100 Days Blog

Day 080 - Regenerative medicine

Submitted by Sam on 8 August, 2011 - 22:07

The older a population gets, the greater the social and financial cost of its healthcare. With an average population age of thirty, healthcare systems will consider the treatment of minor injuries to be the norm. With an average population age of over fifty, chronic age-related illnesses like diabetes and heart disease become the daily concern for the healthcare system, and these kinds of illness are both expensive and difficult to treat. In older populations, expensive therapies are needed to produce only marginal increases in life quality and life expectancy, and this is because older populations are exposed not only to more diseases that are inherently more difficult to treat than younger populations, but because as populations age, the ratio between workers and retirees with debilitating illnesses decreases, driving up the cost of treatment.

Regenerative medicine aims to change this unsustainable trend by diagnosing diseases early and providing treatments which offer dramatic improvements in the quality of life by accelerating the rate at which the body heals itself, combating the disease itself rather than just its symptoms. Revolutionary technologies such as the stem cell therapy offer a new paradigm for medicine with profound social and economic implications.

Stem cells are single cells which have the capacity to divide and create offspring that are either an undiffentiated copy of themselves or are instead destined to differentiate into any type of cell specialized for any tissue or organ in the whole body. As they can create copies of themselves, stem cells are self-replenishing, and as they create cells that become specialized, they are a constant source of cells for specialized tissues and organs throughout the body. In contrast to stem cells, most cells in the body cannot self-renew, and instead become progressively more specialized and restricted in what they can do. Some stem cells have the unique ability of being able to differentiate into almost any cell type, and are consequently termed pluripotent stem cells. Pluripotent stem cells are derived from the inner cell mass of mammalian embryos in their earliest stages of development – between four to five days old in humans – and are also known as embryonic stem cells. In contrast, adult stem cells are much more limited in what they can become, as a blood stem cell generates blood cells, an epidermal stem cell generates skin cells and a neural stem cell generates nerve cells. Whilst adult stem cells can never usually differentiate into another type of specialized cell, the promise of stem cell therapies lies in unlocking these mature stem cells and converting them back into their embryonic, pluripotent form, allowing them to replace almost any cell type anywhere in the body.

Releasing the power of pluripotent stem cells in this way would allow us to regenerate in much the same way that newts and salamanders do, growing back damaged tissues and organs to a sustained level of functionality, restoring patient independence, and decreasing reliance on chronic care. Investment in stem cells research has the potential to dramatically change the quality of individual life, and simultaneously lower the cost of healthcare and thereby boost national productivity. This kind of medical revolution is becoming critical as populations continue to get older and overburden dwindling workforces; revolutions like this are needed before healthcare systems in industrialized countries collapse.

Day 079 - Regeneration

Submitted by Sam on 8 August, 2011 - 08:32

Salamanders, hydra and planarian flatworms have extraordinarily adaptive regenerative capabilities, and can completely regrow amputated limbs and damaged tissues in a matter of months. Salamanders, including European newts, are unique among vertebrates in their ability to regenerate limbs, eyes, spinal cords, internal organs and their upper and lower jaws. Incredibly, newts can regenerate damaged heart muscle cells, completely repairing their heart after trauma, with no scarring of tissue. This regenerative process occurs through cellular dedifferentiation, where cells revert to an earlier developmental stage, losing their characteristic properties before replicating en masse and specializing once more to rebuild new tissue.

Some reptiles use their potent regenerative abilities as part of a self-defense system to thwart predators, where they will self-amputate part of their tail when captured, allowing them to flee the grasps of the predator and grow it back later. The detached tail will thrash around of its own accord, creating a diversion that distracts attention from the fleeing lizard, which is saved from much blood-loss through contraction of special muscles that surround the artery in its tail. This process is called autotomy, and is a survival adaptation common to octopuses, crabs, spiders and lobsters. The sea-food industry exploits the regenerative ability of autotomic stone crabs, harvesting claws from the living catch before returning them to the sea where they will regenerate within eighteen months.

With the exception of deer, who grow and shed their antlers each year, mammals have lost the ability to regenerate replica replacements for lost or damaged body parts. Regenerative medicine is the field that explores the biology of these phenomena, and holds the promise of bringing this kind of self-repairing power to humans, one day allowing us to regrow limbs, tissues and organs, simultaneously solving the problems of organ transplant rejection and instantly solving the shortage of donor organs.

Day 078 - Lifestyle for longevity

Submitted by Sam on 7 August, 2011 - 00:10

A study of the lives and deaths of 2872 pairs of Danish twins concluded in 1996 that the heritability of longevity is only moderate, that genetic factors account for only around a quarter of how long we live, and that within certain biological limits, our lifestyle plays the most important part in dictating our longevity 1. This study has informed interest in so-called 'Blue Zones', or regions of the world where an unusually high percentage of the population live active lives beyond one-hundred years of age, presumably as a result of a certain longevity-optimized lifestyle.

Dan Buettner, an explorer and writer for National Geographic, has identified five blue zones. In partnership with the National Institute on Aging and National Geographic, he methodically studied their demographies to tease out the cross-cultural factors that informed their longevity. Although not rigorously scientific, the studies indicate that inhabitants of Blue Zones share certain strikingly similar lifestyle characteristics, which seem intuitively probable to contribute to their long and active lives. Common among the geographically confined populations, the consumption of largely plant-based – and often leguminous – diets, the constant moderate level of physical activity, and the lack of smoking coupled with strong familial bonds and social integration at all ages combined to create an inventory of lifestyle characteristics that have potentially life-enhancing and life-extending properties.

Of the Blue Zones studied, the archipelago of Okinawa is perhaps the most striking. On the northern part of the main island, eight-hundred miles south of Tokyo, is the world's oldest living female population. The inhabitants here boast the world's longest disability-free life expectancy, with incidences of only one sixth the rate of cardiovascular disease and one fifth the rate of breast and colon cancers compared with America. As well as eating a diet full of varied vegetables, and as well as eating fewer calories at each sitting than Western cultures, the Okinawans have specific social constructs that seem likely to support longevity. Notably for Dan Buettner, the Okinawan language has no word for retirement, instead vitalizing entire lives with another word, “ikigai” – “a reason for being”, the raison d'etre. Okinawan centenarians questioned in the National Institute of Aging's survey about their ikigai, answered instantantly. For one 102 year old woman, her reason to wake up each morning was simply her great-great-great-granddaughter.

  • 1. Herskind, A. M., Matthew McGue, Niels V. Holm, Thorkild I. A. Sørensen, Bent Harvald, and James W. Vaupel. "The Heritability of Human Longevity: a Population-based Study of 2872 Danish Twin Pairs Born 1870-1900." Human Genetics 97.3 (1996): 319-23. Print.

Day 077 - Intracellular junk

Submitted by Sam on 5 August, 2011 - 22:51

Lysosomes are organelles that act as cellular recycling machinery, breaking down large molecules, waste material and damaged cellular subcomponents using digestive enzymes bathed in an acidic environment. Whilst extremely effective as a waste disposal system, there are some chemical structures that the cell's degradation machinery is simply unable to break down. Over time, these resilient compounds build up in the lysosome as useless junk. This is typically not a problem in cells such as skin cells which divide regularly, as the cellular division distributes the junk at harmlessly low levels. In cells which do not divide so frequently, like those in the back of the eye and some nerve cells, the material accretes to harmful levels, damaging the cells and eventually stopping them working correctly. Unstable build-ups of this material eventually burst, and can cause heart attacks and strokes, whilst failure to remove the intracellular junk in the brain can lead to neurodegenerative diseases such as Alzheimer's and Parkinson's. Macular degeneration, the leading cause of age-related blindness, is also caused by the accumulation of the toxic components of this lysosomal residue.

Lipofuscin is the general term for this undegraded waste material, and it is one of the seven types of ageing damage identified by Aubrey de Grey and combated by his Strategies for Engineered Negligible Senescence (SENS). The proposed strategy for dealing with the age-related pathologies of lipofuscin build-up is to confer lysosomes with enzymes capable of digesting the relevant material using gene therapy.

The feasibility of this solution is given credence by an incidental property of lipofuscin and some cross-disciplinary thinking by Dr. De Grey. Lipofuscin is fluorescent, but graveyards and mass graves don't glow in the dark. What this means is that the soil, which should be unusually full of the intracellular waste from decaying bodies, should itself fluoresce; the fact that it doesn't suggests that it contains some substance capable of degrading the enzyme-resistant lipofuscin. Soil mirco-organisms have been known for some time to be capable of digesting solvents, pesticides and oil into harmless products, and so De Grey reasons that there are bacteria in the soil containing an enzyme capable of cleaning up our intracellular junk.

Our not-insignificant task now is to identify this enzyme and equip our cellular recycling plants with its powers. With this new potency to degrade even the most resistant materials, their pathological accumulation would not just be mitigated, but may also be reversed, as ageing cells all over the body would be purged of their toxic cargo. In the case of macular degeneration, this reversal would allow the blind to see.

Day 076 - Mitochondrial bomb-shelters

Submitted by Sam on 5 August, 2011 - 01:06

Our cells generate most of the energy they need in tiny structures inside them called mitochondria, which can be thought of as the cells' powerhouses. Mitochondria have their own DNA, independent of the cell's nuclear genome, which is compelling similar to the DNA of bacterial genomes. What this suggests is that many thousands of years ago, mitochondria were not just components of our cells, but were in fact unicellular organisms in their own right. According to this hypothesis – the endosymbiotic theory – mitochondria (and possibly some other organelles) originated as free-living bacteria which later became incorporated inside other cells in a symbiotic relationship.

Like man-made powerhouses, mitochondria produce hazardous by-products as well as useful energy. They are the main source of free radicals in the body – hugely reactive particles which cause damage to all cellular components through oxidative stress. They attack the first thing they come across, which is usually the mitochondrion itself. This hazardous environment has put the genes located in the mitochondrion at risk of mutational damage, and over many years of evolutionary pressure the mitochondrial DNA has gradually moved into the cell's nucleus, where it is comparatively well-protected from the deleterious effects of free-radicals alongside all of the cell's other DNA. This is called allotopic expression, and it has moved all but thirteen of the mitochondrion's full complement of at least one thousand genetic instructions for proteins into the 'bomb-shelter' of the nucleus.

However, the remaining thirteen genes in the mitochondrion itself are subject to the ravages of free-radicals, and are likely to mutate. Mutated mitochondria, as Aubrey de Grey has identified, may indirectly accelerate many aspects of ageing, not least when their mutation causes them to no longer produce the required energy for the cell, in turn impairing the cell's functionality. In order to combat the down-stream ageing damage as a consequence of mitochondrial mutation, de Grey believes that the mitochondrial DNA damage itself needs to be repaired or rendered harmless.

His characteristically bold solution to this problem is to put the mutations themselves beyond use by creating backup copies of the remaining mitochondrial genetic material and storing them in the safety of the cell's nucleus. Allotopically expressed here, like the rest of the mitochondrial DNA, any deletions in the mitochondrial DNA can be safely overwritten by the backup master copy, which is much less likely to mutate hidden away from the constant bombardment of free radicals. There are several difficulties to this solution, not least the fact that the remaining proteins are extremely hydrophobic and so don't 'want' to be moved at all, and additionally the code disparity between the language of the mitochondrial DNA and the nuclear DNA which makes a simple transplantation without translation impossible.

Even if this engineered solution to the problem proves impracticable, at the very least the theory is sound. If we can devise a way systematically defend our mitochondria from their own waste products, we will drastically reduce the number of harmful free radicals exported throughout our bodies, thereby reducing preventing a lot of the damage that distinguishes the young from the old, extending and improving the quality of our lives as a result.

Day 075 - The ageing trance

Submitted by Sam on 3 August, 2011 - 23:10

Dr Aubrey de Grey, a gerontologist from Cambridge, believes that ageing is a disease that can be cured. Like man-made machines, de Grey sees the human body as a system which ages as the result of the accumulation of various types of damage. And like machines, de Grey argues that this damage can be periodically repaired, potentially leading to an indefinite extension of the system's functional life. De Grey believes that just as a mechanic doesn't need to understand precisely how the corrosive processes of iron oxidation degrades an exhaust manifold beyond utility in order to successfully repair the damage, so we can design therapies that combat human ageing without understanding the processes that interact to contribute to our ageing. All we have to do is understand the damage itself.

De Grey is confident that he has identified future technologies that can comprehensively remove the molecular and cellular lesions that degrade our health over time, technologies which will one day overcome ageing once and for all. In order to pursue the active development and systematic testing of these technologies, de Grey has made it part of his mission to break the 'pro-ageing trance' that he sees as a widespread barrier to raising the funding and stimulating the research necessary to successfully combat ageing. De Grey defines this trance as a psychological strategy that people use to cope with ageing, fuelled from the incorrect belief that ageing is forever unavoidable. This trance is coupled with the general wisdom that anti-ageing therapies can only stretch out the years of debilitation and disease which accompany the end of most lifetimes. De Grey contends that by repairing the pathologies of ageing we will in fact be able to eliminate this period completely, postponing it with new treatments for indefinitely longer time periods so that no-one ever catches up with the damage caused by their ageing.

To get over our collective 'trance' it is worth realising that this meme has made perfect psychological sense until very recently. Given the traditional assumption that ageing cannot be countered, delayed or reversed, it has paid to make peace with such a seemingly immutable fact, rather than wasting one's life preoccupied with worrying about it. If we follow de Grey's rationale that the body is a machine that can be repaired and restored, we have to accept that there are potential technologies that can effectively combat ageing, and thus the trance can no longer be rationally maintained.

Day 074 - The mitotic clock

Submitted by Sam on 2 August, 2011 - 23:48

Telomeres are repetitive DNA sequences which cap the ends of chromosomes, protecting them from damage and potentially cancerous breakages and fusings. They act as disposable buffers, much as the plastic aglets at the end of shoelaces prevent fraying. Each time a cell divides, the telomores get shorter as DNA sequences are lost from the end. When telomeres reach a certain critical length, the cell is unable to make new copies of itself, and so organs and tissues that depend on continued cell replication begin to senesce. The shortening of telomeres plays a large part in ageing (although not necessarily a causal one), and so advocates of life extension are exploring the possibility of lengthening telomeres in certain cells by searching for ways to selectively activate the enzyme telomerase, which maintains telemore length by the adding newly synthesized DNA code to their ends. If we could induce certain parts of our bodies to express more telomerase, the theory goes, we will be able to live longer, healthier lives, slowing down the decline of ageing.

Every moment we're fighting a losing battle against our telomeric shortening; at conception our telomeres consist of roughly 15,000 DNA base pairs, shrinking to 10,000 at birth when the telomerase gene becomes largely deactivated. Without the maintenance work of the enzyme our telomeres reduce in length at a rate of about 50 base pairs a year. When some telomeres drop below 5,000 base pairs, their cells lose the ability to divide, becoming unable to perform the work they were designed to carry out, and in some cases also releasing chemicals that are harmful to neighbouring cells. Some particularly prominent cell-types that are affected by the replicative shortening of telomeres include the endothelial cells lining blood vessels leading to the heart, and the cells that make the myelin sheath that protects our brain's neurons. Both brain health and heart health are bound to some degree to the fate of cells with a telomeric fuse. The correlation between telomere length and biological ageing has motivated a hope that one day we will be able to prevent and perhaps reverse the effects of replicative senescence by optimally controlling the action of telomerase.

Day 073 - Evolutionary search

Submitted by Sam on 1 August, 2011 - 23:10

The complexity of synthesizing proteins for specific purposes is so great that predicting the amino acid sequences necessary to generate desired behaviour is a huge challenge. Mutations far away from the protein’s active site can influence its function, and the smallest of changes in the structure of an enzyme can have a large impact on its catalytic efficacy – a key concern for engineers creating proteins for industrial applications. Even for a small protein of only 100 amino acids long there are more possible sequences than there are atoms in the universe.

What this means is that an exhaustive search through the space of all possible proteins for the fittest protein for a particular purpose is essentially unachievable, just as a complete search through all possible chess games to decide the absolutely optimal next move is computationally impractical. This is true both for scientists and for nature. This means that even though evolution has been searching the space of all possible proteins for billions of years for solutions to survival, it has in fact explored only a minute corner of all possible variations. All evolved solutions are likely to be 'good enough' rather than the absolute optimum – it just so happens that the ones already 'discovered' are sufficient to create and maintain the diversity and richness of life on planet earth.

New ways of efficiently searching this vast space of possible sequences will reveal proteins with properties that have never before existed in the natural world, and which will hopefully provide answers to many of our most pressing problems. Directed evolution not only provides a faster way of searching this space than many other methods, but it also leaves a complete 'fossil record' of the evolutionary changes that went into evolving a specific protein, providing data on the intermediate stages which will offer insight after detailed study into the relationship between protein sequence and function. Unlike natural evolution, directed evolution can also explore sequences which aren't directly biologically relevant to a single organism's survival, providing a library of industrially relevant proteins, and perhaps one day creating bacteria capable of answering worldwide problems caused by pollution and fossil fuel shortage.

Day 072 - Evolution machines

Submitted by Sam on 31 July, 2011 - 22:30

Neo-evolution is factorially faster than normal evolutionary processes. Our genetically engineered organisms have already neo-evolved – shortcutting traditional evolution to produce desirable results without the costly time-delay of selection over hundreds or thousands of generations. Higher-yielding and insecticide-resistant crops have been engineered through the painstaking modification of individual genes, achieving better results than years of selective breeding in a fraction of the time. Genetic engineering of humans, both embryonic and those already alive, will perhaps one day bring the benefits of this new type of evolution to our bodies.

At the moment, we simply do not understand how DNA sequences encode useful functions, and so genetic engineering remains a tremendously costly and laborious process. It cost $25 million and took 150 person-years to engineer just a dozen genes in yeast to cause it to produce an antimalarial drug, and commercial production has yet to begin. The amount of time and money required to effect a beneficial result through genetic engineering – even if it involves relatively simple changes to only a dozen genes – is so costly that the transformative idea of neo-evolved humans has been kept at a safe distance.

But there are other ways to neo-evolve that might make the possibility of too-good-to-miss genetic enhancements in humans a reality before long. Earlier this year, for instance, the National Academy of Engineering awarded its Draper Prize to Francis Arnold and Willem Stemmer for their independent work towards 'directed evolution', a technique which harnesses the power of traditional evolution in a highly optimized environment to accelerate the evolution of desirable proteins with properties not found in nature. Rather than attempt to manually code the strings of individual DNA letters necessary to effect a particular trait, directed evolution and its associated 'evolution machines' take a prototype 'parent' gene, create a library of genetic variants from it and apply selection pressures to screen for the strains that produce the desired trait, iterating this process with the best of each batch until the strongest remain. This was first evidenced in 2009, when geneticist Harris Wang used directed evolution to create new proteins in E. coli bacteria that would produce more of the pigment that makes tomatoes red than was previously possible.

To achieve this genetic modification without manually fine-tuning each gene, Wang synthesized 50,000 DNA strands which contained modified sequences of genes that produce the pigment, and multiplied them in his evolution machine. After repeating the process 35 times with the results of each cycle fed into the next, he produced some 15 billion new strains, each with a different combination of mutations in the target pigment-producing genes. Of these new strains, some produced up to five times as much pigment as the original strain, more than the entire biosynthesis industry had ever achieved. The process took days rather than years.

Day 071 - The future of human evolution

Submitted by Sam on 31 July, 2011 - 01:32

There are three distinct possibilities for how technological and medical advancement will impact future human evolution. The first contingency is that the human species will undergo no further natural selection, because we may have already advanced to a position of evolutionary equipoise, where our technologies have artificially preserved genes that would otherwise have been removed by natural selection; evolution no longer has a chance to select. As a species we already control our environment to such an extent that traditional evolutionary pressures have been functionally alleviated – we adapt the environment to us rather than the other way around. Indeed, local mobility and international migration allow populations to genetically integrate to such a degree that the isolation necessary for evolution to take place may in fact already no longer possible.

The second possibility is that we will continue to evolve in the traditional way, through inexorable selection pressures exerted by the natural environment. The isolation necessary to allow the impact of any environmental changes to be selected for in the population will now be on the planetary scale, enabled by colonization of distant space.

The third possibility is that we will evolve in an entirely new way, guided not by unconscious natural forces but by our own conscious design decisions. In this neo-evolution we would use genetic engineering to eliminate diseases like diabetes, protect against strokes and reduce the risks of cancer. We would be compressing a natural process which takes hundreds of thousands of years into single generations, making evolutionarily advantageous adjustments ourselves.

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