is doing something useful for us. This distinction was obscured by the press releases put out by ENCODE, and largely lost on most of the reporters who covered the story. Missing from press releases and news reports was a description of what non-functional DNA looks like: it carries many of the same biochemical landmarks as functional DNA. The widely reported claim of debunked junk DNA is simply wrong.

The media reports on ENCODE used the word 'breakthrough,' but it is too early to fully measure the success of ENCODE, despite the high quality of the data. Ten years out, the reference human genome sequence is a must-have tool for nearly all biomedical researchers. Will the ENCODE results become equally indispensable to our efforts to understand the connection between our genomes and our health? ENCODE's results are very big, but not comprehensive: they don't include every type of cell or class or regulatory protein that we're interested in. As our genome technology improves (which it is doing at a rate that might put the iPhone to shame), we may decide that we need to re-do much of the work done by ENCODE.

And many are worried that our funding agencies have become addicted to Big Science,
prioritizing massive data generation efforts over the more idea-driven work of smaller, individual labs.

The most damaging aspect of our massive failure to get the ENCODE story right was that readers were served up a terrible distortion of the scientific process. A rule of thumb you should apply whenever reading about supposed breakthroughs is this: past scientists weren't as dumb or credulous as they're made out to be. Scientists tend to be a cautious and skeptical lot, not given to cooking up new theories based on a blithe and arrogant dismissal of what they don't understand. They work hard to base their ideas on the best data available at the time, and then they work hard to come up with even better data.

Dr. Michael White is a systems biologist studying genes and their regulation, in the Department of Genetics and the Center for Genome Sciences and Systems Biology at the Washington University School of Medicine in St. Louis. He is co-founder of the online science pub The Finch and Pea.

Forbes: Five Surprises From Billionaire Paul Allen's Mind Map

 by Matthew Herper, Forbes Staff

 

Paul Allen at the Allen Institute for Brain Science in Seattle

Today the cover of Nature, the prestigious scientific journal, is dedicated to a paper that outlines the first findings of the map of the human brain being created by the Allen Institute For Brain Science, the neuroscience Manhattan project being funded by Microsoft co-founder Paul Allen.

The new publication comes out of the Allen Institute’s effort to create a map of which genes are turned on and off in the human brain, a feat the Institute accomplished a half decade ago in the mouse. Already, the mouse map has become a standard tool for neuroscientists, and the hope is that the human brain atlas will be as well. (For more on the institute’s overall effort, see: Inside Paul Allen’s Quest To Reverse Engineer The Brain, from the current issue of Forbes magazine.)

 

 

An animal’s genes are contained in its DNA, locked in the center of its cells; to access the genetic code, the DNA must be transcribed into a related chemical called RNA, which can take messages to the parts of the cell that make the chemicals that comprise most of the body. The Allen Institute’s atlases are measures of what RNA transcripts are in the cell – this is a bit like monitoring what information is being read off the body’s hard disk.

The Nature paper unveils data from the first two human brains completely analyzed by the Allen Institute, with a bit of analysis from a third. There are several surprises – and it’s not clear what they all mean. “At the moment we’re making descriptions,” says Ed Lein, a neuroscientist who is one of the paper’s co-authors. “A key role for the neuroscience community is to understand how these differences relate to the unique properties of the human brain. ”

1. Cells in the “thinking” part of the brain look a lot more similar than scientists had expected. The thinking we do, including the experience we have of being us, is generated in the cortex, the most well-developed part of the brain. You might expect, then, that the cortex would be accessing the DNA code in all sorts of different ways. But the Allen Institute researchers found remarkably little difference between one neuron in the cortex and the next. In terms of how they use their genetic hard drives, these cells are very much the same.
2. Your left brain and right brain are using your DNA in the same way. Another surprising difference: the left and right sides of the brain tend to have different functions. But on the level of gene expression that the atlas measures, these are again hard to detect. The two hemispheres of the brain look very much alike.
3. The differences that do exist are important. There’s not a lot of genetic variation in the landscape of the brain, but what there is is apparently important. The Allen Institute researchers found that they could accurately predict where a neuron would be in the cortex by what genes it was expressing. So these tiny differences apparently matter. One interesting distinction: the neurons involved in getting sensory impressions, like sight, sound, and touch, are similar to one another and different from the rest of the brain.
4. The differences are not where you’d expect. When we think of a brain cell (if we think about brain cells at all), we think of neurons, the spindly nerve cells that transmit signals to each other and make up the circuits of our brains and bodies. But there’s another type of cell in the brain, called a glial cell, that creates the sheaths that protect neurons and the matrices in which they sit. And there is more variation in what genes are expressed in the glia than in the regular neurons. That could mean they are more important than we thought, accounting for the differences between people – or it could mean that variation in glial cells doesn’t matter much, so there’s a lot of it.
5. We are not mice, or monkeys. One of the most important uses of the Allen Atlas will be to figure out how the human brain is different from the brains of the experimental animals scientists can test in their labs. Big drug companies such as Eli Lilly, AstraZeneca, and Pfizer have been struggling to create new medicines for diseases like schizophrenia and Alzheimer’s, largely without success, and the difference between lab mice and people may be one key reason. In one tantalizing clue, the Allen Institute researchers point to differences in a gene called CALB1, which is used to move around calcium ions, which are key chemical messengers for the nervous system. In rhesus macaques and mice, this gene is expressed throughout the hippocampus, the brain region that plays a key role in the creation of memories. But in humans, CALB1 is expressed only in the dentate gyrus, pointing to a potential difference between the brains of these other mammals and ours. It’s not known what this difference means.

One important result of the lack of variation between cells and between different brains is that the Allen Atlas will be completed with just six brains, not the 10 researchers thought they would need when the project started in 2008. The institute is moving on, with a new $300 million investment from Allen, to try to do new experiments to create circuit diagrams of the mouse visual cortex and to understand all the cell types that exist in the human brain.

Allen himself, when I met him this summer at the Allen Institute in Seattle, is prepared for this to be a long, hard slog. He told me that the brain is “hideously complex” and that it’s going to take “decades and decades” of more research to understand. “We are talking about dozens and dozens of Nobel Prizes,” he said, “that have yet to be won to understand how the brain works.” (For more, see Inside Paul Allen’s Quest To Reverse Engineer The Brain.)

More on the "Project ENCODE" DNA Breakthrough Research

by Stephanie Pappas, LiveScience Senior Writer

September 05, 2012



UW genome scientist Dr. John A. Stamatoyannopolous led several major Project ENCODE related studies.


The ENCODE project has looked deeper into "junk DNA" than ever before. And junk it is not: According to more than 30 research papers published today (Sept. 5) in a number of journals including Science and Nature, at least 80 percent of the genome is biologically active, with much non-protein-coding DNA regulating nearby genes in a complex dance of influence. [Mysteries of Human Evolution]

The findings reveal that the genetic basis of many diseases may not be in protein-coding genes at all, but in their regulatory neighbors. For example, genetic variants related to metabolic diseases pop up in genetic regions that activated only in liver cells. Likewise, regions activated in immune cells hold variants that have been associated with autoimmune disorders such as lupus.

"These breakthrough studies provide the first extensive maps of the DNA switches that control human genes," study researcher John Stamatoyannopoulos, associate professor of genome sciences and medicine at the University of Washington, said in a statement. "This information is vital to understanding how the body makes different kinds of cells, and how normal gene circuitry gets rewired in disease. We are now able to read the living human genome at an unprecedented level of detail, and to begin to make sense of the complex instruction set that ultimately influences a wide range of human biology."

In the News: New DNA project shows us living beyond our genes

Well, once again, one man's junk is another man's treasure!

New DNA project shows us living beyond our genes

by Robert Bazell and Maggie Fox, NBC News
In what many scientists say is a revolution in biology, a giant new project is rewriting our understanding not only of what causes diseases or what makes our eyes a certain color, but what makes us human. And it turns out scientists have been looking in the wrong place for a very long time.

The bounty of new discoveries, released in a batch of 40 research papers on Wednesday, shows the stretches of DNA that we call genes are only a very small piece of what makes the body work. Much more important is the stuff in between the genes – stuff once dismissed as “junk DNA”. It turns out that junk DNA is what is in control, they report in the series of papers in the journals Nature, Science and elsewhere.

“This has opened up whole new galaxies.  It’s like having a bigger telescope,” says Dr. Bruce Stillman, president of Cold Spring Harbor Laboratory, which played a major role in the work.

Scientists already knew in 2003, as they finished the giant Human Genome Project, that they did not have the understanding they had hoped for.  It turned out that humans had just a measly 22,000 genes – fewer than some animals and far fewer even than a plant such as rice. How could something as complex and advanced as a human be boiled down into something so simple?

“We understood precious little about the processes that turns genes on and off. In short we had more questions than answers about how the human genome works,” said Dr. Eric Green, director of the National Human Genome Research Institute, which conducted the study.

The next phase of work, called ENCODE for Encyclopedia of DNA Elements, shows there’s nothing simple about it. As many as 40 million different switches are controlling these genes, turning them on and off in complex and subtle ways.

“The genome is loaded with gene controlling switches. There are literally millions of these,” Dr. John Stamatoyannopoulos of the University of Washington, who worked on the studies, told reporters in a telephone briefing.

Dr. Francis Collins, director of the National Institutes of Health, calls the findings “awesome and elegant.”

“This is the first truly comprehensive view, of how the three billion letter instruction book for human biology actually carries out its work, across many tissues and over the course of development,” he told NBC News in an interview.

Stanford University genomic expert Michael Snyder says it looks like gene mutations -- the changes in DNA sequences that we associate with causing diseases -- may only affect rare diseases. Common diseases, like heart disease, cancer, and allergy, are probably controlled elsewhere. “We think that most of the changes that affect disease don’t lie in the genes themselves, but the switches,” Snyder says.

So treating these common diseases may lie in trying to affect the switches. “The pharmaceutical industry has largely given up on genomics and the genome in favor of older approaches,” said Stamatoyannopoulos. These new findings may reinvigorate new drug research, he said. “Now we have a huge amount of genetic data about human disease that we can actually put to work to find the right kind of genes and proteins to target,” he said.

This new data will also help doctors diagnose disease in the first place, predict which treatments will work best for patients, and monitor their progress. It  points the way to studies to determine the causes of hundreds of diseases including  all kinds of cancer, Alzheimer’s disease, schizophrenia, heart disease, type 1 and type 2 diabetes, lupus, rheumatoid arthritis and asthma. 

It also may lead to a better understanding of how our genetics determine such non-disease factors as height, weight and expected life span.

Not only that – it can help explain why humans and chimpanzees share 98 percent or more of our genes, yet are so different.

"Genes occupy only a tiny fraction of the genome, and most efforts to map the genetic causes of disease were frustrated by signals that pointed away from genes. Now we know that these efforts were not in vain, and that the signals were in fact pointing to the genome's 'operating system' -- the instructions for which are hidden in millions of locations around the genome," said Stamatoyannopoulos. "The findings provide a new lens through which to view the role of genetics and genome function in disease."

Another surprising finding was that the regulatory circuitry blueprints could be used to pinpoint cell types that play a role in specific diseases -- without requiring any prior knowledge about how the disease worked. For example, DNA changes associated with Crohn's disease (a common type of inflammatory bowel disease) are concentrated in the switches controlling two types of immune cells.

Researchers can use this same method to identify cell types not previously known to play a role in a particular disease, expanding our understanding of the disease process and potentially leading to new therapies.

"We now have a parts list of what makes us human," says Mark Gerstein of Yale university, who worked on the project. "What we are doing is figuring out the wiring diagram of how it all works."

The findings rewrite biology 101 for most of us.  Each gene, we were taught, provided the code for a single protein. The proteins were the building blocks of cells, and the products made by the cells, from compounds called growth factors to signal-carrying chemicals. An intermediary genetic structure called RNA carried this information. ENCODE shows this is not quite so straightforward, that RNA generates the 40 million switches that can affect how and when many things happen within the cells.

“This is another grand chapter in the ongoing and historic research story that is unraveling the details about how life works, and how disease occurs,” Collins said.

In the News: Genome Brings Ancient Girl to Life

This replica of a tiny finger bone from Denisova Cave yielded an entire genome. Photo: Max Planck Institute for Evolutionary Anthropology.

by Adrian Cho, ScienceNOW

In a stunning technical feat, an international team of scientists has sequenced the genome of an archaic Siberian girl 31 times over, using a new method that amplifies single strands of DNA. The sequencing is so complete that researchers have as sharp a picture of this ancient genome as they would of a living person’s, revealing, for example that the girl had brown eyes, hair, and skin. “No one thought we would have an archaic human genome of such quality,” says Matthias Meyer, a postdoc at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. “Everyone was shocked by the counts. That includes me.”


That precision allows the team to compare the nuclear genome of this girl, who lived in Siberia’s Denisova Cave more than 50,000 years ago, directly to the genomes of living people, producing a “near-complete” catalog of the small number of genetic changes that make us different from the Denisovans, who were close relatives of Neandertals. “This is the genetic recipe for being a modern human,” says team leader Svante Pääbo, a paleogeneticist at the institute.

Ironically, this high-resolution genome means that the Denisovans, who are represented in the fossil record by only one tiny finger bone and two teeth, are much better known genetically than any other ancient human—including Neandertals, of which there are hundreds of specimens. The team confirms that the Denisovans interbred with the ancestors of some living humans and found that Denisovans had little genetic diversity, suggesting that their small population waned further as populations of modern humans expanded. “Meyer and the consortium have set up the field of ancient DNA to be revolutionized—again,” says Beth Shapiro, an evolutionary biologist at the University of California, Santa Cruz, who was not part of the team. Evolutionary geneticist Sarah Tishkoff of the University of Pennsylvania agrees: “It’s really going to move the field forward.”


Pääbo’s group first gave the field a jolt in May 2010 by reporting a low-coverage sequence (1.3 copies on average) of the composite nuclear genome from three Neandertals. They found that 1% to 4% of the DNA of Europeans and Asians, but not of Africans, was shared with Neandertals and concluded that modern humans interbred with Neandertals at low levels.

Just 7 months later, the same group published 1.9 copies on average of a nuclear genome from a girl’s pinky finger bone from Denisova Cave. They found she was neither a Neandertal nor a modern human—although bones of both species had been found in the cave—but a new lineage that they called Denisovan. The team found “Denisovan DNA” in some island Southeast Asians and concluded that their ancestors also interbred with the ancestors of Denisovans, probably in Asia.

But these genomes were too low quality to produce a reliable catalog of differences. Part of the problem was that ancient DNA is fragmentary, and most of it breaks down into single strands after it is extracted from bone.

Meyer’s breakthrough came in developing a method to start the sequencing process with single strands of DNA instead of double strands, as is usually done. By binding special molecules to the ends of a single strand, the ancient DNA was held in place while enzymes copied its sequence. The result was a sixfold to 22-fold increase in the amount of Denisovan DNA sequenced from a meager 10-milligram sample from the girl’s finger. The team was able to cover 99.9% of the mappable nucleotide positions in the genome at least once, and more than 92% of the sites at least 20 times, which is considered a benchmark for identifying sites reliably. About half of the 31 copies came from the girl’s mother and half from her father, producing a genome “of equivalent quality to a recent human genome,” says paleoanthropologist John Hawks of the University of Wisconsin, Madison, who was not part of the team.

Now, the view of the ancient genome is so clear that Meyer and his colleagues were able to detect for the first time that Denisovans, like modern humans, had 23 pairs of chromosomes, rather than 24 pairs, as in chimpanzees. By aligning the Denisovan genome with that of the reference human genome and counting mutations, the team calculated that the Denisovan and modern human populations finally split between 170,000 and 700,000 years ago.

The researchers also estimated ancient Denisovan population sizes by using methods to estimate the age of various gene lineages and the amount of difference between the chromosomes the girl inherited from her mother and father. They found that Denisovan genetic diversity, already low, shrank even more 400,000 years ago, reflecting small populations at that time. By contrast, our ancestors’ population apparently doubled before their exodus from Africa.
The team also counted the differences between Denisovans and chimps, and found that they have fewer differences than do modern people and chimps. The girl’s lineage had less time to accumulate mutations, and the “missing evolution” suggests she died about 80,000 years ago, although the date is tentative, says co-author David Reich, a population geneticist at Harvard University. If this date—the first proof that a fossil can be directly dated from its genome—holds up, it is considerably older than the very rough dates of 30,000 to more than 50,000 years for the layer of sediment where the fossils of Denisovans, Neandertals, and modern humans all were found.

The team says the new genome confirms their previous findings, showing that about 3% of the genomes of living people in Papua New Guinea come from Denisovans, while the Han and Dai on mainland China have only a trace of Denisovan DNA. Furthermore, the team determined that Papuans have more Denisovan DNA on their autosomes, inherited equally often from both parents, than on their X chromosomes, inherited twice as often from the mother. This curious pattern suggests several possible scenarios, including that male Denisovans interbred with female modern humans, or that these unions were genetically incompatible, with natural selection weeding out some of the X chromosomes, Reich says.

The new genome also suggests one odd result. By using the detailed Denisovan genome to sharpen the view of their close cousins the Neandertals, the team concludes that living East Asians have more Neandertal DNA than Europeans have. But most Neandertal fossils are from Europe; paleoanthropologist Richard Klein of Stanford University in Palo Alto, California, calls the result “peculiar.”

Most exciting to Pääbo is the “nearly complete catalog” of differences in genes between the groups. This includes 111,812 single nucleotides that changed in modern humans in the past 100,000 years or so. Of those, eight were in genes associated with the wiring of the nervous system, including those involved in the growth of axons and dendrites and a gene implicated in autism. Pääbo is intrigued in particular by a change in a gene that is regulated by the so-called FOXP2 gene, implicated in speech disorders. It is “tempting to speculate that crucial aspects of synaptic transmission may have changed in modern humans,” the team wrote. Thirty-four genes are associated with disease in humans. The list suggests some obvious candidates for gene-expression studies. “The cool thing is that it isn’t an astronomically large list,” Pääbo says. “Our group and others will probably be able to analyze most of them in the next decade or two.”

Back in Leipzig, the mood is upbeat, as researchers pull fossil samples off the shelf to test anew with “Matthias’s method.” First on Pääbo’s list: Neandertal bone samples, to try to produce a Neandertal genome to rival that of the little Denisovan girl.

This story provided by ScienceNow, the daily online news service of the journal Science.

Researchers Find a Gene for Fear

Harvard Gazette Archives

Vadim Bolshakov (right) turned normally timid mice into daredevils by 'knocking out' one of their genes. The knockout rodents were more willing to explore unknown places and less intimidated by shocks and loud noises. With Bolshakov are research fellows Ryong-Moon Shin (left) and Keith Tully. (Staff photo Rose Lincoln/Harvard News Office)

Researchers find a gene for fear

May lead to new anxiety drugs

by William J. Cromie
Harvard News Office

A team of researchers from Harvard, Columbia, and Rutgers universities has found the seat of fear. It's located in a pea-sized area deep in the brain of all mammals, from gerbils, to lions, to humans. And it's involved in both inborn fear and the dread we acquire from dealing with people and things that hurt us.
 
The scientists already knew that fear forms in the amygdala (a-mig-da-la), an almond-shaped mass of gray matter. But a closer look revealed the presence of a gene that produces a protein known as "stathmin," a stimulant of fear and anxiety. The scientists' investigations were done with mice because they involved genetic engineering and surgical slicing of the brain.   "This is the first time it has been shown that the protein stathmin is linked to brain circuits that register both inborn alarm and acquired memories of fear," says Vadim Bolshakov of Harvard Medical School and Harvard-affiliated McLean Hospital. "Because it is so essential for survival, memory for fear is easily established, very resistant to extinction, and normally lasts for a lifetime."  

The finding provides a deeper understanding of how learning and memory take place. It also could lead to new treatments for a variety of mental disorders including generalized anxiety, panic, phobias, obsessive-compulsive disorder, and the post-traumatic stress disorder that is being brought back from the battlefields of Iraq and Afghanistan.   Besides Bolshakov and his colleagues at McLean Hospital, the research team involved Eric Kandel and colleagues at Columbia University, and Gleb Shumyatsky and colleagues at Rutgers. Kandel won the 2000 Nobel Prize in medicine. They reported their results in the November issue of the journal Cell.

Overcoming anxiety

Once you find a protein like stathmin, you have to prove that it does what you think it does. One sure way is to remove, or knock out, the gene behind the protein and test the reaction of the mice in fearful situations.   Both the "knockouts" and a comparison group of normal mice received a mild electric shock to their feet, a jolt accompanied by a loud sound. The rodents quickly associate the sound and the shock. When they heard the sound they froze in expectation. But mice without the stathmin gene froze for a significantly shorter time than the normal ones.  
Mice placed in new surroundings naturally avoid the most open or exposed areas. But those uninhibited by stathmin spent more time exploring open, unknown spaces.  

Other tests were run to rule out the possibility that the gene loss left the knockouts with less pain sensitivity, enhanced locomotion, or less intelligence. Only one conclusion remained: Without the restraining effects of stathmin, mice display less fear in response to both learned (shock) and natural (open space) situations.  

The fact that human brain circuits involved in fear are believed to be similar to those of mice suggests that stathmin-knockout mice can be used to further explore innate and learned dread in humans, the researchers note. "Individual human differences in inborn fear levels, as well as the ability to acquire fear, might result from different levels of gene expression," Bolshakov points out. "Thus it should be possible to determine each person's predisposition to the development of different anxiety states." In other words, how adverse an individual would be to bullying by classmates, the stress of combat, or family tragedies.  

However, Bolshakov cautions, "It's important to realize that stathmin is not the only gene whose activity might regulate learned and inborn fear behaviors. The mechanisms which we have identified in our study are likely to act in concert with other mechanisms and other genes to achieve the highly efficient and lasting system of fear response."

Human questions

Among the possibilities opened up by this discovery is the opportunity to compare levels of stathmin activity in humans with different forms of anxiety. "I'm sure that medical researchers and drug companies are going to pursue this line of study, and that we'll be hearing a lot about that in the next few years," Bolshakov says.  

As director of the Cellular Neurobiology Laboratory at McLean Hospital, however, he will be traveling another road. "I am personally interested in more fundamental work that could lead to better understanding of the brain changes that accompany learning and memory."   According to a long-held theory, learning takes place and memories form when the same signals travel repeatedly between specific brain cells.

Communication between these cells grows stronger with repetition. Eventually, these cells no longer need to be stimulated by an outside source such as a familiar landscape or input from a teacher. "Our study of the stathmin gene and fear," notes Bolshakov, "is the first time anyone has been able to correlate a change in specific gene activity with a change in brain circuit function and with behavior, i.e., acquiring a memory."

Being born with fear and acquiring memories of it from dangerous situations is so important for survival, it's something that must have been around for millions of years. Birds, as well as snakes and other reptiles, boast amygdalae. Fish also possess a brain structure that seems to function like one. "It appears that all these animals could be conditioned to fear, and that they will demonstrate fear response, such as an increased heart rate," Balshakov says.

Scishow Youtube video on Epigenetics

Hank Green and cat.

Scishow and Crash Course: Why Isn’t School This Cool?
By Bart Leib
Science education and Doctor Who references, together at last! Expect nothing less when geeks are given the stage.

Scishow is a thrice-weekly education channel on YouTube. Hosted by singer/songwriter, entertainer, entrepreneur and Vlogbrother Hank Green, Scishow delves into all thing science, from Jupiter’s sixth moon Europa to epigenetics to awesome inventions by African Americans. They’re amusing, and teach in a manner so straightforward that my five-year-old son follows and enjoys most of them.

Hank and his brother John, a bestselling novelist, are possibly best known for their Vlogbrothers YouTube channel, which they started in 2007 and has more than 200 million combined views. Hank and John share another YouTube Channel, Crash Course. On Crash Course Hank teaches biology, while John covers history:

(These YouTube channels are part of a larger YouTube project called YouTube EDU, which is dedicated to delivering a broad range of educational videos.)

Scishow and Crash Course are both clever, fast-paced, and entertaining. More importantly, the information they deliver sticks. When my son found a nickel at the bottom of his backpack he immediately started chattering about a recent Scishow video Earth’s Not-So-Juicy Center (although I did have to explain to him that, no, there aren’t tons of melted U.S. five-cent coins at the center of the earth…).

Hank and John are great examples of geeks who use their powers to do good, and they deserve separate posts for all their many awesome projects. Their educational videos are a terrific way to engage your kids in history and science without boring them to tears.

Here's a link to the show on epigenetics:

http://www.youtube.com/watch?v=kp1bZEUgqVI

NOVA Program: Epigentics

Epigenetics
Environmental factors can alter the way our genes are expressed, making even identical twins different. Aired on July 24, 2007 on PBS.

Once nurture seemed clearly distinct from nature. Now it appears that our diets and lifestyles can change the expression of our genes. How? By influencing a network of chemical switches within our cells collectively known as the epigenome. This new understanding may lead us to potent new medical therapies. Epigenetic cancer therapy, for one, already seems to be yielding promising results.

http://www.pbs.org/wgbh/nova/body/epigenetics.html

More Complexity, Please: Health -- Not Just Genes -- Epigenetics

From yee Wiki:

 In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence – hence the name epi- (Greek: επί- over, above, outer) - genetics. It refers to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such changes are DNA methylation and histone modification, both of which serve to regulate gene expression without altering the underlying DNA sequence.

Conclusive evidence supporting epigenetics show that these mechanisms can enable the effects of parents' experiences to be passed down to subsequent generations.

These changes may remain through cell divisions for the remainder of the cell's life and may also last for multiple generations. However, there is no change in the underlying DNA sequence of the organism; instead, non-genetic factors cause the organism's genes to behave (or "express themselves") differently.

One example of epigenetic changes in eukaryotic biology is the process of cellular differentiation. During morphogenesis, totipotent stem cells become the various pluripotent cell lines of the embryo, which in turn become fully differentiated cells. In other words, a single fertilized egg cell – the zygote – changes into the many cell types including neurons, muscle cells, epithelium, endothelium of blood vessels, etc. as it continues to divide. It does so by activating some genes while inhibiting others.

In 2011, it was demonstrated that the methylation of mRNA has a critical role in human energy homeostasis. Obesity associated FTO gene is shown to be able to demethylate N6-methyladenosine in RNA. This opened the related field of RNA epigenetics.

For more on Wiki:


http://en.wikipedia.org/wiki/Epigenetics

In the News: Frankenjelly

Artificial Jellyfish, 'Medusoid,' Made From Rat Heart Cells

By Ned Potter July 23, 2012

A close-up view of engineered rat cardiac muscle researchers used to power an artificial, tissue-engineered jellyfish. (Janna Nawroth/Caltech)

If you watch the mesmerizing pulses of a jellyfish in water, it might occur to you that they sometimes resemble the pulses of the human heart. A jellyfish doesn't swim so much as it beats, pushing its way forward.

Kevin Kit Parker, a professor at Harvard University, had that thought on a visit to the New England Aquarium, and teamed up with John Dabiri and Janna Nawroth of the California Institute of Technology. They all work in the nascent field of bioengineering, and they and their team might have started something.

They created a sort of artificial jellyfish -- it looks like one, and swims like one but doesn't have a single cell of jellyfish tissue in its body.

Instead, they grew their jellyfish from the heart muscle cells of a rat. Yes, a rat. They gave it the nickname "Medusoid" and published their results in the journal Nature Biotechnology.

"What we were able to do was replace jellyfish muscle with muscle from a heart," said Dabiri. "And then we were able to replace the jelly, if you will, in a jellyfish with a silicone rubber substance. And by putting those components together, the rat heart muscle and the silicone rubber, we were able to re-engineer the function of a living jellyfish."

The scientists grew Medusoid on a tiny frame, so that it had a round shape and eight appendages, much as a real jellyfish does. They used computer engineering to make sure what shape would work best. They placed it in a tank, applied a small electric charge, and it pulsed its way through the water, looking very much like a jellyfish.

Why do such an experiment? The scientists say it really has very little to do with jellyfish or rats, and a lot to do with the human body.

In the not-too-distant future, Dabiri, said, it may be possible to give patients heart valves or pacemakers made from their own cells. No metal box to implant, no batteries to replace, and much less risk that the body will reject it.

"Instead of heart valves made out of aluminum or plastic, they would be built out of your own biological material, your heart cells, your tissue," he said. "That makes it more biocompatable and potentially longer-lived."

There are many problems still to be solved, say the researchers; their artificial jellyfish, for instance, is far simpler than a real one. A real one can steer through the water; Medusoid could only go straight.

But If Medusoid can be made to mimic a jellyfish, something that mimics part of a heart may not be far off.

"We're not as far away as you might think," said Dabiri. "I think within the next five to 10 years you can start to see these therapies actually be used."

Let's hope someone doesn't bioengineer the Blob,