Tag Archives: epigenetic

Study on mice: Exercising later in life can keep your muscles young

Exercising can not only make you feel younger, but it can also actually keep you younger as well. A study on mice suggests that exercising, even later in life, can do wonders for your muscles. In addition to underscoring the importance of staying active, the study could also help us uncover some of the secrets of rejuvenation.

Even though some diseases are inherited, we can still improve our overall health through lifestyle choices such as diet and exercise. Still, whatever the reason, the genes related to some of these conditions must be expressed for them to develop. So how does this happen?

A new study has brought us closer to an answer by mapping the genetic changes involved in rejuvenating the muscle cells of elderly mice put on an exercise program.

Turning genes on and off

The analysis centers on DNA, the “blueprint” for our bodies. DNA consists of four bases, called cytosine, guanine, adenine, and thymine, and the process used to help manage these massive helixes: a methyl molecule composed of one carbon and three hydrogen atoms. These atoms attach themselves to one of the four bases (cytosine) to form what’s known as a CpG site.

When this occurs, the CpG becomes methylated and the site produces proteins to regulate something in the body — whatever that something may be. In contrast, the region becomes unmethylated when you lose that methyl group, turning that gene off. In this way, a process called DNA methylation can promote or inhibit the expression of specific genes — whether it’s stopping a tumor, preventing cancer, or activating genes responsible for causing wrinkles in old age. This process is constant, occurring billions of times a second in every cell throughout the body, and we’re just starting to understand it.

DNA methylation is one of the many mechanisms of epigenetics, where inborn or acquired changes in DNA don’t touch the actual sequence – meaning a person can potentially reverse things like fat deposits through diet or exercise. More and more studies are starting to suggest that this is an unharnessed and robust process, linked to longevity and the regulation of lifespan in most organisms on earth.

The current study attempts to further this theory using lifestyle interventions such as exercise to roll back genetic aging in skeletal muscle – measuring the animal’s ‘epigenetic clock’ for accuracy. This clock is measured via methylation levels in the blood to reflect exposures and disease risks independent of chronological age, providing an early-warning system and a true representation of a period of existence.

Kevin Murach, an assistant professor at the University of Arkansas, says, “DNA methylation changes in a lifespan tend to happen in a somewhat systematic fashion. To the point, you can look at someone’s DNA from a given tissue sample and with a fair degree of accuracy predict their chronological age.”

Using exercise to turn back the clock

The study design was relatively simple: mice nearing the end of their natural lifespan, at 22 months, were given access to a weighted exercise wheel to ensure they built muscle. They required no coercion to run on the wheel, with older mice running from six to eight kilometers a day, mostly in spurts, and younger mice running up to 10-12 kilometers.

Results from the elderly mice after two months of weighted wheel running suggested they were the epigenetic age of mice eight weeks younger, compared to sedentary mice of the same maturity.

The team also used the epigenetic clock to map a multitude of genes involved in the formation and function of muscles, including those affected by exercise. Blood work indicated that the genes usually over methylated (hypermethylated) in old age resumed normal methylation in the active aged mice, unlike those mapped in their sedentary counterparts.

For instance, the rbm10 gene is usually hypermethylated in old age, disrupting the production of proteins involved in motor neuron survival, muscle weight & function, and the growth of striated muscle. Here it was shown to undergo less methylation in older mice who exercised, improving its performance. Normal methylation levels also resumed across the Timm8a1 gene, keeping mitochondrial function and oxidant defense at workable levels – even where neighboring sites exhibited dysfunctional epigenetic alterations.

More work is needed to harness DNA methylation

Murach notes that when a lifespan is measured incrementally in months, as with this mouse strain, an extra eight weeks — roughly 10 percent of that lifespan — is a noteworthy gain, further commending the importance of exercise in later life.

He adds: that although the connection between methylation and aging is clear, methylation and muscle function are less clear. Despite these sturdy results, Murach will not categorically state that the reversal of methylation with exercise is causative for improved muscle health. “That’s not what the study was set up to do,” he explained. However, he intends to pursue future studies to determine if “changes in methylation result in altered muscle function.”

And, “If so, what are the consequences of this?” he continued. “Do changes on these very specific methylation sites have an actual phenotype that emerges from that? Is it what’s causing aging or is it just associated with it? Is it just something that happens in concert with a variety of other things that are happening during the aging process? So that’s what we don’t know.”

He summarizes that once the medical community has mapped the mechanics of dynamic DNA methylation in muscle, their work could provide modifiable epigenetic markers to improve muscle health in the elderly. 

How dad’s bad diet may have impacted your disease risk

We all know that expecting moms need to take good care of themselves, so that the environment in the womb is as optimal as possible to reduce disease risk to the developing fetus. That means eating a healthy well balanced diet, achieving the appropriate amount of weight gain during pregnancy, managing metabolic problems like gestational diabetes if they arise, and avoiding harmful exposures like alcohol and recreational drugs.

Evidence shows that a father's diet prior to conception, may impact gene expression and future health, in his offspring.

Evidence shows that a father’s diet prior to conception, may impact gene expression and future health, in his offspring.

A growing body of evidence now also implicates a role for dad in the risk of disease imparted to the fetus. By this, we’re not speaking of the inheritance of genetic mutations, but instead effects that arise in the father due to his environmental exposures, which are then passed onto the fetus at the time of conception. These types of inheritable traits are known as epigenetic, as opposed to genetic, because they are not passed on from parent to child through changes in the DNA. In rats, it has been shown that there is good evidence that dad’s diet can have an influence on his offspring’s risk for diabetes, high blood pressure, and high cholesterol (Rando and Simmons). But, if these risks are not passed from father to offspring by the inheritance of his DNA, then how is the affect passed on? In the January 22, 2016 issue of the journal Science, Oliver Rando, in Lyon, France demonstrates one possible mechanism, by which the environment of the father, prior to fertilization of the mother’s egg with his sperm, leads to profound and long-lasting changes in the development of their fetus.

Dr. Rando, and his team, were able to show that when male rats were fed a diet low in protein, there was a measurable shift in the number and types of small RNA molecules found in their mature sperm. A significant increase was observed in the amount of certain transfer-RNA (tRNA) molecules in the sperm of male rats fed the low protein diet versus those on a normal diet. The conventional function of tRNA is to deliver amino acids to the ribosome, so they can be joined together to make a protein. There are different tRNAs molecules that are specific for each amino acid.

Upon fertilization of the egg cell, the sperm introduces small RNA molecules which influence genetic programming of the developing embryo.

Upon fertilization of the egg cell, the sperm introduces small RNA molecules which influence genetic programming of the developing embryo.

Rando’s team found that the increase in sperm tRNA, seen in low protein fed rats, were not whole molecules, but only fragments of tRNA. The tRNA fragments were not produced by the developing sperm cells themselves, as might be expected, but were fragmented in other cells of the male reproductive tract, then transferred into the sperm as they underwent their maturation process. Upon fertilization of the egg, these small RNAs enter the egg from the sperm, altering expression of genes in the developing embryo. Using embryonic stem cells, it was shown that the effect of these tRNA fragments in the fertilized egg, is at least in part, realized by the changes they produce an endogenous retroelement called MERVL, a factor known to be an important in enhancing gene expression in the early embryo. This ultimately leads to an over expression of some genes along the cholesterol pathway in the developing fetal liver, potentially influencing future metabolic health.

The dietary changes in the male rats led to changes in the the small RNA molecules in their reproductive tract, which were transferred into their sperm, ultimately affecting gene expression in the fertilized egg, and adversely affecting the risk of disease in the offspring. It is not known if these same mechanisms would apply to humans -although there is no reason to think that they might not – or which other environmental exposures of the future father could also be important in the health of his offspring. It may still be too early to make any evidence based recommendations for guys hoping to start a family, but perhaps further research will help better define how much impact diet, exercise, and other habits have on their future health of their sons and daughters.

 

Reference Articles:
1. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals.
Science. 2016 Jan 22;351(6271):391-6. doi: 10.1126/science.aad6780. Epub 2015 Dec 31.
Sharma U1, Conine CC1, Shea JM1, Boskovic A1, Derr AG2, Bing XY1, Belleannee C3, Kucukural A2, Serra RW1, Sun F1, Song L1, Carone BR1, Ricci EP4, Li XZ5, Fauquier L1, Moore MJ6, Sullivan R3, Mello CC7, Garber M2, Rando OJ

2. I’m eating for two: parental dietary effects on offspring metabolism.Cell. 2015 Mar 26;161(1):93-105. doi: 10.1016/j.cell. 2015.02.021.
Rando OJ1, Simmons RA2.

3. Retrotransposons shape species-specific embryonic stem cell gene expression. Luisa Robbez-Masson and Helen M Rowe
Retrovirology201512:45 DOI: 10.1186/s12977-015-0173-5

4. Regulation of Mouse Retroelement MuERV-L/MERVL Expression by REX1 and Epigenetic Control of Stem Cell Potency
Front Oncol. 2014; 4: 14. Published online 2014 Feb 6. doi:  10.3389/fonc.2014.00014
Jon Schoorlemmer,1,2,* Raquel Pérez-Palacios,1 María Climent,3,† Diana Guallar,1,† and Pedro Muniesa3

starvation

Genetic response to starvation is passed down to at least three generations

starvation

Photo: newgrounds.com

In 1944, the Nazis caused widespread famine in Western Netherlands after they blocked food supplies. A group of pregnant women living in the Netherlands, labouring under starvation conditions imposed by a harsh winter and food embargo, gave birth to relatively small babies. When their children grew up, in relative prosperity, to have children of their own their babies were unexpectedly small. This was the birth place of epigenetics – the study of genetic changes sparked by external factors that become passed down to subsequent generations. A new study may have discovered underlying  mechanism that transfers starvation response to future generations, after they studied food-deprived worms.

The famine that lingers

“There are possibly several different genetic mechanisms that enable inheritance of traits in response to changes in the environment. This is a new field, so these mechanisms are only now being discovered,” said Dr. Oded Rechavi of Tel Aviv University’s Faculty of Life Sciences and Sagol School of Neuroscience. “We identified a mechanism called ‘small RNA inheritance’ that enables worms to pass on the memory of starvation to multiple generations.”

RNA (ribonucleic acid) molecules differ from DNA molecules in several ways. RNA molecules are single-stranded, and their nucleotides contain ribose rather than deoxyribose sugar. Like DNA, RNA nucleotides each contain one of four organic bases, but whereas adenine, cytosine, and guanine nucleotides occur in both DNA and RNA, thymine nucleotides are found only in DNA. In place of thymine nucleotides, RNA molecules contain uracil nucleotides. A type of RNA, messenger RNA molecules (mRNA) instruct the production of certain proteins that allows cells to function properly. Basically, all RNA have a regulatory function with different types of RNA being involved in different types regulatory activity. Small RNAs are maybe the most intriguing – short molecules, hence the name, that regulate gene expression by shutting them on or off.

Dr. Rechavi first became interested in studying starvation-induced epigenetic responses following a discovery made as a post doctorate in Prof. Hobert’s lab at Columbia University Medical Center in New York. “Back then, we found that small RNAs were inherited, and that this inheritance affected antiviral immunity in worms. It was obvious that this was only the tip of the iceberg,” he said.

The researchers grew common worms (C.elegans nematodes) in a food-deprived environment and followed their genetic markup. They noticed the starved worms  responded by producing small RNAs, which function by regulating genes through a process that is known as RNA interference (RNAi). The researchers discovered that the starvation-responsive small RNAs target genes that are involved in nutrition and that these became inherited by at least three subsequent generations of worm specimens.

“We were also surprised to find that the great-grandchildren of the starved worms had an extended life span,” said Dr. Rechavi. “To the best of our knowledge, our paper provides the first concrete evidence that it’s enough to simply experience a particular environment — in this case, an environment without food — for small RNA inheritance and RNA interference to ensue. In this case, the environmental challenge is starvation, a very physiologically relevant challenge, and it is likely that other environments induce transgenerational inheritance of small RNAs as well.

“We identified genes that are essential for production and for the inheritance of starvation-responsive small RNAs. RNA inheritance could prove to be an important genetic mechanism in other organisms, including humans, acting parallel to DNA. This could possibly allow parents to prepare their progeny for hardships similar to the ones that they experience,” Dr. Rechavi said.

There are many reasons why this research is really important. It shows yet again how important external factors are to development and how quickly responses to significant changes or events in our lives are passed on to offspring. For instance, we know that fear and trauma are transmitted to our children and children’s children – even sexual promiscuity.

The findings were reported in the journal Cell.

Harpegnathos saltator ants undergo dramatic physiological changes triggered by heightened dopamine levels, following ascension of the colony's social ladder. It's not just in their heads, when these ants climb in their society, they change their bodies as well!

Brawls for colony domination transforms winning worker ants into queens without DNA changes

Harpegnathos saltator ants undergo dramatic physiological changes triggered by heightened dopamine levels, following ascension of the colony's social ladder. It's not just in their heads, when these ants climb in their society, they change their bodies as well!

Harpegnathos saltator ants undergo dramatic physiological changes triggered by heightened dopamine levels, following ascension of the colony’s social ladder. It’s not just in their heads, when these ants climb in their society, they change their bodies as well! Photo: scienceblogs.com

In the animal kingdom, especially among those that are social, you’ll see a number of strategies employed to help the group’s chances of surviving. To each his own. For instance most ant colonies employ a social hierarchy where most members, like the worker ants, are rendered functionally sterile and only the absolute top of the ladder is allowed to reproduce (the queen). A particular ant species stands out in this respect because of the uncanny behavior of some of its worker ants, who are able to morph into queens – that is to obtain reproductive capabilities – by suffering dramatic physical changes. All, however, without any chances succumbing to the DNA code. Now, researchers at North Carolina State University, Arizona State University and the U.S. Department of Agriculture have found out why and how this happens: more dopamine.

A morphing ant

The Indian jumping ants (Harpegnathos saltator) are one of the most fascinating insects and an unique ant species. When an H. saltator colony’s queen dies, the female workers engage in ritual fights to establish dominance. While these battles can be fierce, they rarely result in physical injury to the workers. Ultimately, a group of approximately 12 workers will establish dominance and become a cadre of worker queens or “gamergates.”

Here’s where the interesting stuff happens, though. The worker ants who have proven themselves to be part of the elite undergo dramatic physical changes:   their brains shrink by 25 percent; their ovaries expand to fill their abdomens; and their life expectancy jumps from about six months to several years or more. These changes occur after certain genes are either switched on or off, which in turn are influenced by environmental factors, thus epigenetics.

“We wanted to know what’s responsible for these physical changes,” says Dr. Clint Penick, lead author of a paper describing the work and a postdoctoral researcher at NC State. “The answer appears to be dopamine. We found that gamergates have dopamine levels two to three times higher than other workers.”

Dopamine: the winner’s hormone

The researchers took a subset of workers from a colony (Colony A) and separated them from their gamergates. These workers effectively formed their own colony (Colony B) and began fighting to establish dominance, as expected. Those workers who began to distinguish themselves as future gamergates of Colony B were removed at their own turn from the colony. Subsequent analysis reveled that these dominant ants produced more dopamine than regular worker ants, yet still lower than full fledged gamergates.

Finally, the researchers introduced these dominant worker ants back to colony A where the workers there recognized the changes in the dominant workers and exhibited “policing” behavior, holding down the dominant ants so that they couldn’t move. Within 24 hours, the dopamine levels in the dominant workers had dropped back to normal; they were just regular worker ants again. This proved that dopamine was the key factor that elicited this kind of behavior and triggered the massive physiological changes witnessed by the researchers.

“This tells us that the very act of winning these ritual battles increases dopamine levels in H. saltator, which ultimately leads to the physical changes we see in gamergates,” Penick says. “Similarly, losing these fights pushes dopamine levels down.”

The findings, reported in a paper published in The Journal of Experimental Biology, could help shed light on other similar social behaviors reported in other insects.

“Policing behavior occurs in wasps and other ant species, and this study shows just how that behavior can regulate hormone levels to affect physiology and ensure that workers don’t reproduce,” he explains.

This male mouse has left brownish scent marks by depositing pheromone-rich urine on a fence separating his territory from those of other mice. (c) Doug Cornwall, University of Utah

Promiscuous female mice breed sexier male offspring. Research may help conservation efforts

University of Utah researchers found that female mice that live in a competitive social environment and choose to mate casually with multiple partners give birth to males who are much more attractive to female mice, at the cost of a dramatic cut in life expectancy however. You only have one life, says the sexy male mouse.

The research is a fantastic example of epigenitics at work –  how parents’ environment modifies their offspring’s genes; in other words, not only do parents’ gene count, but also a great contribution in the overall offspring genetic mark-up depends on the environment.

“If your sons are particularly sexy, and mate more than they would otherwise, it’s helping get your genes more efficiently into the next generation,” says biology professor Wayne Potts, senior author of the new study.

“Only recently have we started to understand that environmental conditions experienced by parents can influence the characteristics of their offspring. This study is one of the first to show this kind of ‘epigenetic’ process working in a way that increases the mating success of sons.”

A promiscuous family

Typically, lab mice breeding is skewed from the animals’ natural conditions. Domesticated mice are generally monogamous and hardly touch each other in the cage – go figure.   “In nature, mice must seek out and choose their own mates – a process that is eliminated in standard lab breeding conditions,” says   University of Utah doctoral student Adam C. Nelson.

This male mouse has left brownish scent marks by depositing pheromone-rich urine on a fence separating his territory from those of other mice. (c) Doug Cornwall, University of Utah

This male mouse has left brownish scent marks by depositing pheromone-rich urine on a fence separating his territory from those of other mice. (c) Doug Cornwall, University of Utah

To simulate seminatural conditions, the researchers bred mice in a  22-foot-by-13.5-foot enclosure (mice barn),  divided by wire mesh fencing into six sections or territories which were easy to cross in and out by the mice. However, some of these territories were made more appealing than others, as they had more food, water or a more spacious nest box. So, the mice had to compete with each other – almost like in natural conditions. As a measure of control, the mice which were introduced descended from wild mice and were bred for 10 consecutive generations  in domesticated conditions: in cages with assigned mates.

Prospective parents first lived in one of two environments: the promiscuous mouse barn or monogamous cages. They were removed after eight weeks and bred in cages in four combinations: mother and father from promiscuous environment; both from monogamous environment; mother from promiscuous environment and father from monogamous environment; and vice versa.

Regardless of the father’s origin, the researchers found that females which came from promiscuous environments gave birth to sons which  produced more pheromones than sons of monogamous, domesticated moms.  More than just a classy perfume, mice pheromones are a sex magnet and the stronger the scent, the harder it is for females to resist the call. Hey, guys, stop looking for deodorants online now – it doesn’t work for humans that way.

Back to pheromones. Yes, lady mice love these, understandably: the more the male’s scent is saturated with  pheromones produced in mouse urine and other glands the more the said male with mate. Apparently, male mice who came from promiscuous parents produced 31 percent more major urinary proteins or “sexy” pheromones  than male mice from caged monogamous parents. Previous research established that male mice with promiscuous parents actually produce about one-third more progeny than sons of monogamous parents.

It’s clear that the social life of female mice has a great impact on their male offspring, something that is described through epigenetic inheritance. In epigenetic inheritance, however, genes aren’t mutated, instead genes are either activated or expressed. So, epigenetics deals with gene modification and a common mechanism is methylation , a change that reduces a gene’s production of a protein.  In the new study, Nelson and co-authors looked at a pheromone gene named Mup11. They found that methylation of the gene was twice as high in sons of monogamous, domesticated mice than it was in sons of promiscuous, social mice. So the sons of the promiscuous mice were able to produce more pheromone.

Sexy to die for

This illustration depicts how the researchers liken the way mouse pheromones act much like a male peacock’s tail to attract mates. Illustration by Sarah Bush, University of Utah

This illustration depicts how the researchers liken the way mouse pheromones act much like a male peacock’s tail to attract mates. Illustration by Sarah Bush, University of Utah

You win some, you lose some. Apparently, those enhanced pheromones come at a huge price tag, though. n. Only 48 percent of them lived to the end of the experiment, compared with 80 percent of the male mice whose parents lived monogamously in cages.

“Production of pheromones is outrageously expensive,” says biology professor Wayne Potts, senior author of the new study.  “A single mouse’s investment in pheromone production compares with the investment that 10 male peacocks make in the production of their tails, which also are used to attract females.”

Besides gaining insights in mice sex habits and practices, the University of Utah preset research has some important practical applications. Through a better understanding of how pheromones work and how these influence mating, scientists, workers or volunteers associated with conservation efforts may improve their success with captive-breeding programs. It might be better, for instance, than forcing pandas to watch panda porn in hope they might get aroused and actually get off their lazy butts to mate.

“It’s amazing how often reintroduction of captive-breed endangered species fails – it’s estimated to be as high as 89 percent,” says Potts. “Domestication stimulates epigenetic mechanisms that make animals less fit for nature.”

 

how a pig is cloned

Cloned animals aren’t identical – we’re still far from the perfect clone

It is generally believed that a cloned animal is identical to its host from where cells were initially harvested, however this may be wrong. Researchers at the  National Veterinary Institute at the Technical University of Denmark have provided evidence that suggests cloned pigs are just as genetically varied as normally bred pigs, supporting the idea that cloning as it is performed today is far from being perfect. The findings are the latest in a number of similar reports from other Universities, calling for attention to the matter and consideration of this fact when carrying research on cloned animals – especially in the field of medicine.

Currently it is believed that cloned animals are more akin to one another compared to normally bred animals, since they are copies of one another just like identical twins are. This means they have fewer genetic variants, allowing scientists to gather results with fewer specimens at hand. Researchers from Denmark however argue that this isn’t true, and that actually  pig clones are often highly varied and also respond differently than non-clones – which goes against the popular belief.

For their study, the researchers looked at how the immune system of cloned and normally bred pigs responded to obesity. Comparisons were made of so-called acute phase proteins in the blood and of the gene expression of immune factors in three types of adipose tissue and in liver tissue.

Why clones aren’t identical

Their findings suggest that cloned animals have an altered immune system compared to normally bred ones. For instance, the amount of acute phase proteins in the blood increases dramatically during inflammation, however for the clones the levels of some markers were upregulated in relation to the levels in the non-cloned group.

Most importantly, though, it was observed that the variation in the expression of these genetic markers was just as great for cloned pigs as in non-cloned pigs. As an analogy, this is as saying that a quintuplets’ innate immune systems are as different as five regular siblings’. This means cloned animals are indeed different.

how a pig is cloned

It was also observed that cloned animals behave differently from non-cloned animals. For instance cloned pigs were more fearful and anxious than naturally bred pigs. They also weigh less and are often found to have a higher metabolism than non-clones.

Part of the explanation lies in the current methods of cloning, which disrupt the sensitive processes that take place during embryonic development. Then there’s epigenetics – heritable changes in gene expression, which are not caused by changes in the underlying DNA sequence. In other words, you can have two pigs with identical DNA sequences however these cloned animals will be far from being identical since they’ll express completely different genes and thus make them look entirely different.

Hence, researchers have yet to crack the code on how we can control genomic imprinting. Until this happens, the perfect clone is still out of reach. Now, this knowledge is highly important to consider, especially since a lot of scientists working with clones apparently aren’t fully aware of this, according to the Danish researchers.

via  Science Nordic

DANA SMITH

Beating cancer by making it forget what it is [TED VIDEO]

DANA SMITH

(c) DANA SMITH

Dr. Jay Bradner, a physician and chemical biologist at the Dana-Farber Cancer Institute in Boston, makes beating cancer sound easy – darn easy! Through the wonderful information that epigenetics science has delivered in the past decade, he believes cancer can be defeated simply by re-writing its genetic information such that it forgets that it’s a cancer, and starts behaving like a regular cell.

“With all the things cancer is trying to do to kill our patient, how does it remember it is cancer?” asks Bradner.

Researchers in Bradner’s lab have developed a compound that  manipulates epigenetic instructions, and he has sent it out to hundreds of collaborators worldwide. “That’s not common in practice,” says Bradner, “but from first principles, it’s the right thing to do.”

Almost exclusively, research for a prototype drug is kept top-secret by labs, keeping its structure and research findings completely oblivious to the rest of the world. Bradner took an alternate route and simply made it freely accessible from the get to, first by reporting his findings in a paper, then by sending samples to just about any lab interest (you too can ask the good doctor for a sample – you just need to e-mail). Results poured in just after a few months, as possible treatments for other afflictions, besides the rare form of cancer Bradner’s research targeted, such as leukemia, while another lab showed that the compound could be used to poise fat cells to forget they’re fat cells as well. Yes, you could basically eat all you want without gaining weight or fatty tissue.

This research is phenomenal, right on the cutting edge of science, and while Bradner and his team still have quite a while before the first clinical trial is released, their progress is worth noting and, especially, following. For more scientific info and details on results, please check this article on Nature. For an easy to digest pill of insight on the subject at hand, book 10 minutes of your day and watch this incredible TED speech at Boston by Bradner himself.