Tuesday, January 01, 2013

Richer Fuller Lives: What Can We Learn from Einstein's Brain?

One of the more tragic aspects of human existence is the common loss of the brain's mental powers, just when a person has experienced enough of life to begin putting many of the pieces of the puzzle together.

Exceptional brains appear to see more of the big picture earlier, and to exhibit a greater resistance to dementia in later life. Why are some brains exceptional, and is it possible to learn enough about the genetics of brain anatomy and function to bring more human brains into an exceptional state of function?
Einstein's Brain

Detailed photographs of the brain of Albert Einstein taken at post-mortem have recently been re-examined by scientists, in an attempt to understand the differences in brain structure which contributed to the physicist's exceptional life and contributions to human knowledge. Einstein's brain displayed some remarkable features which were summarised in the images above, and in the caption below.
(A) Figure 2 [see image above] of the left lateral surface of Einstein’s brain highlighted to summarize interesting features, which have been darkened. These include a connected precentral superior and inferior sulcus, a long unnamed sulcus in the inferior primary somatosensory cortex, and a posterior ascending limb of the Sylvian fissure that, contrary to the literature, is not confluent with the postcentral inferior sulcus. Unusually expanded primary somatosensory (posterior to the central sulcus) and primary motor cortices (rectangular region below the precentral inferior sulcus) are highlighted in yellow, as are the unusually convoluted surface of the pars triangularis (part of Broca’s speech area) and the frontal polar region.

(B) Figure 7 of an occipital view of Einstein’s brain coloured to indicate the approximate boundaries of the superior parietal lobule (purple), inferior parietal lobule (aqua/blue) and occipital lobes (salmon). Presence of four transverse occipital sulci (darkened) is extremely rare, if not unique. Parts of the posterior temporal lobes are uncoloured below the inferior parietal lobules and rostral to the occipital lobes. Although the small striped patch between the superior and inferior parietal lobules on the right belongs with the superior parietal lobule rather than the angular gyrus of the inferior parietal lobule, its relationship with the bordering intraparietal sulcus is usually associated with a location in the angular gyrus. It would therefore be interesting to study the cytoarchitecture of this enigmatic patch of cortex. Notice that the inferior parietal lobule is favoured on the left (and see Fig. 4), while the superior parietal lobule is relatively greater on the right. There is also an asymmetry that favours the right posterior temporal region, and the right occipital lobe is shifted forward relative to the left.

(C) Figure 2 of the right lateral surface of Einstein’s brain highlighted to summarize interesting features, including sulci that are darkened. Unusual sulcal patterns include a connected precentral superior and inferior sulcus, a caudal segment of the inferior frontal sulcus that is connected with both the diagonal and precentral inferior sulci, and a long midfrontal sulcus that terminates in the fronto-marginal sulcus of Wernicke. The midfrontal sulcus divides the middle frontal region into two distinct gyri (highlighted in yellow), which causes Einstein’s right frontal lobe to have four rather than the typical three gyri. The enlarged ‘knob’ that probably represents motor cortex for the left hand and the highly convoluted frontal polar region are also highlighted in yellow.

(D) Figure 8 of the right medial surface of Einstein’s brain with unusual features highlighted in yellow. The cingulate gyrus has a long unnamed sulcus, the transverse parietal sulcus seems relatively elongated and the cuneus appears to be unusually convoluted.

(E) Figure 6 of the basal surface of Einstein’s brain highlighted to show that the left collateral sulcus is divided into two segments, and that part of the fusiform gyrus bridges between these segments to merge with the parahippocampal gyrus.

(F) Figure 8 of the left medial surface of Einstein’s brain with unusual features highlighted in yellow. The cingulate gyrus has a long unnamed sulcus, and the cingulate sulcus gives off four inferiorly directed branches (two of which are tiny), which suggest that the cingulate gyrus may be relatively convoluted. The cuneus appears to be unusually convoluted. The figures are reproduced with permission from the National Museum of Health and Medicine. _Cerebral Cortex of Albert Einstein _ Oxford Journals

Figure 8 from the recent journal Brain study of Einstein's brain photographs is only partially described in the captions "D" and "F" above. The photographs reveal far more detail than the drawings.

Both brain volume and brain gyral patterns are under significant genetic control (PDF), although brain volume heritability appears to be greater -- over 90%. Heritability of brain gyral patterns may be closer to 50%.

One interesting gyral pattern variation is the presence or absence of a "paracingulate gyrus" which exists in many people in parallel with the cingulate gyrus. Einstein appears to demonstrate some very interesting variations on the cingulate / paracingulate pattern.

In dementia of various types, brain volume tends to shrink significantly, along with a number of other gross and microscopic changes in morphology. All of these structural changes are also accompanied by changes in gene expression in both neurons and in glial support cells.

The question then arises as to how we might be able to influence gene expression -- in both the healthy and the diseased brain -- in order to improve brain function above and beyond what is currently being experienced.

A rich and full life benefits not only from many years of existence, but also from a depth of understanding of the world around us. Understanding exceptional brains such as Einstein's, may help us to learn what we need to do to enrich the lives of more ordinary humans.

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Friday, December 07, 2012

Brain Implant for Alzheimer's Treatment

Johns Hopkins researchers are implanting electronic "pacemaker" devices in the brain fornix -- the nerve input to the hippocampus -- in Alzheimer's patients. This study is a follow-on to an earlier Canadian study which showed promising results for such a procedure.
The surgery involves drilling holes into the skull to implant wires into the fornix on either side of the brain. The fornix is a brain pathway instrumental in bringing information to the hippocampus, the portion of the brain where learning begins and memories are made, and where the earliest symptoms of Alzheimer’s appear to arise. The wires are attached to a pacemaker-like device, the "stimulator," which generates tiny electrical impulses into the brain 130 times a second. The patients don’t feel the current, Rosenberg says.

For the trial, all of the patients will be implanted with the devices. Half will have their stimulators turned on two weeks after surgery, while the other half will have their stimulators turned on after one year. Neither the patients nor the doctors treating them will know which group gets an early or later start.

"Deep brain stimulation might prove to be a useful mechanism for treating Alzheimer’s disease, or it might help us develop less invasive treatments based on the same mechanism," Rosenberg says.

By 2050, the number of people age 65 and older with Alzheimer’s disease may triple, experts say, from 5.2 million to a projected 11 million to 16 million, unless effective treatments are found. _Johns Hopkins _via_ ExtremeLongevity
The actual deficit in Alzheimer's involves multiple breakdowns in both neural pathways and processing centres of the brain. A "brain pacemaker" which keeps the hippocampus primed and healthy, should help tremendously in the early and middle stages of the disease. It may even prolong the early and middle stages -- postponing the final decline of mental function.

But to actually cure Alzheimer's disease, scientists will need to understand the underlying processes and predispositions much more clearly.

In the meantime, any route to improvement and mitigation is likely to be welcome, by most sufferers and their families.


Tuesday, November 27, 2012

Low Muscle Tone in Youth Linked to Early Death

Swedish experts who tracked more than a million teenage boys for 24 years found those with low muscle strength - weaker leg and arm muscles and a limp grip - were at increased risk of early death. _BBC
Part of the risk for early death is likely related to a more sedentary lifestyle and less regular exercise. But there are a number of unanswered questions as to other possible connections between the weak muscles and the early deaths.
The teenagers, who were all conscripts to the Swedish military, were asked to grip and to do some leg curls and arm push ups against resistance to measure muscle strength.

...Over the course of the study, 26,145 (2.3%) of the men died. The leading single cause of death was accidental injury, followed by suicide, cancer, heart disease and stroke.

A third of the deaths were due to other causes and the researchers grouped these together for their calculations.

The teenagers who scored above average on muscular strength at the start of the study had a 20-35% lower risk of early death from any cause and also from cardiovascular diseases.

They also had a 20-30% lower risk of early death from suicide and were up to 65% less likely to have any psychiatric diagnosis, such as schizophrenia or depression.

In comparison, the 16- to 19-year-olds with the lowest level of muscular strength had the highest risk of dying before they reached their mid-50s. _BBC
It is not clear how many of these early deaths would be prevented by placing these conscripts on a regular exercise and muscle strengthening program. And in the age of electro-toning devices and injectable muscle growth factors -- including myostatin inhibitors -- we have multiple ways of testing the connection.

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Thursday, November 22, 2012

Rejuvenating Aged Human Cells w/ Cytokine Growth Factors

A recent collaboration between researchers in Toronto and researchers in Harbin, China, has uncovered the ability to rejuvenate adult mesenchymal stem cells to be used on scaffolds as a healthy replacement for damaged heart tissue -- in heart failure and after massive myocardial infarction.
In the present study, the researchers report a new method to repair damaged hearts that could occur from heart attacks.

Specifically they studied the ability to rejuvenate adult bone marrow cells and embed them into a biodegradable patch which could then be implanted into damaged hearts.

To perform the study, the researchers first created a biodegradable collagen scaffold upon which they coated two growth factors known to promote cell growth, VEGF and bFGF.

Next they seeded human mesenchymal stromal cells from the bone marrow of middle aged (50) and old aged (75 ) donors onto the scaffold.

The scaffolds were then grown in culture and examined for cell growth and function in rats with damaged hearts. They grew patches both with and without the growth factors.

They found that old cells didn’t grow as well into the patches than young cells and the patches were not as effective when implanted in rats.

However adding the rejuvenative cytokines caused the old cells to rejuvenate. After treatment these cells grew in better and the patches performed better.

The researchers determined that the old cells had a different RNA pattern after exposure to the growth agent. In particular a gene called p16 which is expressed in all aged senescent cells was markedly reduced. _Extremelongevity.net
This new ability to transform the gene expression of old stem cells to more closely match the gene expression of young stem cells, offers a general promise of rejuvenation to all aging cells -- once scientists discover safer ways of inducing such revitalising transformations.

Restoration of cardiac function was possible with a cytokine-enhanced, tissue-engineered patch that rejuvenated aged cells. Covalent immobilization of 2 proangiogenic cytokines, VEGF and bFGF, onto a collagen scaffold enhanced cell proliferation in vitro and prolonged cell survival and improved angiogenesis to restore ventricular morphology and function in vivo. Of note, the improvement was most obvious with patches seeded with cells from old donors. This novel cytokine-conjugated, sustained-release system provides a practical and promising platform for cardiac repair in elderly survivors of an extensive MI, an important advance in an increasingly aging society _Jn. Am. Coll. Cardiology (PDF) via extremelongevity.net

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Saturday, October 20, 2012

FGF21: Learning to Live Longer from Starving Mice

Biologists have known for several decades that putting mice on a starvation diet leads the mice to live longer -- although not necessarily happier. Humans derive too much pleasure from food to broadly adopt this approach to a longer life, but there may be easier ways to get the same benefit.
In 1934, in a famous experiment at Cornell University, it was discovered that laboratory mice could live twice as long as expected if they were fed a low-calorie diet that included enough nutrients to avoid malnutrition. This phenomenon has since been observed in species ranging from worms to primates, but not in humans. Reducing calorie intake leads to longer lives by modifying a number of the biochemical pathways that sense nutrients, including pathways that involve insulin and various other biomolecules. Chemical and genetic methods can also increase longevity by modifying these pathways, which suggests that it might be possible to develop drugs that can increase lifespan without the reducing calorie intake. _Bioscholar News

"In our study, we found transgenic mice that produced more of the hormone fibroblast growth factor-21 (FGF21) got the benefits of dieting without having to limit their food intake," says professor Steven Kliewer of UT Southwestern Medical Center. "Male mice that overproduced the hormone had about a 30 percent increase in average life span and female mice had about a 40 percent increase in average life span." When it comes to maximum life expectancy, the data isn't even all in yet: while none of the untreated mice lived longer than about three years, some of the female mice that overproduced FGF21 will soon reach the age of four. _TGDaily

If the life extension benefits from mice were to transfer to humans, men would live over 20 years longer with more FGF21, and women would live over 30 years longer. And they would be able to eat a normal diet, without starving themselves.

FGF21 is only a part of a complex network of proteins and hormones that affect metabolism and growth. But it appears to be a central part of the network, which may work as a key to unlock some important doors of understanding of metabolic diseases such as diabetes mellitus type 2, mechanisms of growth, as well as providing insights into the ageing process and diseases of ageing.
Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, increases insulin sensitivity, blocks somatic growth and causes bone loss. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting markers of NAD+ metabolism or AMP kinase and mTOR signaling. Transcriptomic analysis suggests that FGF21 acts primarily by blunting the growth hormone/insulin-like growth factor-1 signaling pathway in liver. These findings raise the possibility that FGF21 can be used to extend lifespan in other species. _eLife
There are too many unanswered questions regarding the entire tapestry of hormones involved in growth, metabolism, and ageing, for scientists to recommend use of FGF21 in humans.

The relationship of FGF21 to diabetes and bone density must be teased out and better defined. An intriguing relationship between FGF21 and hibernation should also be better illuminated and clarified.

FGF21 is certainly not THE answer to ageing. But it is very likely to lead us to a number of better questions. And eventually, it may add a decade or two of healthy lifespan to people of the near future.

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Thursday, October 11, 2012

Anti-Dementia Research Goes on the Offensive

Rather than fighting a rear-guard action against advancing dementia, some researchers are taking an offensive approach -- a "procognitive" approach. This means that instead of trying to slow down the inevitable decline of dementia, these researchers aim to rebuild brain tissues and brain function. They aim to push back against the decline and reverse it.
Scientists have developed a small peptide that they say can reverse some of the cognitive repercussions of neurodegenerative and potentially trauma-related brain disorders such as Alzheimer’s disease, by increasing synaptogenesis. The peptide, called dihexa, is a stabilized derivative of angiotensin IV (AngIV)...

...Washington State University’s Joseph W. Harding, Ph.D., Alene T. McCoy, Ph.D., and colleagues based their development on prior work demonstrating that the three terminal amino acids of AngIV and its analog Norleucine1-angiotensin IV (Nle1-AngIV) are central to the precognitive activities of the peptides. The team thus set out to develop much smaller, more stable derivatives of Nle1-AngIV that retained the active structure but could be administered orally and cross the blood-brain barrier.

The resulting lead compound, dihexia (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) not only fulfilled these requirements, but proved to be active at picomolar concentrations, and led to dramatic improvements in the cognitive abilities of a scopolamine-treated rat model of learning deficits, and also aged Sprague-Dawley rats.

Importantly, the treatment was effective whether the animals received it directly into the brain, via injection, or orally. Further analyses indicated that dihexia’s precognitive activity was associated with a drug-induced stimulation of dendritic spinogenesis in the hippocampal brain region, and that the newly formed dendritic spins were creating functional synapses. Encouragingly, dihexia was even more potent than brain-derived neurotrophic factor (BDNF), a growth-promoting protein that is used to create neuronal connections, but which hasn’t yet been developed for therapeutic use.

“At its core dementia results from a combination of diminished synaptic connectivity among neurons and neuronal death in the entorhinal cortex, hippocampus, and neocortex,” the researchers note in their published paper in the Journal of Pharmacology and Experimental Therapeutics. However, previous attempts to develop protein neurotrophic factors as therapeutics has been limited by their inability to cross the blood-brain barrier, and the need to manufacture such agents by recombinant methods, which is costly. “The development of dihexa has seemingly overcome these impediments by virtue of its oral activity, demonstrated pro-cognitive/anti-dementia activity, and anticipated low manufacturing costs.” _Gen Engineering News

Another interesting candidate for procognitive therapy is ABT-288, an H3 receptor antagonist.

Another very interesting class of procognitive drugs is the Ampakines. Ampakine CX546 is a recent drug candidate undergoing study.

Here are two different approaches to procognition in the context of developing novel anti-psychotic drugs:

Egis 11150 which has broad spectrum adrenergic, serotenergic, and dopaminergic antagonist activity
New anti-psychotics with 5HT2C receptor agonist and 5HT6 receptor antagonist activity

It is important for neuropharmacologists to take this fateful step, of taking the offensive in the fight against dementia. Repairing and rebuilding the damaged tissues in the brain will likely get better results than a piecemeal promotion of this neurotransmitter, or combating this protein or another. A procognitive approach holds out the possibility of a return to normal function, rather than a mere slowing of inevitable decline.

The technology of the early diagnosis of future dementia is advancing on multiple fronts, from better brain scanners to genetic testing to two recent interesting developments:

Virtual Reality Functional Capacity Assessment Tool (VRFCAT). Not only does VRFCAT promise to provide early diagnosis of cognitive problems, but it should also prove useful for monitoring of different therapeutic regimens.

New mathematical approaches to model the brain as a complex network of interconnected processing nodes Such mathematical modeling approaches should provide new ways of diagnosing normal vs. impaired brain network activity, as well as new ways to monitor effects of therapies on brain network function.

Eventually, what we will want from procognitive treatments, is for all of us to be able to become capable of clearer and deeper thought. For now, we will be happy to watch dementia sufferers coming back into themselves.

But once we see that beginning to happen, we are likely to want to "spread the wealth around" to include more and more people, maybe even ourselves.


Monday, October 08, 2012

Beyond a Personal Sense of Urgency

Each person feels his own sense of urgency -- varying with age and state of health -- regarding his own lifespan, and his ability to live out his remaining lifetime to its fullest.   But it is time for modern human society as a whole to feel an existential sense of urgency, as demographic trends begin to place constraints on humanity's ability to work itself out of a deepening hole.

The problem is one of diminishing human brain power, and one aspect of this problem is the rapid increase in proportion of individuals suffering from dementia -- Alzheimer's dementia and other types.

One illustration of the effect of dementia on the brain of an individual, is the following set of paintings by an American artist living in London, who was diagnosed with dementia at the beginning of the series:

The latest global demographic analysis, from a World Health Organization report issued earlier this year, paints the dimensions of that slow-motion catastrophe in quick strokes. An estimated 36 million people worldwide currently suffer from dementia; experts predict the number will double, to approximately 70 million, by 2030 and triple by 2050. (China, India, and Latin America in particular face daunting medico-economic crises.) Since the prevalence of the disease doubles with every five-year age increment after 65, projections for 2050 put the total global population at risk for dementia (people 65 or older) at two billion. The calculus is as grim as it is simple: as more people live longer, more slide into dementia. Care for those patients currently costs $100 billion a year in the United States, with a projected cost over the next 40 years of $20 trillion; by 2050, the cost to U.S. society is projected to be $1 trillion a year.

An even more sobering perspective on the problem comes from a small unpublished pilot study that Granieri and her colleagues at Columbia recently undertook. They did a standard cognitive evaluation of every person 70 or older who was admitted to Allen Hospital for any reason—heart problems, pain, diabetes, breathing difficulties. The results stunned them. "In this hospital, of patients 70 years of age or older, 90 percent have cognitive impairment of some kind, which is much higher than we anticipated," she says.

Not only is dementia distressingly widespread, but the complex overlap of symptoms and possible causes makes addressing the problem broader and trickier than just treating Alzheimer's. The emerging reality, which has become increasingly apparent with better brain imaging, is that the majority of cases among the elderly are so-called "mixed dementias"; the cognitive impairment is due to a combination of vascular problems, such as mini-strokes in discrete parts of the brain, and the more classic Alzheimer's pattern of amyloid plaques. Large-scale international studies in the past three years have shown, according to a recent scientific summary, that dementias caused by blood-vessel lesions in the brain, including vascular dementia and mixed dementia, "together comprise the most common forms of dementia at autopsy in community-based studies." _The Dementia Plague

At this point, no one knows if medical science is any closer to an effective treatment for dementia than it was 30 years ago. Several competing hypotheses are scrambling for research funds, while the underlying problem itself continues to swell, around the world.

As populations continue to age in most countries except in sub Saharan Africa and tribal areas of Asia, the population proportion susceptible to these dementias will continue to grow. And unfortunately, the regions of the world where young populations will continue to outnumber old populations for the foreseeable future, are also regions with populations possessing rather low average IQ. This means that more and more resources in the developed world will be spent on the tertiary care of dementia patients, while the undeveloped world is likely to sink below its pre-colonial baseline due to overpopulation.

At the same time, the developed world will be suffering from excessive debt, unwise immigration policies, and massively oversized governments of a parasitic nature. All of these problems will converge to make large-scale research programs very difficult to fund.

And so there is a sense of urgency now, not to waste resources on frivolous pursuits of an ideological nature, but to rather focus on problems which are critical and undeniable.

If we allow our best minds to slip away uncontested and un-utilised, we will be throwing away our chances to achieve longer, healthier, more fulfilling, more productive, wide-ranging lives.

We need to move beyond ideology, beyond political correctness, and dedicate ourselves to the very dangerous pursuit of an abundant human future.


Friday, September 14, 2012

More Potentially Revolutionary Developments in Gene Expression

In "Steps Toward the Mastery of DNA Based Life" we looked at amazing developments in manipulating DNA transcription. Today we will look at an intriguing development in designing novel functioning RNA. It is important to remember that while DNA holds the instructions for creating and maintaining a functioning organism, it is RNAs -- along with specific proteins -- that do most of the hard work. That means that the ability to design and manipulate RNA function may provide us with the quickest route to a powerful control of gene expression.

More on the new development:
For synthetic biologists a key goal is to use RNA to automatically engineer synthetic sequences that encode functional RNA sequences in living cells. While earlier RNA design attempts have mostly been developed in vitro or needed fragments of natural sequences to be viable, scientists at Institut de biologie systémique et synthétique in France have recently developed a fully automated design methodology and experimental validation of synthetic RNA interaction circuits working in a cellular environment. Their results demonstrate that engineering interacting RNAs with allosteric behavior in living cells can be accomplished using a first-principles computation.

...Drs. Alfonso Jaramillo, Guillermo Rodrigo, and Thomas E. Landrain had to address several challenges in their study. "It is common practice – and unavoidable – to use computational algorithms to aid in the design of RNA molecules," Jaramillo tells Phys.org. For example, he illustrates, computing minimum energy conformation, since one single nucleotide can stabilize an alternative conformation. Until now researchers have used computer assisted design to design synthetic RNAs that could combine functional fragments from known RNAs.

...This evolutionary computation technique relies on mimicking the relevant steps of natural evolution, that is, the iterative improvement of a given solution by using selection. "However, we don't have to be slaves of analogy and are free to consider what we think is more relevant to our problem," Jaramillo points out. "We would start from a random sequence and would randomly modify it by applying simulated annealing techniques, implemented by a Metropolis Monte Carlo algorithm," which solves a problem by generating suitable random numbers and observing that fraction of the numbers obeying some property or properties. "Contrary to natural evolution, our walks would not be completely adaptive but we could allow a decrease in fitness. We aim at the engineering of an ensemble of RNA species that could interact in a predefined way. Our first challenge was that in living cells, such molecules are very prone to degradation if they do not have a stable structure."

...After publishing the PNAS manuscript, Jaramillo adds, the team further validated the orthogonality (the ability to selectively translate mRNA) of their RNAs in E. coli. They're also constructing a XOR gate device working inside the cell – something never done in bacteria and just recently achieved in mammals1.

The researchers are planning to extend the methodology to include the RNA-small molecule interactions and the incorporation of known functional RNA sequence fragments (such as ribozyme sequences) to create complex RNA interactions never seen before. "We've already succeeded in experimentally validating in E. coli a new type of such an interaction, consisting of an inactivated riboregulator that could be activated by a ribozyme after the introduction of a small-molecule inducer."In this type of reaction, the number of different species is not conserved, as after the introduction of the inducer we get a RNA cleavage. "We've named this new riboregulator-ribozyme chimera a regazyme, and have also validated the full design of a riboswitch.

Jaramillo also notes that other research might benefit from their findings, including the high-throughput design of new regulators for large-scale engineering projects. "Also, we can foresee using allosteric RNAs to sense mRNAs by being subject to a conformational change after binding that could trigger a reporter." This would open the way to genetically-encoded and non invasive monitoring of gene expression dynamics – an important and unmet challenge in biophysics. "We're also exploring the use of RNA," Jaramillo concludes, "to create artificial signal transduction cascades." _Phys.org
These are interesting and powerful ideas. Not only can this technique be used to provide new levels of control and monitoring of gene expression -- they can also be used to create new types of computational devices using biological materials.

Study abstract in PNAS

Using DNA, RNA, or proteins to create logic circuits in cells may seem like a waste of time when we already have such powerful silicon-based computational devices. But the ability to embed designed computation at the cellular level provides humans with a level of explicit and specific fine control over biological functions which was only dreamed of in the past.

And it is likely that we will need that level of control to accomplish the conquest of cancer, degenerative disease, and ageing -- to say nothing of our quest to grow ever wiser and brighter.


Friday, September 07, 2012

Encode Project Opens Unimagined Vistas of Discovery

The more we learn about the mechanisms of life, the more we discover there is yet to be learned. Results from the "Encode Project" have reminded us of how little we know about the human genome and epigenome -- while at the same time opening the door to previously unimagined possibilities for discovery and scientific advancement. With this new opportunity for acquiring vast new knowledge, the road to longer lifespans and better brains has just gotten wider, smoother, and more solid.

We are just beginning to learn how our genes are regulated on a moment to moment basis. If we are to achieve our goals for longer, more capable, and more fulfilling lives, we will have to use all of our wits and tools -- and develop a lot of new ones.
When the Human Genome Project revealed that only around two percent of the genome is made up of protein-coding genes, it was suggested that the rest was made up of "junk DNA". The unsatisfactory conclusion left many geneticists skeptical, and Encode's findings now prove beyond doubt that the theory was way off mark.

The new research instead shows that 80 percent of the 98% unaccounted for has some kind of biochemical function, with 10,000 genes tasked with regulating the DNA responsible for coding proteins -- these 10,000 are responsible for building single-strand RNA molecules that regulate the 20,000 protein-coding genes. The mass of otherwise unaccounted for DNA actually represents a series of around four million "switches" that regulate other genes, and around nine percent of DNA helps code these switches (the figure could end up being nearer 20 percent, however).

...Encode has its work cut out. Having identified these millions of genes and investigated what turns them on an off, the team needs to track how they are connected and which genes they control. This will prove particularly challenging, considering genes in the three-dimensional genome are not mapped out in a straightforward manner -- a gene-controlling switch could be located somewhere entirely different from the gene it controls. Understanding the complex circuit route is key to understanding the human genome while, according to Birney, identification of the entire genome is only about 10 percent done.

... _Wired.co.uk

A User's Guide to the ENCODE Project (PDF)

First came the Human Genome Project, focusing on protein-coding genes. Next came the Encode Project, focusing on genes that regulate other genes. Now we will have to learn how the entire complex works together, for the sake of a better human future.


Sunday, August 05, 2012

Steps Toward the Mastery of DNA Based Life

Synthetic biologists are hard at work designing ways for microbes to produce new drugs, fuels, high value chemicals, and other important products to facilitate an abundant human future. Much of this work is being held back by the difficulty of moving beyond the primitive prokaryote bottleneck of bacterial cell signaling and transcription factors -- toward the mastery of more complex eukaryotic cells and gene expression found in yeast and higher organisms.

MIT's Timothy Lu and his collaborators at Boston University, have created 19 new transcription factor which work in (eukaryotic) yeast. They are hoping that some of them will also work in algae and other higher eukaryotic organisms.
So far, most researchers have designed their synthetic circuits using transcription factors found in bacteria. However, these don’t always translate well to nonbacterial cells and can be a challenge to scale, making it harder to create complex circuits, says Timothy Lu, assistant professor of electrical engineering and computer science and a member of MIT’s Research Laboratory of Electronics.

...“If you look at a parts registry, a lot of these parts come from a hodgepodge of different organisms. You put them together into your organism of choice and hope that it works,” says Lu, corresponding author of a paper describing the new transcription factor design technique in the Aug. 3 issue of the journal Cell. _MITNews_via_NBF

The project is part of a larger, ongoing effort to develop genetic “parts” that can be assembled into circuits to achieve specific functions. Through this endeavor, Dr. Lu and his colleagues hope to make it easier to develop circuits that do exactly what a researcher wants.

...Recent advances in designing proteins that bind to DNA gave the researchers the boost they needed to start building a new library of transcription factors. In many transcription factors, the DNA-binding section consists of zinc finger proteins, which target different DNA sequences depending on their structure. The researchers based their new zinc finger designs on the structure of a naturally occurring zinc finger protein. “By modifying specific amino acids within that zinc finger, you can get them to bind with new target sequences,” Dr. Lu says.

The researchers attached the new zinc fingers to existing activator segments, allowing them to create many combinations of varying strength and specificity. They also designed transcription factors that work together, so that a gene can only be turned on if the factors bind each other.

Such transcription factors should make it easier for synthetic biologists to design circuits to perform tasks such as sensing a cell’s environmental conditions. The researchers built some simple circuits in yeast, but they plan to develop more complex circuits in future studies. “We didn’t build a massive 10- or 15-transcription factor circuit, but that’s something that we’re definitely planning to do down the road,” Dr. Lu says. “We want to see how far we can scale the type of circuits we can build out of this framework.”

The researchers are also planning to try their new transcription factors in other species of yeast, and eventually in mammalian cells including human cells. “What we’re really hoping at the end of the day is that yeast are a good launching pad for designing those circuits,” Dr. Lu says. “Working on mammalian cells is slower and more tedious, so if we can build verified circuits and parts in yeast and then import them over, that would be the ideal situation. But we haven’t proven that we can do that yet.” _Genetic Engineering News

Cell article abstract

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Wednesday, August 01, 2012

Breakthroughs in Stroke, Brain Cancer, and Tissue Engineering

We may dream of discovering a "fountain of youth," a magic bullet treatment to achieve immortality with just a single elixir, fruit, capsule, or injection. But the modern reality of the anti-aging effort is that, for now, we must attack each killer disease individually.

An impressive new treatment for cerebrovascular accidents -- brain strokes -- was developed at the University of Manchester.
Researchers induced a stroke in the rats and the drug IL-1Ra, or a placebo for comparison, was injected under the skin. The researchers did not know which animals had been given which drug. This is a similar process to what happens in clinical trials of medicines.

The results were startling. MRI scans revealed that the rats that were given IL-1Ra up to three hours after the stroke had only about half the brain damage of the placebo group.

Professor Rothwell said: “This is the first time that we are aware of a potential new treatment for stroke being tested in animals with the same sort of diseases and risk factors that most patients have. The results are very promising and we hope to undertake further clinical studies in stroke patients soon.”

IL-1Ra works by blocking the naturally occurring protein interleukin 1. Researchers at The University of Manchester have identified that it is a key cause of brain injury following a stroke.

Interleukin 1 encourages inflammation in the area of the brain affected by stroke. This sends out signals to attract white blood cells and to switch on microglia cells in the brain. Because the barrier surrounding the brain has been weakened by the stroke the white blood cells find it easier to enter the brain. But instead of helping the inflamed area they actually kill nerve cells and worsen the injury. The increasing presence of these cells also explains why the damage in the brain gets worse over time following a stroke.

IL-1Ra also reduces the amount of damage to the blood-brain barrier following a stroke so the harmful cells can’t enter the brain. In the recent experiments IL-1Ra reduced the damage to the blood-brain barrier by 55% in healthy rats and 45% in rats with underlying health conditions. In all types of rats the drug reduced the amount of activated microglia cells by 40% compared to the placebo group. _Manchester
A similar type of anti-inflammatory therapy is also being developed to combat Alzheimer's, multiple sclerosis, traumatic brain injury, and other forms of neurodegenerative and inflammatory brain disease.

The fight against brain cancer and other solid tumours was advanced recently by the University of Tennessee Space Institute. The technique utilises a femtosecond laser to both precisely target and destroy tumours.
“Using ultra-short light pulses gives us the ability to focus in a well confined region and the ability for intense radiation,” said Parigger. “This allows us to come in and leave a specific area quickly so we can diagnose and attack tumorous cells fast.”

Once the cancerous area is precisely targeted, only the intensity of the laser radiation needs to be turned up in order to irradiate, or burn off, the tumor. This method has the potential to be more exact than current methods and to be done as an outpatient procedure replacing intensive surgery.

“Because the femtosecond laser radiation can be precisely focused both spatially and temporally, one can avoid heating up too many other things that you do not want heated,” said Parigger. “Using longer laser-light pulses is similar to leaving a light bulb on, which gets warm and can damage healthy tissue.”

The technology can be especially helpful to brain cancer victims. The imaging mechanism can non-invasively permeate thin layers of bone, such as the skull, and can help define a targeted treatment strategy for persistent cancer. The method also overcomes limitations posed by current treatments in which radiation may damage portions of healthy brain tissue. It also may overcome limitations of photodynamic therapy that has restricted acceptance and surgery that may not be an option if not all carcinogenic tissue can be removed. _UTSI

Combining the targeting function with the therapeutic heating function saves time and improves therapeutic precision, and the improved precision of targeting saves surrounding normal tissue.

Research engineers at the University of Toronto have developed a new, rapid method of tissue engineering, capable of creating 3-D layered tissues in an advanced hydrogel.
Scientists manipulate biomaterials into the micro-device through several channels. The biomaterials are then mixed, causing a chemical reaction that forms a "mosaic hydrogel"—a sheet-like substance compatible with the growth of cells into living tissues, into which different types of cells can be seeded in very precise and controlled placements.

Unique to this new approach to tissue engineering, however, and unlike more typical methods for tissue engineering (for instance, scaffolding, the seeding of cells onto an artificial structure capable of supporting three-dimensional tissue formation) cells planted onto the mosaic hydrogel sheets are precisely incorporated into the mosaic hydrogel sheet just at the time it's being created—generating the perfect conditions for cells to grow. _UToronto
This approach is likely to evolve rapidly to provide quick replacement tissues of a simpler nature, such as skin grafts. More complex tissues and organs will require sophisticated scaffolds, to allow the tissue to maintain shape and resist a variety of physical forces likely to come to bear in a variety of implant locations.

The fight against deadly diseases and ageing itself, must necessarily take on multiple forms. Humans have not, after all, conquered even the most rudimentary of enemies -- the virus. Despite our best efforts, we are still vulnerable to new outbreaks of emerging infectious diseases. And we will always be vulnerable to chance events such as accidents -- both terrestrial and cosmic.

But it is in the nature of our slightly advanced monkey selves to pursue our continued existence, as long as we can. h/t Brian Wang

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Wednesday, June 27, 2012

Progress in Regenerative Medicine: Anthony Atala at Wake Forest University

[Anthony] Atala currently heads up more than 300 researchers in the Wake Forest University lab who are working on growing more than 30 different organs and body tissues.

In one trial for the U.S. Armed Forces, his team is collecting healthy skin cells from injured soldiers, processing them, and then spraying them onto battle wounds as a tailored treatment for healing. For deeper wounds, they are in the process of developing an ink jet printer that scans a wound and creates a custom map of the defect.

"After the scan, the printer can go back and print multiple layers of cells right over the wound," Atala said.

The idea of using a patient's own cells rather than relying on those of a donor is important because it eliminates the need to find a "match." For any transplant procedure there is a concern that tissues from a donor will be rejected by a recipient's body. _ABC_via_NBF

There are many challenges to creating lab-grown replacements for human organs. But the promise of being able to create a perfect tissue match replacement organ, and no longer being forced to wait at the bag of the organ donour line, is simply too great a promise to ignore.
By the early 1990s, tissue engineering had become an established field of investigation (30). Concurrently, adult stem cells and ESC were isolated in animals (31, 32) and humans (33), and the advent of nuclear transfer technology made animal cloning possible (7, 34–36). These apparently distinct fields of science had one unifying concept, namely the regeneration of living and functioning body parts destined to replace diseased or damaged cells, tissues, or organs (7). In 1999, the term “regenerative medicine” was coined to describe the use of natural human substances, such as genes, proteins, cells, and biomaterials to regenerate diseased or damaged human tissue (4, 7). It is important to note that the terms tissue engineering and regenerative medicine are not synonymous. The term regenerative medicine is used to define a field in the health sciences that aims to replace or regenerate human cells, tissues, or organs to restore or establish normal function (37). The process of regenerating body parts can occur in vivo or ex vivo and may require cells, natural or artificial scaffolding materials, growth factors, or combinations of all three elements. In contrast, the term tissue engineering is narrower in scope and strictly defined as manufacturing body parts ex vivo, by seeding cells on or into a supporting scaffold. _Excerpted from: Regenerative Medicine and Organ Transplantation: Past, Present, and Future (Atala et al)
Since the early days of tissue engineering, advances in stem cell science, genetic engineering, tissue engineering, 3D printing, and related fields, have given the field of regenerative medicine new powers that were not previously imagined. While all of those sciences continue to advance, it remains for the regenerative medicine specialist to bring them all together and create a new state of the art in tissue and organ transplantation.
One useful "shortcut" in creating new organs from a patient's own tissues, is the use of "acellular" scaffoldings. A donour organ is stripped of its cells, leaving only the supporting acellular matrix scaffolding, including vascular matrix. This scaffolding is then seeded with replacement cells and growth factors for the tissue being replaced, ie vascular, renal, hepatic etc.
A significant advancement in the field of bioscaffold design has been the utilization of decellularized tissue as the three-dimensional scaffold in tissue engineering strategies.11 Our laboratory has previously reported the successful decellularization of porcine aortas and urinary bladder submucosa for use as scaffolds for cell seeding.2, 12 These decellularized aortas were seeded with endothelial progenitor cells and implanted into sheep, and the neovessels remained patent for more than 4 months.2 However, effective decellularization of thicker organs and tissues has been very difficult to achieve due to inefficient penetration of the decellularization solution into the organ. More recently, Ott et al. have developed a more effective method for organ decellularization.13 They have shown that by perfusing a detergent solution through the vascular network rather than relying on agitation and diffusion alone, the entire mouse heart could be decellularized and used as a scaffold for tissue engineering. However, cell seeding of three-dimensional, naturally derived scaffolds presents additional challenges.14 For example, to achieve a recellularized human liver adequate for clinical use, one needs to transfer approximately 10 × 1010 liver cells into the scaffold. So far, such a task has not been successfully achieved. Although perfusion bioreactors have been developed to address cell seeding problems,15, 16 cell seeding across the entire thickness of the scaffold has been limited due to the lack of intrascaffold channels.

The goal of our study was to develop a novel scaffold that human liver cells could readily enter in order to repopulate the scaffold volume. We report the production of such a scaffold via a decellularization process that preserves the macrovascular skeleton of the entire liver while removing the cellular components. The intact vascular tree is accessible through one central inlet, which branches into a capillary-like network and then reunites into one central outlet. Human fetal liver and endothelial cells were perfused through the vasculature and were able to repopulate areas throughout the scaffold by engrafting into their putative natural locations in the liver. These cells displayed typical endothelial, hepatic and biliary epithelial markers, thus creating a liver-like tissue in vitro. This technology may provide important tools for the creation of a fully functional bioengineered liver that can be used as an alternative for donor liver transplantation. _Hepatology 2011 (Atala et al)

Ideally, one would wish to grow and/or print the entire organ in the lab, but the intricate 3D complexity of the intercellular scaffolding of many organs makes such a task very difficult at this time.

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H/T NextBigFuture


Saturday, May 26, 2012

AUF1 Hat Trick: Suppresses Inflammation, Reduces Cancer Risk, and Inhibits Cellular Senescence

Researchers at NYU School of Medicine have, for the first time, identified a single gene that simultaneously controls inflammation, accelerated aging and cancer. _NYU SOM
AUF1 is a micro-RNA binding protein that has been found to perform multiple vital cell functions. Engineered mice that lack the AUF1 protein suffer rapid premature aging that worsens with each generation. By replacing AUF1 function in these mice, the harmful premature aging and accelerated cellular senescense can be reversed.
AUF1 binds and strongly activates the transcription promoter for telomerase catalytic subunit Tert. In addition to directing inflammatory cytokine mRNA decay, AUF1 destabilizes cell-cycle checkpoint mRNAs, preventing cellular senescence. Thus, a single gene, AUF1, links maintenance of telomere length and normal aging to attenuation of inflammatory cytokine expression and inhibition of cellular senescence. _Molecular Cell (ScienceDirect)

AUF1 also accelerates the degradation of inflammatory cytokine, reducing the inflammation load on cells and tissues. More from NYU School of Medicine, where much of the recent research on AUF1 was done:
For decades, the scientific community has known that inflammation, accelerated aging and cancer are somehow intertwined, but the connection between them has remained largely a mystery, Dr. Schneider said. What was known, due in part to past studies by Schneider and his team, was that a gene called AUF1 controls inflammation by turning off the inflammatory response to stop the onset of septic shock. But this finding, while significant, did not explain a connection to accelerated aging and cancer.

When the researchers deleted the AUF1 gene, accelerated aging occurred, so they continued to focus their research efforts on the gene. Now, more than a decade in the making, the mystery surrounding the connection between inflammation, advanced aging and cancer is finally being unraveled.

The current study reveals that AUF1, a family of four related genes, not only controls the inflammatory response, but also maintains the integrity of chromosomes by activating the enzyme telomerase to repair the ends of chromosomes, thereby simultaneously reducing inflammation, preventing rapid aging and the development of cancer, Dr. Schneider explained.

“AUF1 is a medical and scientific trinity,” Dr. Schneider said. “Nature has designed a way to simultaneously turn off harmful inflammation and repair our chromosomes, thereby suppressing aging at the cellular level and in the whole animal.”

With this new information, Dr. Schneider and colleagues are examining human populations for specific types of genetic alterations in the AUF1 gene that are associated with the co-development of certain immune diseases, increased rates of aging and higher cancer incidence in individuals to determine exactly how the alterations manifest and present themselves clinically. _NYU

This is an exciting and potentially important finding. But it takes time for exciting research discoveries to be converted into potentially revolutionary therapies against cancer, aging, and crippling inflammatory diseases.

Early attempts to capitalise on this discovery are likely to be disappointing, particularly as expectations will tend to be raised prematurely. But as the ability to generate safe, effective, affordable treatments begins to catch up to the ability to discover the mechanisms of biological function at multiple levels, the pace of change may grow at a startling rate.

The important thing is to get the basic science findings into the hands of the research community for replication, clarification, and elaboration. After that, scientists can begin finding ways to make the research work in favour of an abundant human future.

Original 1997 identification of AUF1 at Rutgers and Wake Forest (PDF)

H/T Nextbigfuture

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Tuesday, May 15, 2012

Intravenous Stem Cells: Where Do They Go? What Do They Do?

We usually think of stem cell therapy in terms of replacing damaged cells or tissues with stem cells, which can differentiate and become the type of cell or tissue which is being replaced. But there is more to it than that, particularly in the case of intravenous stem cell infusion.
Researchers have tracked the migration of stem cells administered intravenously following an injury. At first the majority of the cells lodge within the lung, where they appear to interact with pulmonary macrophages altering the type of cell signaling molecules those macrophages release into the blood. Next the stem cells migrate to the organs of the reticuloendothelial system which includes the spleen. Surprisingly, less than 3% of infused stem cells migrate into brain tissue. So the immunomodulatory effect does not require the majority of infused stem cells to interact directly with injured brain tissue. _SciAm
It turns out that much of the beneficial effect from the intravenous infusion of stem cells comes from their effect on the immune system. IV infused stem cells apparently shift the immune system's response to injury and rejuvenation, creating a more favourable environment for healing and regeneration.

This allows the few stems cells which make it all the way to the damaged tissue, to promote regeneration locally without a harmful immune response.
Immunomodulatory stem cell studies attempt to adjust the immune response in a way that minimizes the damage associated with the initial injury, and then allows the individual’s native repair machinery to function optimally.

With even mild injury, the immune system is activated. Macrophages are a type of immune cell which participate in the post-injury immune response. With “classic” macrophage activation, the immune response is aggressively induced. Classically activated macrophages are described as having an “M1” phenotype. In the nervous system, the M1 immune response can increase the severity of an injury. Alternatively activated or “M2” macrophages, are associated with a less destructive pattern of immune system activation. This alternate/M2 response results in less immune mediated post-injury damage, as well as the possible disinhibition of native nervous system repair.

Following traumatic brain injury (TBI) children experience a loss of 12-15% of their brain tissue in the 12 months following their injury (Levin). In a study where we treated TBI children with their own bone marrow stem cells, there was minimal post injury brain volume loss in the year after TBI (Cox). In animal models of TBI, animals that experienced injury were found to have M1 macrophages throughout their injured brain tissue.

Animals treated with stem cells after TBI were found to have M2 macrophages in their brain parenchyma. Interestingly, if an animal’s spleen was removed before stem cell infusion, the benefit of the stem cell treatment was eliminated. Somehow stem cell infusion causes a change in the pattern of macrophage activation from M1 to M2, which results in a less aggressive immune response and less post-injury brain tissue death. This effect requires an intact spleen. _SciAm
So you see that in an optimal response to stem cell infusion following an injury, the patient will experience both immunomodulatory effect and a regenerative effect from the IV stem cell infusion.

When the stem cells being infused are of a broad-spectrum nature -- such as cord blood, embryonic stem cells, or pluripotent adult stem cells -- the door is wide open for other effects beyond the immunomodulatory and the regenerative (replacement) effects. It should be clear that other rejuvenative effects are also possible from broad spectrum stem cell infusion. It will simply require a good deal of research and consideration before most of those effects can be discovered and decoded for optimal therapies in the future.

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Friday, May 11, 2012

Staggered Drug Therapies Hit Some Cancer Cells Harder

This treatment worked not only in cancer cells grown in a lab dish, but also in mice with tumors. When treated with a one-two punch of erlotinib and doxorubicin, the tumors shrank and did not grow back for the duration of the experiment (two weeks). With chemotherapy alone, or when the two drugs were given at the same time, the tumors initially shrank but then grew back. _MIT
Differential cell responses to chemotherapy treatment. The photo shows a range of responses of similar cells to the chemotherapeutic drug doxorubicin. The most intensely responding drugs are shown in yellow, many of which will die. Green cells are alive but not dividing. Red cells are continuing to grow and divide. Yaffe and colleagues have figured out how to increase the proprotion of triple negative breast cancer cells that can be killed by a specific time-ordered regiment of growth factor inhibitors and chemotherapy, with direct application to clinical treatment. Image courtesy of Neil Ganem, Michael Yaffe and David Pellman

Staggering the administration of cancer chemotherapy drugs can effectively treat some types of cancer which are highly resistant to conventional modes of chemotherapy treatment. MIT cancer researchers are leading the research to discover why a staggered treatment seems more effective, and to determine which types of cancer are most susceptible to this method of drug administration.
In the new paper, published in Cell on May 11, the researchers showed that staggering the doses of two specific drugs dramatically boosts their ability to kill a particularly malignant type of breast cancer cells.

The researchers, led by Michael Yaffe, the David H. Koch Professor of Biology and Biological Engineering at MIT, are now working with researchers at Dana-Farber Cancer Institute to plan clinical trials of the staggered drug therapy. Both drugs — erlotinib and doxorubicin — are already approved for cancer treatment.

Yaffe and postdoc Michael Lee, lead author of the Cell paper, focused their study on a type of breast cancer cells known as triple negative, meaning that they don’t have overactive estrogen, progesterone or HER2 receptors. Triple-negative tumors, which account for about 16 percent of breast cancer cases, are much more aggressive than other types and tend to strike younger women.

“For triple-negative breast cancer cells, there is no good treatment. The standard of care is combination chemotherapy, and although it has a good initial response rate, a significant number of patients develop recurrent cancer,” says Yaffe, who is a member of the David H. Koch Institute for Integrative Cancer Research at MIT.

Uncontrolled growth

For the past eight years, Yaffe has been studying the complex cell-signaling pathways that control cells’ behavior: how much they grow, when they divide, when they die. In cancer cells, these pathways often go haywire, causing the cells to grow even in the absence of any stimulus and to ignore signals that they should undergo cell suicide.

Yaffe became intrigued by the idea that drug-induced changes in these signaling pathways, if staggered in time, could switch a cancerous cell into a less malignant state. “Our previous systems-biology work had primed us to the idea that you could potentially drive a cell from a state in which only a fraction of the tumor cells were responsive to chemotherapy into a state where many more of them were responsive by therapeutically rewiring their signaling networks in a very time-dependent way,” he says.

Specifically, he and Lee thought it might be possible to sensitize cancer cells to DNA-damaging drugs — the backbone of most chemotherapy — by first giving them another drug that shuts down one of the haywire pathways that promote uncontrollable growth. They tested different combinations of 10 DNA-damaging drugs and a dozen drugs that inhibit different cancerous pathways, using different timing schedules.

“We thought we would retest a series of drugs that everyone else had already tested, but we would put in wrinkles — like time delays — that, for biological reasons, we thought were important,” Lee says. “I think had it not worked, we would have gotten a lot of pushback, but we were pretty convinced that there was a lot of information being left on the table by everyone else.”

Of all combinations they tried, they saw the best results with pretreatment using erlotinib followed by doxorubicin, a common chemotherapy agent. Erlotinib, approved by the FDA to treat pancreatic cancer and some types of lung cancer, inhibits a protein found on cell surfaces called the epidermal growth factor (EGF) receptor. When constantly active, as it is in many cancer cells, the EGF receptor stimulates a signaling pathway that promotes uncontrolled growth and division.

The researchers found that giving erlotinib between four and 48 hours before doxorubicin dramatically increased cancer-cell death. Staggered doses killed up to 50 percent of triple-negative cells, while simultaneous administration killed about 20 percent. About 2,000 genes were affected by pretreatment with erlotinib, the researchers found, resulting in the shutdown of pathways involved in uncontrolled growth.

“Instead of looking like this classic triple-negative type of tumor, which is very aggressive and fast-growing and metastatic, they lose their tumorigenic quality and become a different type of tumor that is actually quite unaggressive, and very easy to kill,” Lee says.

However, if the drugs were given in the reverse order, doxorubicin became less effective than if given alone.

...A combination of high-throughput measurements and computer modeling was used to reveal the mechanism for increased tumor killing, and to identify a biomarker for drug response. The researchers found that the treatment was most effective in a subset of triple-negative breast cancer cells with the highest levels of EGF receptor activity. This should allow doctors to screen patients’ tumors to determine which would be most likely to respond to this novel treatment.

The research is “groundbreaking in its demonstration that the principles of order and time are essential to the development of effective therapies against complex diseases,” Rune Linding, research group leader at the Technical University of Denmark, and Janine Erler, associate professor at the University of Copenhagen, wrote in a commentary accompanying the paper in Cell. “As disease researchers, we must consider network states, and this and other studies serve as a model for a new generation of cancer biologists.”

The concept of staggering drug treatments to maximize impact could be very broadly applicable, Yaffe says. The researchers found similar boosts in tumor killing by pretreating HER2-positive breast cancer cells with a HER2 inhibitor, followed by a DNA-damaging drug. They also saw good results with erlotinib and doxorubicin in some types of lung cancer.

“The drugs are going to be different for each cancer case, but the concept that time-staggered inhibition will be a strong determinant of efficacy has been universally true. It’s just a matter of finding the right combinations,” Lee says.

The findings also highlight the importance of systems biology in studying cancer, Yaffe says. “Our findings illustrate how systems engineering approaches to cell signaling can have large potential impact on disease treatment,” he says. _MITNews
The scientists have barely begun to discover the mechanisms behind the effectiveness of staggered treatments.

What is not mentioned is that we are likely to discover methods of treating ageing, once we more fully understand the reasons for the success of staggered cancer chemotherapy. Because of the time sensitive nature of DNA repair and epigenetic shifting, certain combinations of interventions which affect the genetic and epigenetic apparatus need to be given at certain times in relation to each other. In other words, some interventions facilitate other interventions, but only for specific periods of time, until the system reverts to its original status.

There is a rich gold mine of discovery associated with this phenomenon. Stem cell research has already confronted this discovery, and is exploring it to good effect. Cancer research is likewise beginning to see the light. Soon, anti-ageing research will wield this powerful tool. Time-sensitive paired (and more) interventions are likely to revolutionise the field of genetic intervention across multiple fields.


Monday, May 07, 2012

Mastering Cell Signaling: A Worthy Goal

Cells make decisions in fluctuating environments using inherently noisy biochemical mechanisms. Such effects create considerable, unpredictable variation – known as ‘stochasticity’– both over time and between genetically identical cells. To understand how cells exploit and control these biochemical fluctuations, scientists must identify the sources of stochasticity, quantify their effects, and distinguish variation that carries information about the biological environment from confounding noise.

In their PNAS paper, Dr Bowsher and Professor Swain show how to decompose the fluctuations of biochemical networks into multiple components and how to design experimental ‘reporters’ to measure these components in living cells.

The paper, which describes the application of this approach to yeast cells, shows that the majority of cellular variation may be informational in origin and due to fluctuations in the cellular environment. The results pave the way to a better understanding of the dynamics of signal processing and decision-making by cells. _SD
Cell Signaling Network, Preliminary Sketch

We begin to comprehend the potential power of cell signaling mastery, when we observe research breakthroughs such as the following:
In laboratory experiments with mouse cells, the researchers found that a specific protein that regulates cell aging also controls a process that causes blood-making stem cells to age. Using drugs to inhibit the action of this protein (called Cdc42) reversed aging of the hematopoietic stem cells and restored their function to a level similar to that of younger stem cells.

It had been [previously] believed that the aging of hematopoietic stem cells was locked in by nature and could not be reversed by using drugs, according to a hospital news release.

...The study by scientists at Cincinnati Children's Hospital Medical Center and Ulm University Medicine in Germany appeared online May 3 in the journal Cell Stem Cell. _USN
Turning old hematopoietic stem cells into young hematopoietic stem cells is nothing to sneeze at. And it is only a slight foretaste of what is becoming possible, as we better understand cell signaling networks and the signaling involved in gene expression.

One of the more exciting near-to-intermediate term possibility arising from the coming mastery of cell signaling, is the ability to reverse neurodegenerative diseases which involve abnormal protein folding. Diseases such as Alzheimer's, Huntington's, Parkinson's, and "mad cow disease," for example, involve abnormal proteins leading to cell destruction and loss of neural function.
Researchers at the University of Leicester uncovered how the build-up of proteins in mice with prion disease resulted in brain cells dying.

They showed that as misfolded protein levels rise in the brain, cells respond by trying to shut down the production of all new proteins.

...The team at the Medical Research Council laboratory in Leicester then tried to manipulate the switch which turned the protein factory off. When they prevented cells from shutting down, they prevented the brain dying. The mice then lived significantly longer.

Each neuro-degenerative disease results in a unique set of misfolded proteins being produced, which are then thought to lead to brain cells dying.

Prof Giovanna Mallucci told the BBC: "The novelty here is we're just targeting the protein shut-down, we're ignoring the prion protein and that's what makes it potentially relevant across the board."

The idea, which has not yet been tested, is that if preventing the shut down protects the brain in prion disease - it might work in all diseases that have misfolded proteins.

Prof Mallucci added: "What it gives you is an appealing concept that one pathway and therefore one treatment could have benefits across a range of disorders. _BBC
Nature article

Complex cell signaling is also involved in the control of gene expression, including critically important DNA repair, and control of telomere length in cells -- which controls the number of cell doublings allowed.

If you click on the image above, you can view an enlarged version of a portion of a cell signaling network. Such complexity explains the need for high powered computational backup in the attempt to decode these networks, as a prelude to their mastery.

Cellular processes take place very quickly, and in a closely controlled and balanced chemical milieu. If we are to learn to intervene on the level of the cell in a beneficial way, we must proceed with care. But we definitely aim to proceed.


Tuesday, March 27, 2012

Stanford U. Researchers Fire Potent Shot Across the Bow of Solid Tumour Cancers

A single drug can shrink or cure human breast, ovary, colon, bladder, brain, liver, and prostate tumors that have been transplanted into mice, researchers have found. The treatment, an antibody that blocks a "do not eat" signal normally displayed on tumor cells, coaxes the immune system to destroy the cancer cells. _ScienceMagNews
In research published on PNAS (Full PDF), Stanford researchers demonstrated the ability to successfully destroy human cancer growing in mice, using monoclonal antibodies targeted against the cellular protein CD47.

CD47 is overexpressed in many cancers, and allows the tumour cells to "fly beneath the immune system's radar," thus escaping destruction. By blocking CD47, the scientists demonstrated that the immune system was able to destroy tumour cells that would have been otherwise ignored.
To determine whether blocking CD47 was beneficial, the scientists exposed tumor cells to macrophages, a type of immune cell, and anti-CD47 molecules in petri dishes. Without the drug, the macrophages ignored the cancerous cells. But when the CD47 was present, the macrophages engulfed and destroyed cancer cells from all tumor types.

Next, the team transplanted human tumors into the feet of mice, where tumors can be easily monitored. When they treated the rodents with anti-CD47, the tumors shrank and did not spread to the rest of the body. In mice given human bladder cancer tumors, for example, 10 of 10 untreated mice had cancer that spread to their lymph nodes. Only one of 10 mice treated with anti-CD47 had a lymph node with signs of cancer. Moreover, the implanted tumor often got smaller after treatment -- colon cancers transplanted into the mice shrank to less than one-third of their original size, on average. And in five mice with breast cancer tumors, anti-CD47 eliminated all signs of the cancer cells, and the animals remained cancer-free 4 months after the treatment stopped.

"We showed that even after the tumor has taken hold, the antibody can either cure the tumor or slow its growth and prevent metastasis," says Weissman.

Although macrophages also attacked blood cells expressing CD47 when mice were given the antibody, the researchers found that the decrease in blood cells was short-lived; the animals turned up production of new blood cells to replace those they lost from the treatment, the team reports online today in the Proceedings of the National Academy of Sciences.

Cancer researcher Tyler Jacks of the Massachusetts Institute of Technology in Cambridge says that although the new study is promising, more research is needed to see whether the results hold true in humans. "The microenvironment of a real tumor is quite a bit more complicated than the microenvironment of a transplanted tumor," he notes, "and it's possible that a real tumor has additional immune suppressing effects."

Another important question, Jacks says, is how CD47 antibodies would complement existing treatments. "In what ways might they work together and in what ways might they be antagonistic?" Using anti-CD47 in addition to chemotherapy, for example, could be counterproductive if the stress from chemotherapy causes normal cells to produce more CD47 than usual. _SciencemagNews
This approach would probably not qualify as a solo therapy, but would rather be used along with other anti-cancer therapies, to either cure a cancer or to limit its growth and spread where cure is not possible.

Researchers believe that all solid tumours may well be vulnerable to this approach.

This treatment will not be without side effects, and not all cancer patients would benefit or qualify for such treatment. But it is very promising.

H/T NextBigFuture


Wednesday, March 14, 2012

Another Approach to Treating Alzheimer's In Early Stages

A study published this week in the Journal of Neuroscience shows that the compound epothilone D (EpoD) is effective in preventing further neurological damage and improving cognitive performance in a mouse model of Alzheimer's disease (AD). The results establish how the drug might be used in early-stage AD patients.

...EpoD acts by the same microtubule-stabilizing mechanism as the FDA-approved cancer drug paclitaxel (Taxol™). These drugs prevent cancer cell proliferation by over-stabilizing specialized microtubules involved in the separation of chromosomes during the process of cell division. However, the Penn researchers previously demonstrated that EpoD, unlike paclitaxel, readily enters the brain and so may be useful for treating AD and related disorders.

After three months of receiving EpoD, additional tau clumps did not form in the brains of the aged AD mice, and nerve-cell function was increased compared to the AD mice that did not receive drug. What’s more, the EpoD-treated mice showed improvements in learning and memory. Importantly, the doses of EpoD that resulted in these benefits were much lower than had previously been used in Phase II clinical testing of EpoD in cancer patients. The investigators observed no side-effects — including the suppression of the immune system and peripheral nerve damage -- in the transgenic mice that received EpoD. _UPennNews
Most approaches to treating Alzheimer's dementia aim to either affect the levels of neurotransmitters in the brain -- particularly acetylcholine -- or to decrease accumulation of amyloid beta protein.

The idea of over-stabilising neurotubules to prevent tau tangles from forming in early stage Alzheimer's is an intriguing approach, and dates to earlier studies attempting to discover the true etiological origins of Alzheimer's. More from a 2011 study published in The Journal of Neuroscience:
Alzheimer's disease (AD) pathology is characterized by senile plaques (SPs) and neurofibrillary tangles (NFTs) (Selkoe, 2001). SPs are extracellular deposits of amyloid-β (Aβ), a 3–4 kDa peptide derived from proteolytic cleavage of the amyloid precursor protein (APP) by β-site APP cleavage enzyme 1 (BACE) (Hussain et al., 1999; Sinha et al., 1999; Vassar et al., 1999; Yan et al., 1999) and the presenilin (PS)-containing γ-secretase complex (De Strooper et al., 1998; Wolfe et al., 1999). NFTs are intracellular accumulations of hyperphosphorylated tau (Lee et al., 2001). About 5% of AD cases are linked to pathogenic mutations in APP, PS1, or PS2 genes (Selkoe, 2001). Tau gene mutations are pathogenic for familial frontotemporal lobar degeneration characterized by tau pathology without SPs, indicating that tau abnormalities alone cause neurodegenerative disease (Lee et al., 2001). _Journal of Neuroscience 25 May 2011, 31(21): 7691-7699; doi: 10.1523/​JNEUROSCI.6637-10.2011
Note that researchers are still attempting to unravel the apparent multiple strings of causation involved in Alzheimer's Disease (AD) and similar neurodegenerative diseases of the brain.

The new research involving microtubule stabilisation, was performed in transgenic mice, meaning that results in human populations using such treatments may be quite different. The fact that both amyloid placques and tau tangles are seen in pathological brain specimens from AD patients suggests that more than one treatment approach may ultimately be required for many, if not most AD sufferers.

Cross-posted from Al Fin blog


Tuesday, March 13, 2012

Progress on Two Important SENS Anti-Ageing Themes

Aging Damage Discovery SENS Solution
Cell loss, tissue atrophy 19551 Stem cells and tissue engineering (RepleniSENS)
Nuclear [epi]mutations

(only cancer matters)
19592, 19823 Removal of telomere-lengthening machinery (OncoSENS)
Mutant mitochondria 19724 Allotopic expression of 13 proteins (MitoSENS)
Death-resistant cells 19655 Targeted ablation (ApoptoSENS)
Tissue stiffening 19586, 19817 AGE-breaking molecules (GlycoSENS); tissue engineering
Extracellular aggregates 19078 Immunotherapeutic clearance (AmyloSENS)
Intracellular aggregates 19599 Novel lysosomal hydrolases (LysoSENS)
The "seven pillars of SENS anti-aging strategies" are shown in the table above, with a timeline of the discovery of their importance shown in the image below.
Important progress has recently been made on two of the pillars of SENS: Correcting for mutant mitochondria, and an improved clearing of cellular junk.

First, correcting human mitochondrial mutations:
Researchers at the UCLA stem cell center and the departments of chemistry and biochemistry and pathology and laboratory medicine have identified, for the first time, a generic way to correct mutations in human mitochondrial DNA by targeting corrective RNAs, a finding with implications for treating a host of mitochondrial diseases. Mutations in the human mitochondrial genome are implicated in neuromuscular diseases, metabolic defects and aging. There currently are no methods to successfully repair or compensate for these mutations, said study co-senior author Dr. Michael Teitell, a professor of pathology and laboratory medicine and a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Between 1,000 and 4,000 children per year in the United States are born with a mitochondrial disease and up to one in 4,000 children in the U.S. will develop a mitochondrial disease by the age of 10, according to Mito Action, a nonprofit organization supporting research into mitochondrial diseases. In adults, many diseases of aging have been associated with defects of mitochondrial function, including diabetes, Parkinson's disease, heart disease, stroke, Alzheimer's disease and cancer.

"I think this is a finding that could change the field," Teitell said. "We've been looking to do this for a long time and we had a very reasoned approach, but some key steps were missing. Now we have developed this method and the next step is to show that what we can do in human cell lines with mutant mitochondria can translate into animal models and, ultimately, into humans."

The study appears March 12, 2012 in the peer-reviewed journal Proceedings of the National Academy of Sciences. _esciencenews
More at the link.

Next, clearing cellular trash aggregates:
A University of Michigan cell biologist and his colleagues have identified a potential drug that speeds up trash removal from the cell's recycling center, the lysosome.

The finding suggests a new way to treat rare inherited metabolic disorders such as Niemann-Pick disease and mucolipidosis Type IV, as well as more common neurodegenerative diseases like Alzheimer's and Parkinson's, said Haoxing Xu, who led a U-M team that reported its findings March 13 in the online, multidisciplinary journal Nature Communications.

"The implications are far-reaching," said Xu, an assistant professor of molecular, cellular and developmental biology. "We have introduced a novel concept—a potential drug to increase clearance of cellular waste—that could have a big impact on medicine." _UMich News
More at the link.

Both of these developments will require a number of years to perfect and shape into useful therapies. But as noted, improved therapies in either domain would provide hope for slowing the ageing process, and for treating many of the degenerative scourges of human existence.

The SENS Foundation has worked to promote research in the seven areas pictured above. And at least partially due to the efforts of SENS, more researchers and funding agencies are picking up the same themes.

Cross-posted from Al Fin blog

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