Another Reason Why You are Not a Chimp

U. Toronto

Humans and chimpanzees share remarkably similar sets of genes.  When measured conventionally, the genes of humans and the genes of chimps are 99% alike.   And yet, chimps do not build cities, do not publish encyclopedias, and do not launch spaceships to Mars and beyond.


Two recent studies:

N. L. Barbosa-Morais et al., “The Evolutionary Landscape of alternative splicing in vertebrate species,” Science, 388, 1587-93, 2012.

J. Merkin et al., “Evolutionary dynamics of gene and isoform regulation in mammalian tissues,”Science, 388, 1593-99, 2012.

provide new information on how two species with very similar DNA patterns can develop so differently in the real world.

The studies from MIT and the University of Toronto, reveal the remarkable degree of difference alternative gene splicing between species -- resulting in distinctly different proteins from the same gene.

“It was somewhat generally assumed that splicing differences that you see between brain and muscle in the mouse would be similar between brain and muscle in the human,” said Donny Licatalosi, professor of RNA molecular biology at Case Western Reserve University in Cleveland, Ohio, who did not participate in the studies, “but what both of these studies are showing is that is not the case. There is a large amount of species-specific alternative splicing.”

...“how do physical and behavioral differences arise if we have a very similar set of genes to that of the mouse, chicken, or frog?” said Ben Blencowe, a cell and molecular biology professor at the University of Toronto, who led one of the studies. A commonly discussed mechanism was variable levels of gene expression, but both Blencowe and Chris Burge, biology and biological engineering professor at Massachusetts Institute of Technology and lead author of the second paper, found that gene expression is relatively conserved among species.

...To assess alternative splicing patterns as well as transcription levels, both groups performed high-throughput sequencing of messenger RNA. They extracted RNA from a large array of organs of different vertebrate species, including frogs, chickens, primates, and humans. “It’s a massive amount of data,” said Cooper.

Blencowe’s team showed that the species-specific alternative splicing changes tended to be driven by differences in the transcripts themselves, which carry a splicing code that guides the splicing machinery—rather than differences in the splicing machinery. For example, human transcripts expressed in mouse cells exhibited human, not mouse, splicing patterns, despite being spliced by mouse machinery.

“These are very important papers that provide for the first time a large-scale view of the evolution of alternative splicing in vertebrates,” said Brent Graveley, professor of genetics and developmental biology at the University of Connecticut, who was not involved in the research. “They demonstrate how dramatically rapidly alternative splicing evolves, and suggest that it might play a role in speciation.”

The incredible capacity for alternative splicing could enable cells to try-out new versions of proteins without risking the complete loss of the originals, said Burge. Of course, if a new version then offers an advantage, the associated sequence changes to the splicing code will be selected for. “It is certainly an attractive model, and we think it is what’s going on,” said Burge. _TheScientist

This remarkably rapid and competitive evolutionary activity is taking place within each cell of almost every tissue inside your body.

Not only does this epigenetic process provide more reasons for differences between species, but it also likely provides more reasons for differences between sub-species. It will probably also eventually reveal significant differences in gene expression between identical twins.

A number of other genetic and epigenetic processes such as copy number variants, transposable elements, non-coding RNAs, non-coding DNAs, unique mutations (each person has about 100 unique mutations in his genome), etc. -- and more to be discovered -- have already provided us with reasons why two individuals with very similar DNA can easily develop significant differences in gene expression.

The alternative splicing mechanisms being elaborated in the two studies above, provide another very powerful source of difference in gene expression -- not only between individuals, but also between body tissues within the same individual. This evolutionary mechanism even introduces differences in gene expression between different cells of the same tissue type.

Biology just keeps getting more and more interesting all the time.

The Promise of Epigenetic Brain Control

[Biotech company Alnylam is] working with a medical device maker, Medtronic, on a way to deliver RNAi [RNA interference] treatment directly to the brain.... RNAi therapy involves researchers producing snippets of RNA, a close relative of DNA, that match a portion of a gene of interest. When administered, this so-called small interfering RNA (siRNA) causes the destruction of that gene's products before it can be turned into a protein. The specificity of RNAi for targeting particular genes has attracted a lot of interest from people who want to use it as a clinical treatment. _Technology Review

Alnylam wants to use RNAi to alter gene expression in Huntington's Disease and other neurodegenerative conditions of the brain.

Technology Review

RNAi control of gene expression is safer than some other forms of genetic therapy, in that the effect of RNAi is temporary -- self-limited. But that means that the therapeutic agent must be introduced repeatedly for the therapeutic effect to continue.

...a recurring challenge for the therapeutic RNAi field is how to deliver the siRNAs to the right place in the body. On their own, the small molecules do not survive long in the bloodstream, so simply injecting a patient with a solution of unprotected siRNAs is not effective. "The key technical hurdle is getting the siRNA [inside] the right cells," says Greene.

For several of its projects, Alnylam uses nanoparticles to protect and deliver its siRNAs, which can then be delivered by injection. But for genetic diseases that originate in the brain, the body's own defenses, namely the blood-brain barrier, complicate delivery further. To circumvent the blood-brain barrier, which prevents most molecules from leaving the bloodstream and entering the brain, Alnylam has looked to a different delivery mechanism: direct dosing of unpackaged siRNAs.

Medtronic, a Minneapolis company that designs and manufactures medical devices, has devised a way to allow this. Together, the companies have developed a treatment that combines Alnylam's RNAi therapeutic with Medtronic's drug delivery technology to treat Huntington's.

Huntington's, for which there is no cure, is caused by the loss of neurons due to a toxic protein made by a tainted gene. The idea behind the new treatment is to stop at least some of that protein's production so that it cannot damage the brain.

The treatment would use a device made by Medtronic that is already implanted in more than 250,000 patients to treat chronic pain and spasticity. The device features a catheter connected to a drug pump that's surgically implanted into the abdomen. The pump pushes drugs through the device and into the fluid around the spinal cord. In the case of the Huntington's RNAi work, the system is adapted to deliver liquids directly into the brain tissue. _Technology Review

In one way, this is a cautious approach to control of gene expression. But constant infusion of a therapeutic agent directly into the brain is both risky and expensive. Only the risk of a deadly disease such as Huntington's could justify that level of invasiveness.

A more ideal method of correcting genetic defects in brain tissue might be the introduction of engineered stem cells which will deliver the therapeutic agent continuously without the need for invasive hardware devices.

Even more ideal would be the permanent genetic alteration of the faulty brain cells which produce the faulty protein. But it will take more time to develop a safe way of doing that.

Our brains make us who we are. In Huntington's, victims of their own genes lose themselves in a one-way slide to a dark oblivion.

Genetic and epigenetic control of the brain will make a big difference. You might even call it a disruptive technology.

How Faith in Neo-Darwinism May Be Holding Us Back

Do you believe in Neo-Darwinist evolution? New-Darwinism is often used as something of a shibboleth to separate the scientific cognoscenti from the flat-earthers and creationists. But is such a "test of scientific rationality" justified? Only if there are no alternatives to Neo-Darwinism which better fit the observed facts. But what if there were better alternatives? Who would be the flat-earthers then?

Lynn Margulis is a prominent thorn in the side of institutional neo-darwinism, and one of the foremost promoters of the theory of Symbiogenesis. On occasion, Margulis can seem like something of a flake, but it is just that quality which allows her to stand up to the pressures of conventional thinking and make her own way against the crowd and its political consensus.

Faith in any conventional form or ideology will hold humans back from discoveries that may seem to contradict those forms and ideologies. We live in an unfortunate age when academic and intellectual thought has been largely taken over by one general ideology -- which actively suppresses debate and open epistemological inquiry into topics which may be too near and dear to the hearts of the thought leaders within the uber-dominant ideology.

Even the so-called "skeptics" today are often nothing better than papered-over consensualists. "Skeptic" Michael Shermer has written a book called The Believing Brain, in which he attempts to explain human belief using game theory, neuroscience, and evolutionary psychology. But as skeptics go, Shermer tends to be something of a credulous skeptic, as he tends to accede to "consensus" a bit too easily. Like many writers and historians of science who are not actually scientists, Shermer relies on second- and third-hand anecdotes and clever phrasing a bit more than he perhaps should. One can learn nothing about the next level from "skeptics" like Shermer, who is a fashionable and consensual kind of skeptic, always safe and well far behind the cannon fodder.

Fortunately, Neo-Darwinism is only peripheral to the central political issues that drive the dictators, critics, and pseudo-skeptics of modern academia, media, and politics, so it is still permissible to question some aspects of neo-darwinian theory as long as one is not too threatening to the status quo. For example, scientists are learning that some "acquired characteristics" of parents and grand-parents can be inherited by children and grandchildren, via epigenetic means. We are likely to discover many more contradictions to conventional genetic and evolutionary theory as we go along.

But none of these piecemeal discoveries are likely to be as liberating as the potential explosion of knowledge which might arise from a real-world demonstration of controlled symbiogenesis in action.

Neo-Darwinian evolution may be the best theory we've got to explain evolution -- or there may be something better. There are still many profound discoveries waiting to be made, using the mental framework of neo-darwinian theory. It will always be useful in the sense that Newtonian physics will always be useful -- within specific limited domains.

Who is going to come closer to the global optimum, the path to rapid expansion of knowledge in evolution and biology? The rational gadfly who is unafraid to question popular convention, or the uber-conventionalist who hides behind a faith in crowd consensus?

Things can change very rapidly when radical theories and tools are discovered. Modern hierarchies of ideas and power can be overturned almost instantly in the face of the type of discoveries which are possible. Which societies are capable of withstanding radical change, which is bound to occur sooner or later? A society whose women are increasingly choosing not to have children because children cramp their style? Or a society of people who welcome change, even as they continue the eternal cycles of love, family, child-raising, birth, death, and continuation in the face of all odds and challenges?

It can be frightening to step outside the mainstream -- particularly if you do so by yourself without the support of a group. But if you take a look at the state of the modern world, it should not take you long to see that the mainstream has very little to offer a conscientious seeker or a driven pathfinder. In fact, the mainstream appears to be taking an express train to the Idiocracy.

In basic rescue and resuscitation, we first look at the ABC: airway, breathing, and circulation. Then we proceed to the finer points of diagnosis and intervention. In your lives, you need to take a similar prioritised approach. But try not to get so caught up in basic survival issues that you do not keep one eye on the sky, for falling sacred cows and orthodoxies.

Just one, small and seemingly insignificant scientific or technological discovery could overturn almost all the conventional wisdom and hierarchical power structure of your society. And there are a lot of discoveries in the pipeline at this time. Not all of them will be developed to their potential -- particularly in our modern age of faux environmentalist energy starvation and a general aversion to disruptive technologies by the ruling classes and thought leaders.

But in reality, it is not up to them any longer. They just do not realise it yet.

Poor, Bare, Forked Animals Begin to Decipher Epigenome

NIH
The epigenome is the system of genome modifiers that guide gene expression. Epigenetics determines whether a cell will be a brain cell or a liver cell, even though both cells possess the same genome. Some preliminary results are beginning to come in from the US NIH's modENCODE program.

Sarah C.R. Elgin, PhD, the Viktor Hamburger Distinguished Professor in Arts & Sciences, who led the Washington University lab that is part of one of the modENCODE teams offers an explanation.

“We learned many things from the Human Genome Project,” Elgin says, “but of course it didn’t answer every question we had!

“Including one of the oldest: We all start life as a single cell. That cell divides into many cells, each of which carries the same DNA. So why are we poor, bare, forked creatures, as Shakespeare [Al Fin: Lear ActIII SceneIV] put it, instead of ever-expanding balls of identical cells?

“This work,” says Elgin, “will help us learn the answer to this question and to many others. It will help us to put meat on the bones of the DNA sequences.” _WUNewsroom

Wikipedia

The epigenetic code that determines whether genes are silenced or expressed consists of chemical modifications to the DNA, to “tails” that hang off the histones, or other packaging proteins.

“ENCODE and modENCODE are much more complicated projects than the Human Genome Project,” Elgin says, “because the DNA sequence is pretty much the same in every cell type, whereas the chromatin structure is different in every cell type. In fact we believe it is the chromatin structure that differentiates one cell type from another.

“That means we can’t just do one genome for the organism. We have to do every different cell type to get a complete picture of the organism, and that’s a daunting prospect.” _WU

The research relies upon the most advanced bio-research and computing technologies. The amount of data generated is staggering, and far beyond what an unaided human could organise and comprehend.

But this is the beginning of the true meat of genetics. Sure, they are looking at worms and fruit flies now. But humans and all human symbionts and parasites are on the list to be comprehensively studied. The knowledge to be gained will provide unimaginable benefits.

A Fine Meth (ylome) You've Gotten Us Into This Time

Source
The methylome is the pattern of DNA methylation in cells as they become relatively differentiated. Methylomics is a branch of epigenetics -- non-coding control of gene expression. Even identical twins will have different gene expression, in part due to differing methylomes. Methylomes of cancer cells are of particular interest to medical scientists.

Chinese scientists have decoded the methylome of mature peripheral blood mononuclear cells. The tools they used may prove useful for decoding the methylomes of other types of mature and cancerous cells.

. Understanding the mechanisms and functions of DNA methylation and how it varies from tissue to tissue and between individuals will have profound implications for human health and disease.

A team of Chinese researchers decoded the essentially complete methylome (an inventory of all the bases that are methylated) of the human genome using peripheral blood mononuclear cells (PBMCs). The results are published in the online, open access journal PLoS Biology.

The research is part of YanHuang (YH) Project, which has been launched by BGI (previous known as Beijing Genomics Institute) at Shenzhen, which aims to sequence 100 Chinese individuals in 3 years to accelerate the discovery of disease genes and mutations in an Asian population.

...The research not only provides a comprehensive resource for future epigenomic research but also demonstrates a paradigm for epigenetic studies through new sequencing technology. The PBMC methylome data has been deposited to NCBI (http://www.ncbi.nlm.nih.gov/Traces/sra/, accession number: SRA008544). It is expected to form a lasting resource as part of the International Human Epigenome Project. _SD

The methylome is a unique signature of the development of a particular cell or cell type. This development was affected by both the individual's genome and his environment. A person's methylome -- in its unbelievable complexity -- is but one more way in which persons are different from each other.

We have only begun to comprehend how much we have yet to learn.

Update 10Nov10: U of Chicago researchers have made an important discovery into the nature of "demethylation" of DNA

Greater Human Genetic Diversity Than Previously Believed

ImgSource

As humans look more deeply into their genetic and epigenetic complement, they are discovering far greater genomic differences between humans than previously believed possible. The 1000 Genomes Project is reporting on results from its pilot phase:

Evan E. Eichler and coworkers of the University of Washington, Seattle, used data from the 1000 Genomes Project to analyze copy-number variations, which are differences in the number of times a particular gene sequence appears in the genome (Science 2010, 330, 641). About 1,000 genes "have been largely inaccessible to traditional genetic study as a result of their repetitive nature," Eichler said at the press briefing. Using newly developed sequence analysis algorithms and sequence tags, his team investigated copy-number variations in these genes, he said.

Eichler's team found that copy-number variations occur in fewer than 10% of human genes. Many of these genes map to regions that had been previously identified as highly repetitive and have been implicated in diseases such as schizophrenia and autism, the authors note.

Even at the pilot stage, the 1000 Genomes Project has already provided "a more complete catalog" of human genetic variation than was available previously, Durbin said. The project is already moving forward with its main phase, with the goal of sequencing 2,500 genomes. _ACSPubs

Whether 1000 genomes or 2500 genomes, the study is still quite preliminary, in terms of understanding the astounding magnitude of variation within the broad human genome and epigenome. As we begin to comprehend the vast numbers of differences in gene expression between even the closest of relatives, we may get a glimmer of understanding of how our molecular makeup generates the diverse worlds we inhabit.

Abstract of paper:

Copy number variants affect both disease and normal phenotypic variation, but those lying within heavily duplicated, highly identical sequence have been difficult to assay. By analyzing short-read mapping depth for 159 human genomes, we demonstrated accurate estimation of absolute copy number for duplications as small as 1.9 kilobase pairs, ranging from 0 to 48 copies. We identified 4.1 million "singly unique nucleotide" positions informative in distinguishing specific copies and used them to genotype the copy and content of specific paralogs within highly duplicated gene families. These data identify human-specific expansions in genes associated with brain development, reveal extensive population genetic diversity, and detect signatures consistent with gene conversion in the human species. Our approach makes ~1000 genes accessible to genetic studies of disease association.

A Hint of Epigenetics

The term “epigenetics” most commonly refers to heritable changes in gene activity not accounted for by alterations or mutations in the DNA sequence. But in order to understand the important developments now underway in biology, it’s more useful to take “epigenetics” in its broadest sense as “putting the gene in its living context.” _NewAtlantis

Source

Epigenetics -- non-coding control over gene expression -- is one of the most exciting areas of science at this time. We are learning that the genetic code is only the short, first chapter in a very long book. The non-genetic "code" -- the non-coding DNA and RNA -- has a logic all its own. We are just beginning to decrypt the obscure cipher. The possibilities for the transformation of life as we know it seem just as grandiose as were the hopes of the early promoters of the human genome enterprise. Only this time, we are working at a deeper level of sophistication. How many more levels will we need to descend before we reach the promised land of genetic medicine?

... some 95 or 98 percent of human DNA was useless for making proteins. Most of this “noncoding DNA” was at first dismissed as “junk” — meaningless evolutionary detritus accumulated over the ages. At best, it was viewed as a kind of bag of spare parts, borne by cells from one generation to another for possible employment in future genomic innovations. But that’s an awful lot of junk for a cell to have to lug around, duplicate at every cell division, and otherwise manage on a continuing basis.

...As organisms rise on the evolutionary scale, they tend to have more “junk DNA.” Noncoding DNA accounts for some 10 percent of the genome in many one-celled organisms, 75 percent in roundworms, and 98 percent in humans. The ironic suspicion became too obvious to ignore: maybe it’s precisely our “junk” that differentiates us from water fleas. Maybe what counts most is not so much the genes themselves as the way they are regulated and expressed. Noncoding DNA could provide the complex regulatory functions that direct genes toward service of the organism’s needs, including its developmental needs.

...Over successive generations, cells destined to become a particular type lose their ability to be transformed into any other tissue type. And so the path of differentiation leads from totipotency (the single-celled zygote is capable of developing into every cell of the body), to pluripotency (embryonic stem cells can transform themselves into many, but not all, tissue types during fetal development), to multipotency (blood stem cells can yield red cells, white cells, and platelets), to the final, fully differentiated cell of a particular tissue....Cells of the mature heart and brain, then, have inherited entirely different destinies, but the difference in those destinies was not written in their DNA sequences, which remain identical in both organs.

... _NewAtlantis

The author goes on to describe several ways in which gene expression can be drastically altered by other means than the coding of genes -- specifically by non-coding DNA and by protein :: DNA interactions. Non-coding DNA appears to play a huge role in gene expression -- as does non-coding RNA.
The ongoing discoveries of a previously-hidden epigenetic oversight of gene expression, is exciting. Yet, it is the epigenetics (and epi-epigenetics) that remain undiscovered which hold the keys to the mysteries that confound us.

The ability to reach into the subtle mechanisms of gene expression -- without mucking everything up -- will mark the beginning of a new phase of human existence.

Always the Doom You Don't Expect That Gets You

Synthetic biology involves the production of novel living organisms that are self-replicating and potentially uncontrollable if something goes wrong.....

QUEST on KQED Public Media.
A .... concern is the deliberate construction and release of a pathogen more virulent and transmissible than anything in nature. The perpetrator might be a malevolent individual with a knowledge of synthetic biology or a terrorist group seeking the ultimate bioweapon. Fuelling such fears is the rapidly growing availability of BioBricks and other “standard biological parts”, which enable even undergraduates to engineer their own microbes.

We probably have at least five years grace before synthetic biology has reached the point... FT

.... where it can destroy our current gullible faith in the safety of the commons. We may have five years. Sooner or later, resentful child-men and child-women will have the power to turn the life-giving air, water, food, and biosphere of the planet into agents of certain death -- or worse.

Synthetic biology will have to learn how to manipulate much more than DNA and genomes to become truly dangerous, of course. Without the epigenome and other components of life, the genome is an empty shell.

Epigenetics, a relatively new endeavor in science, refers to the control of the patterns of gene expression in cells, which gives rise to the necessary differences responsible for creating the complex and interacting tissues in the body.

Scientists globally have begun working on a Human Epigenome Project in a bid to compile detailed data documenting, within a person, the epigenetic changes in different types of cells and tissues, something that will complement the already-completed Human Genome Project. _Source

Links and video via Machines Like Us

We are accustomed to breathing from a common air supply, drinking from a common water supply, eating from a common food supply, and immersing ourselves in a common biosphere. In the not-so-distant future, humans may have to jettison this childlike faith in the safety of the bio-commons, and take steps to assure the safety of our own food, water, and air supplies. On a local -- even household -- level. Mass society could become a thing of the past, as multiple existential threats simultaneously sever the threads of trust that presently hold cultures and societies together.

Who will prevent this dissolution of trust and safety? Not the clueless clowns of the present US governmental reich. They are too busy destroying political enemies and grabbing as much political power as possible, to even consider attending to real world existential threats. The type of competence required to anticipate, interdict, and prevent such threats, is in very short supply -- and little valued in the current political / academic / media climate.

It is up to individuals and groups working outside the mainstream, to devise protective solutions to these somewhat probable threats. Fortunately, many genuinely useful preventative measures apply almost equally to a wide range of existential threats.

Nature and Nurture Linked by Epigenetics

You cannot separate a person's genes from his environment. The two are irrevocably linked by several mechanisms. One of the most important ways in which the environment affects gene expression is via an epigenetic mechanism called "methylation." DNA methylation is always at work in the animal, initially helping guide differentiation and development of tissues and organs, and responding to the environment and shaping gene expression by putting parts of the DNA "off limits" to the gene expression system, or in de-methylation putting parts of the DNA back "on-line".

Johns Hopkins researchers who studied the genomes of people in Iceland and Utah say they may have found a clue to why people are increasingly prone to disease as they age...a person could become more prone to heart disease, cancer and other diseases of aging because certain genes that used to function no longer do so - or vice versa. Animal studies have shown that such changes can be triggered by environmental forces such as diet...Collaborating with scientists at the University of Iceland, the Hopkins researchers studied two populations over time to see if they could observe changes in the amount of "methylation" present in a person's genome.

...The degree of methylation is part of a person's epigenetics - aspects of an individual's makeup that exist apart from the genes themselves...The researchers tapped into continuing studies in Utah and Iceland, both havens for genetic research because of homogeneous populations. The researchers obtained DNA samples given over a decade apart by 111 people in Iceland and 126 in Utah.

For each person, they measured the amount of methylation present at each point in time - about a third of the subjects in Iceland and 30 percent in Utah had substantial changes over the period.

...Environmental factors can increase the amount and the location of methylation along the genome, influencing whether genes are functioning or not. The changes can also occur randomly, as cells divide and information gets lost or jumbled. __Source_via_Kurzweilai.net

Being able to investigate the state of methylation and other epigenetic states and processes, takes understanding of gene expression light-years beyond the mere genome. Methylation is one means by which a once-pristine genome is "marked by life." As scientists better learn to read the language of epigenetic markers, they will be able to better understand the history and current state of particular organisms (and people).

Of course, being able to modify epigenetic states will be a therapeutic tool even more potent--initially--than gene insertion. The reason for this is that the existing genes already know how to work together. When you pop a new gene into the sequence, you are never quite sure ahead of time how it will work.

More here.

Nano, Micro, Merely Small, etc.

The curious shapes you see pictured above are DNA building blocks, examples of what a DNA architecture might achieve.

A team of scientists has created a versatile strategy for building three dimensional structures on the nanometre (billionth of a metre) scale by coaxing strands of DNA to from a basic building block that can then assemble spontaneously into complex three dimensional shapes over distances of around ten to twenty billionths of a metre.___Telegraph

Meanwhile, inside living organisms, modifications to DNA seem to determine whether an individual will be schizophrenic, bi-polar, or normal.

Arturas Petronis, senior scientist at the Krembil Family Epigenetic Laboratory at the Centre for Addiction and Mental Health in Toronto, has found there is a distinctive pattern in the on-off switches controlling roughly 40 different genes in the brains of psychiatric patients suffering from schizophrenia and bipolar disorder....They looked at 12,000 genes and found significant differences in the brains of the patients who suffered from serious mental illnesses. There were distinct differences in the methylation of 40 genes. Some of the differences were shared between the schizophrenia and bipolar patients, and some were unique to each disease.___GlobeandMail

This "epigenetic" control of gene expression can lead to different experiences of health and disease in two individuals whose genomic DNA sequences are identical. Clearly, epigenetics is a huge repository of "environmental" effect.

Meanwhile, in worm and yeast DNA, scientists are zeroing in on genes that may account for differences in lifespan between individuals.

The researchers began by scouring the scientific literature for genes that have an influence on the life span of nematode worms. The worms are often used in ageing research because they have a short natural life span and are easy to genetically modify. The scientists found that of the 276 genes known to affect ageing in nematode worms, only 25 were also present in yeast. At least 15 of these have similar versions in humans.___Guardian

Learning how to trigger or block certain of these genes (or gene products) may provide the first effective treatments for "aging".

Japanese researchers are developing nano-sized mechanical computers capable of performing massively parallel simultaneous computations.

The team plans to turn the 2D wheel of 16 molecules into a 3D sphere - a structure that would consist of 1,024 molecules. This spherical device could perform 1,024 instructions at once, theoretically making it capable of 4^1024 different states. ___Source

On a larger scale, "sugar cube-sized" robots that are capable of linking up and forming larger robots for various purposes, announce the application of the "swarm concept" to robotics.

If a machine has to travel a long distance, it could assemble into a rolling ball, before changing shape into a four-legged machine to clamber over rubble, said Winfield. By mimicking evolution, the robot will test different strategies and settle on whichever seems to work best.

The principle is similar to an ant or termite colony, where individuals cooperate to such a degree they behave like one large organism, even though there is no central "brain" instructing it what to do.

"A Symbrion swarm could be released into a collapsed building following an earthquake ... they could form themselves into teams searching for survivors or to lift rubble off stranded people. Some might form a chain allowing rescue workers to communicate with survivors while others assemble themselves into a 'medicine-bot' to give first aid," Winfield added.___Source

While human disciplines are organised by "field of study", in real life there are no "fields of study." In real life, everything is interdisciplinary. More intelligent humans will adapt their educational practises to reflect the interdisciplinary nature of the real universe. Hyper-specialisation is a fact of life at universities, but in nature it is a certain recipe for extinction.

Stem Cells and Cancer: The Exquisite Dance

As many as 20% of cancers or more originate in stem cells. Our bodies are homes to hordes of stem cells, sometimes quiescent, sometimes regenerative, and sometimes proliferating out of control. The female breast is one organ that is amply supplied with stem cells.

"People have long suspected there should be a stem cell population in the human breast gland," said Sigurdsson who is part of the ESF-funded team led by Thorarinn Gudjonsson. A 'virgin' breast, before pregnancy, is very different to a fully functioning, milk-producing breast. With lactation, the breast becomes fully differentiated, and once this stage is over, it involutes. This cycle of proliferation, differentiation and apoptosis also happens in every menstrual cycle and in a more dramatic form during pregnancy. "This caught our attention, and has driven our research," Sigurdsson pointed out.

Breast cancer almost always occurs in the luminal epithelial compartment, which is also where milk is produced. Perhaps it is not surprising then, that stem cells reside in this compartment. In 2002, Thorarinn Gudjonsson, successfully isolated cells from the human breast with stem cell properties.

Gudjonsson immortalised these cells and grew them in three dimensional matrix that mimics the real, living tissue. Biologists have long relied on 2-dimensional cell cultures as the basic tool of their trade. But there is a big difference between a flat layer of cells and culturing cells in three-dimensions. The Icelandic researchers, realizing just how much a cells context matters, used the 3-D cell culture pioneered by Mina Bissell, at the Lawrence Berkeley National Laboratory in California. "We can build up a 3-D breast structure similar to what you have in vivo," says Gudjonsson.

"You can analyse cell-cell interactions and signaling pathways in these cells during morphogenesis and in cancer progression." The Icelandic researchers are now focusing their efforts on how endothelial cells convey signals to stem cells in normal breast formation and in cancer. In collaboration with another Icelandic research team, the Gudjonsson lab is now unraveling the role of tyrosine kinase receptors and their downstream signaling events. Source.

And so we see that stem cells are a two-edged sword in the breast. The same is true in other tissues. Stem cells are vital for regenerative functions, but must be held in check by tumour suppressor genes.

[A tumour suppressor gene,]PTEN functions to decide whether to progress further though the cell cycle or return to a quiescent (G0) state. Disrupting PTEN in stem cells results in more active cycling and a loss of the quiescent pool of stems cells that is necessary for long-term stem cell maintenance.

PTEN can be phosphorylated in response to other signals that modulate its function. The Li Lab's work demonstrated distinct populations of hematopoetic stem cells (HSCs) with phosphorylated and unphosphorylated forms of PTEN, suggesting that PTEN phosphorylation may be a 'sensor' that could help integrate external cues with the HSC quiescence/activation switch.

"Although the primary mutation occurs in stem cells, leading to short-term expansion of normal stem cells, this mutation alone is not enough to support unlimited expansion of either normal or cancer stem cells," said Dr. Li. "A secondary mutation is therefore required to empower the leukemia cells resulting from this mutation to undergo unlimited expansion. Exploring the nature of the secondary mutation, together with the primary mutation in PTEN, can help to understand the self-renewal ability of stem cells and perhaps will identify new molecules that can be targeted to provide effective leukemia treatment without adversely affecting normal stem cells." Source.

Sometimes the tumour suppressor genes are silenced, and if the tumour cells can maintain the silencing of the suppressor genes, the tumours are free to grow. Methylation is one means of gene silencing that tumours take advantage of.

Our cells become cancerous when the normal controls over cell growth and death go awry. This deregulation has traditionally been linked to DNA mutations of single genes or deletion of large sections of the chromosome. However more recently it has become clear that gene silencing in cancer can also occur, in the absence of changes to the DNA sequence: a phenomenon known as 'epigenetics'. DNA methylation is one of the main epigenetic processes.

In cancer, the DNA methylation pattern of many genes changes. However, until now, it was believed that only individual single genes were silenced by methylation. But this is not necessarily the case. "What we've found is that non-methylated genes that reside in a particular suburb near methylated genes are also silenced. Their physical proximity to the methylated genes affects their ability to function. It's a case of being in the wrong neighbourhood at the wrong time", says Assoc. Professor Clark.

The Garvan team developed a new method to scan the entire complement of the 30 000 plus genes - the entire genome - in the cancer tissue samples, which allowed widespread changes to be identified in specific parts of the genome.

They were amazed to find the extent of gene silencing. Assoc. Professor Clark adds: "What we want to do now is determine if these same regions are switched off in other types of cancers". Source.

Given that adult male testicles carry a sizable contingent of stem cells, it is perhaps surprising that testicular cancer is no more common than it is. There is considerable interest in testicular stem cells, and their possible potential in regenerative medicine. Projects are currently underway to learn how to extract and culture testicular stem cells in vitro. The following describes a project to culture specifically the spermatogonial stem cells, although more pluripotent cells are present.

"Our plan is to develop a culture system for spermatogonial stem cells" de Rooij told conference attendees. Although admitting the leap to humans is considerable, the colonised mouse testes are already providing useful insights.

"We'd like to know how to culture human spermatogenic stem cells to restore male fertility after cancer therapy," says Hannu Sariola, from the University of Helsinki in Finland who is also working towards a similar goal.

Bizarrely, a brain cell growth factor also has a powerful influence on spermatogonial stem cells. Glial cell derived neurotrophic factor (GDNF) is also involved in spermatogenesis: levels are high during the neonatal period and drop in adulthood. Indeed, mice that have been genetically manipulated to express high levels of GDNF in the testes produce huge clusters of spermatogonial stem cells. But the risk of cancer is boosted too, so it is not just about turning on the GDNF tap indiscriminately. It must be tightly regulated, Sariola pointed out.

The Dutch researchers are also hunting for the ideal conditions and nutrients that will coax spermatogonial stem cells into becoming sperm. So far, they have found that growth factors GDNF and fibroblast growth factor (FGF) seem to be necessary to enhance cell growth. The team's next move is to transplant monkey and human cells into the mouse testes system. Source.

Such are a few of the many molecular moves of the exquisite dance of the cell. It is not surprising that so many things sometimes go wrong. Rather, it is amazing that so many things go right for so long. But then, that is evolution's doing--we cannot take credit. The things that are coming, well, that is another matter.

Human Heart, Brain, Bone and Cartilage Cells from Stem Cells Found in Adult Male Testes

First a German team found pluripotent stem cells in mouse testes, and now a California Lab has found pluripotent stem cells in human testes.

In a breakthrough for stem cell research and cellular replacement therapies, PrimeGen Biotech LLC (www.primegenbiotech.com) today announced that its researchers have successfully developed the first human adult therapeutic germ stem cell. Derived from adult stem cells but with the advantageous genetic characteristics of embryonic stem cells, PrimeCells have successfully been transformed into human heart, brain, bone and cartilage cells -- cardio, neuro, osteo and chondrocytes.

Therapeutically reprogrammed from germ line stem cells found in the testes of adult human males, PrimeCell(TM) is the first non-embryonic stem cell showing the potential to become any type of cell from any organ, something previously thought possible only for embryonic stem cells -- the definition of true pluripotency.

This week, the company's researchers are scheduled to present a summary of their complete data and manuscript in a poster presentation at the Serono Symposia International's Therapeutic Potential of Stem Cells In Reproductive Medicine conference in Valencia, Spain. PrimeGen first presented its preliminary human experimental data at the 1st International Symposium on Germ Cells, Epigenetics, Reprogramming and Embryonic Stem Cells, held in November 2005 in Kyoto, Japan.

"We have demonstrated that there's a novel source of adult stem cells which, aside from having a role in reproduction, can be reprogrammed and used therapeutically," said Thomas C.K. Yuen, PrimeGen chairman and CEO. "We have taken the most well-preserved, highest-quality stem cell and made it pluripotent -- representing one of the most significant breakthroughs in regenerative medicine. These cells advance the potential for cellular replacement therapy for everyone."

To form PrimeCell(TM), PrimeGen extracts cells from the most protected adult stem cell source in the body -- the "germ," or reproductive, cell line, which intrinsically only can form sperm and eggs. Then, PrimeGen uses a proprietary process to reprogram the cells to become pluripotent, giving them the ability to transform into virtually any other cell type.

Because it started as a germ-line stem cell, PrimeCell retains the most conserved, highest-quality DNA generated by an organism. It suffers no damage from aging, chronic disease or injury. It is also shielded from free radical, ribosomal and mitochondrial damage -- all inherent limitations of adult stem cells, until now.

PrimeGen's mouse model Proof of Concept is similar to that referenced in an article published by German researchers in this month's issue of the journal Nature, and described in a March 24 Reuters article. But PrimeGen is further along -- company researchers have already begun creating therapeutically viable cell lines from human tissue. In a paper currently submitted for peer-review, PrimeGen describes the first evidence of isolation and therapeutic reprogramming of adult human germ line stem cells into heart, brain, cartilage and bone cells.

PrimeGen obtains its human tissue samples from consenting adult males between the ages of 26 and 50. For women, PrimeGen currently is reviewing the work of Jonathon Tilly, who has shown that female germ cells exist after birth, contrary to popular belief. The company is developing a female model to attempt to reproduce the results achieved using male germ line stem cells.

"We are very pleased to see that the laboratory in Germany has independently confirmed our results -- which we first described and presented in Singapore in 2005 -- on the therapeutic reprogramming of post-natal germ cells," said Francisco Silva, PrimeGen's executive vice president of research and development, and the lead researcher for the PrimeCell initiative. "Our initial research is extremely promising and we have every reason to believe that our human PrimeCells will show true pluripotentiality, as we have observed in our mouse model."

"We've already been able to reproducibly differentiate heart, brain, bone and cartilage cells, and we are excited to begin testing how these cells incorporate into tissues," Silva said. "Our goal is to create the most potent cell lines to enable the most effective treatments and therapies for as many diseases as possible. Our human PrimeCells represent a significant step in that direction."

As you can see from reading the entire report, the California lab actually preceded the German lab in terms of actual results and reporting of the results.

Thanks to Anne Leonard, whose excellent Stem Cell Research Blog has done a fine job of following this story.

As I discussed in this post, there are many sources of stem cells. Eventually, it is quite likely that virtually any cell type will have the potential to turn into just about any other cell type, given the proper sequence of inducements.

The many new sources of stem cells should stimulate new research in the area of organ regeneration in situ, and organ regrowth for transplantation. Replacing old, tired organs should get easier as the number of replacement methods multiplies.

DNA Methylation: Reversible Gene Expression in Cancer and Development

DNA methylation is one way that gene expression is controlled. In a previous post I discussed the use of hypomethylating drugs to de-methylate tumor suppressor genes, thus reactivating them, as a good way to treat cancer.

DNA methylation is involved from the very beginning of human embryonic development. In early development (fertilisation to 8-cell stage), the eukaryotic genome is demethylated. From the 8-cell stage to the morula, de novo methylation of the genome occurs, modifying and adding epigenetic information to the genome. By blastula stage, the methylation is complete. This process is referred to as "epigenetic reprogramming".

This newsrelease discusses new findings in DNA methylation--how methylation can be thought of more as a dimmer switch, and less as an on-off switch.

A gene is like a long sentence that describes the structure of a protein. The letters in the sentence are spelled out in the building blocks of the DNA strand of which the gene is part.

Like a sentence, a gene has a well-defined starting point, called the start site. Unlike a sentence, a gene has a second region that runs to the left of the start site. That region is known as the promoter, and this is the off-and-on switch for the gene.

DNA methylation involves chemical changes that take place in the promoter region. These changes alter the gene so that it cannot be turned on. Usually, these chemical changes occur in areas of the promoter that are close to the start site, and that’s where others have looked for them in the C/EBPa gene.

Plass and his colleagues, however, looked two to three times farther from the start site than usual.

“We were surprised to find that methylation had occurred along this region far upstream from the start site,” Plass says.

DNA methylation is very complex, and central to both animal development, and gene expression of the mature animal. Methylation can shut down oncogenes--preventing cancer--and methylation can shut down tumor suppressor genes--allowing cancer to progress. The B-vitamin Folic Acid is intimately involved in DNA methylation, and this article provides useful background to the critical role of folate in both preventing and promoting cancers.

DNA methylation falls into the category of epigenetics. Epigenetic regulation of gene expression can largely determine the difference between a chimpanzee and a human.

Perhaps mastering epigenetics will reduce the need for vectored gene therapy, at least in the short run.

Resurrecting Tumor Suppressors to Combat Cancer

The human body is prone to developing cancer, from a very early stage of life, until the end of life. The human genome has several built in tumor suppressor genes, whose protein products suppress the formation of tumors. It is important for these tumor suppressor genes to continue expressing their tumor suppressor proteins as long as the person lives. Over time, DNA can be damaged or altered, leading to loss of function of these protective genes. One way these genes can lose their ability to make protective proteins is through methylation.

Methylation is the gradual addition of chemical units known as methyl groups to genes, and as these groups accumulate, the gene gradually shuts down. Some drugs prevent the methylation process, releasing the gene to produce its tumor suppressor. In fact, methylation is a salient characteristic of cancer cells, and can be used as a biomarker for cancer.

Fortunately, researchers are developing new drugs called "hypomethylating agens" that have the ability to remove the methyl groups and restore function to tumor suppressor genes. This Bio.com report discusses one of these new drugs:

The drug, decitabine, is designed to turn on genes that cancer had switched off, and in this study, patients who were treated with it achieved a significantly higher overall response rate, compared to patients receiving supportive care, which includes transfusions of red blood cells and platelets.

Results of the randomized Phase III clinical trial, published March 13, 2006 in the online version of the journal Cancer, also concluded that in treated patients who responded to the drug, the median time to progression of the disease, or death, was 17.5 months, compared to 9.8 months in patients who did not.

"This is a very promising drug that we believe works even better when patients use it for a period that is longer than that tested in this trial," says lead author, Hagop Kantarjian, M.D., chair of the Department of Leukemia at M. D. Anderson.

....Decitabine is a "biological disease modifier" that was given fast-track approval by the Food and Drug Administration in April 2003.

It is a DNA hypomethylating agent that fights cancer by reversing a chemical process (methylation) that turns off tumor-suppressor genes that protect cells from becoming cancerous.

Other hypomethylating agents are being used and developed for several other types of malignancy including leukemia and breast cancer.

These drugs work by turning back time, as it were--gene time. Other drugs are being developed to turn back time for the entire genome. It is a race against the clock, but then, it always has been.

Progress in the Genetics of Cancer

Researchers affiliated with Ohio State University have found a tumor suppressor gene that may open a door for new treatments of lung cancer and other tumors.

Researchers have identified a new and unusual tumor suppressor gene that may be important in cancers of the lung and head and neck. The study shows that restoring the inactivated gene can slow the growth of tumor cells.

The gene, known as TCF21, is silenced in tumor cells through a chemical change known as DNA methylation, a process that is potentially reversible.
Christoph Plass

The findings might therefore lead to new strategies for the treatment and early detection of lung cancer, a disease that killed an estimated 163,510 Americans in 2005. The study could also lead to a better understanding of the molecular changes that occur in tumor cells during lung-cancer progression.

DNA methylation is at the heart of this discovery. Wikipedia gives an introductory explanation of this phenomenon here.

The larger issue of "gene silencing" is discussed in this brief wiki article. For a more thorough understanding, along with CME credits, this 1.5 MB pdf file will give many people something to chew on.

hat tip eurekalert.