Somatic Cell Nuclear Transfer Achieved in Adult Human Cells
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The future of cell therapies includes regenerative treatments and tissue engineering, as well as many other possibilities, but it all depends on the development of highly efficient, low-cost ways to generate a ready supply of cells of any given type from a patient's own cells, such as a skin sample. The lower the cost the faster that research progresses today, and the establishment of low-cost methods of generating patient-specific cells is very much required to enable widespread use of affordable therapies tomorrow.

A little more than a decade ago it looked like the best way to create these cell supplies was to work on a technique called somatic cell nuclear transfer (SCNT), in which the nucleus from a patient's cell is introduced into an egg cell that has had its nucleus removed. The result recapitulates some of the early development of a blastocyst from which pluripotent cells can be harvested and developed into any type of human cell. Unfortunately this turned out to be more challenging than expected from a technical point of view, and as you may recall there was in addition a great deal of foolish political intervention that made it even harder to move forward. Then not so long afterwards the techniques for generating induced pluripotent stem (IPs) cells by direct reprogramming were discovered and the majority of the research community jumped ship for that much easier methodology.

Some researchers kept working on the roadblocks preventing implementation of SCNT in human cells, however, and have now finally achieved an initial success with adult human cells. This is the sort of result that can lead to the infrastructure necessary to generate patient-specific cells, but in this case it has more of the feel of the closing of a chapter. The leading edge of the research community now works with induced pluripotency and related forms of direct cell reprogramming, and is making rapid progress with those techniques. Success with SCNT is to be praised, but I think unlikely that it will gather much support in the present environment.

First Embryonic Stem Cells Cloned From A Man's Skin

Last year, scientists in Oregon said they'd finally done it, using DNA taken from infants. Robert Lanza, chief scientific officer at Advanced Cell Technology, says that was an important step, but not ideal for medical purposes. "There are many diseases, whether it's diabetes, Alzheimer's or Parkinson's disease, that usually increase with age," Lanza says. So ideally scientists would like to be able to extract DNA from the cells of older people - not just cells from infants - to create therapies for adult diseases.

"What we show for the first time is that you can actually take skin cells, from a middle-aged 35-year-old male, but also from an elderly, 75-year-old male" and use the DNA from those cells in this cloning process, Lanza says. They injected it into 77 human egg cells, and from all those attempts, managed to create two viable cells that contained DNA from one or the other man. Each of those two cells is able to divide indefinitely, "so from a small vial of those cells we could grow up as many cells as we would ever want."

Scientists use cloning to make stem cells matched to two adults

Lanza and his colleagues said their experiments revealed that some eggs were better at it than others. Researchers used 49 eggs from three women, though eggs from only two of them produced results. "The magic is in the egg," Lanza said.

Lanza said that most stem cell scientists have "jumped on the iPS bandwagon," but he argued that stem cells created by SCNT could still play a vital role in regenerative medicine. He envisions a day when multiple lines of stem cells are kept in banks and made available to patients based on their biological similarity, much the way blood and donor organs are now handled. "If we had these banks, we would have the raw material to do tissue engineering and grow up organs, or to grow up vessels, tendons or whatever you want."

Human Somatic Cell Nuclear Transfer Using Adult Cells

Derivation of patient-specific human pluripotent stem cells via somatic cell nuclear transfer (SCNT) has the potential for applications in a range of therapeutic contexts. However, successful SCNT with human cells has proved challenging to achieve, and thus far has only been reported with fetal or infant somatic cells. In this study, we describe the application of a recently developed methodology for the generation of human embryonic stem cells via SCNT using dermal fibroblasts from 35- and 75-year-old males. Our study therefore demonstrates the applicability of SCNT for adult human cells and supports further investigation of SCNT as a strategy for regenerative medicine.
The Crossroads for Human Longevity
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In these years we stand at the crossroads for human longevity. A long, slow, and largely unintentional upward trend in health and life expectancy has been running for near two hundred years now, caused by increases in wealth and technological progress, each driving the other. Increased longevity in turn helps to increase wealth and speed progress: all of these benefits are individually but facets of the whole gem.

The medical science of the past has blossomed into full-bored biotechnology, and change and growth in this field has become exceptionally rapid over the past twenty years, mirroring progress in computing hardware and software development. Scientists can now individually carry out tasks in a few months that would have required an entire laboratory staff and years of labor in the early 1990s, if it even possible at all back then. Many researchers advocate that now is the time to approach aging as the medical condition it is, to stop treating it with religious awe, as though it were some mystical thing that stands outside of the rest of medicine, and use the tools we have to make it go away.

Some of these researchers are engaged in a form of networked disruptive innovation within aging research that they hope will eventually displace the present mainstream. This is how progress happens in human organizations: the heretics agitate and prove themselves correct via research and development until such time as the old mainstream gives in and agrees that they were right all along.

That is the high road ahead from the crossroads. Upon this road the research community abandons its reluctance to treat aging, the public comes to think of aging in the same way as they presently think of cancer, research funding flows, and great progress is made towards means of halting and reversing the underlying causes of aging. Age-related diseases start to become things of the past, like widespread cholera and tuberculosis, just a few decades past this turning point.

But there are other roads ahead. Disruptive movements don't always win in their first spin around the block. The old guard can last for decades past their time, poisoning the well and ensuring that progress remains slow. Regulation can also suppress new paradigms, and indeed entire fields of human endeavor, for decades at a time - and medical development certain does not lack for obstructive bureaucracy. The treatment of aging is actually forbidden in the US by regulatory fiat, and there is no effective path towards gaining approval for the commercial application of potential therapy to intervene in the causes of aging. This is well known and the chilling effect percolates all the way back up the chain of research and development to create difficulties in fundraising for such goals.

So there are low roads to either side away from the crossroads. These are largely the ruts of status quo and slow progress in which billions of dollars continue to go towards research that increases our knowledge of the details of the molecular dance that is aging, but which can offer no plausible hope or promise of significantly extending life soon enough to matter to us. Life spans continue to edge upward, but we all die just a little older than our parents, and suffer all of the same age-related conditions, just a little less painfully. It is the road on which the study of aging for the sake of knowledge rather than action continues to dominate, and in which the public continues to be largely disinterested in extended healthy life or avoidance of the diseases of aging: marching towards death in their tens of millions, but never raising a hand to do anything about it.

This possibility is why advocacy for the better options in longevity science and human rejuvenation must exist. Without disruptive change in the public perception of aging and medicine for aging, without disruptive change in the attitudes of the scientific community, then the status quo is what we will get - and it will let us die by failing to take full advantage of all that can be done in this age of biotechnology.

The paper quoted below is a joint effort by Jan Vijg and Aubrey de Grey, both scientists who see the potential for big changes to the field in the years ahead and would like to see those changes come about. It isn't open access, unfortunately, but the abstract is a good encapsulation of the crossroads we presently find ourselves at.

Innovating Aging: Promises and Pitfalls on the Road to Life Extension

One of the main benefits of the dramatic technological progress over the last two centuries is the enormous increase in human life expectancy, which has now reached record highs. After conquering most childhood diseases and a fair fraction of the diseases that plague adulthood, medical technology is now mainly preoccupied by age-related disorders. Further progress is dependent on circumventing the traditional medical focus on individual diseases and instead targeting aging as a whole as the ultimate cause of the health problems that affect humankind at old age.

In principle, a major effort to control the gradual accumulation of molecular and cellular damage - considered by many as the ultimate cause of intrinsic aging - may rapidly lead to interventions for regenerating aged and worn-out tissues and organs. While considered impossible by many, there really is no reason to reject this as scientifically implausible. However, as we posit, it is not only scientific progress that is currently a limiting factor, but societal factors that hinder and may ultimately prevent further progress in testing and adopting the many possible interventions to cure aging.

An Update on DNA Methylation Patterns as a Biomarker of Aging
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The research community is very interested in a reliable method of measuring biological age: not how old you are in years, but how far along you are in the aging process, how much damage has accumulated in cells and macromolecules and how well or poorly your organs and other systems are reacting to that damage. Such a measurement of age is known as a biomarker of aging, and while there are all sorts of measures that correlate fairly well with biological age - good enough for large statistical studies to use in order to mine data for meaning - there is not yet a good, accurate, standardized way to run some numbers and use them as a measure of how aged you are.

Why is this important? Principally because it costs an enormous amount of money to assess the ability of any treatment to slow or reverse aspects of aging and thereby extend healthy life. The only way to know at present is to wait and see, and even in mice that means years and millions of dollars. But what if we could be fairly sure that by taking some measurements after a single treatment, researchers could predict with a high degree of accuracy whether or not aging is reversed or slowed and future life span thus extended? If achieved, that would mean ten times as much work on assessment of possible therapies in mice could take place for a given amount of funding. That's a big deal, even without considering that the only practical way to determine whether a putative life-extending treatment actually works or not in humans is to establish an accurate biomarker of aging based on short term, immediate measures. It simply isn't practical to take the wait and see approach for decades.

Personally I rather hope that the arrival of an accepted biomarker of aging will do much to damp down the level of fraud and misinformation that spills forth from the "anti-aging" marketplace. There's always someone trying to sell a lie to the masses, and it is unfortunate that their voices are so very much louder than those of the scientific community. Given that pretty much nothing sold on the market today will move the needle at all on human life span, and nothing is yet shown to even match the benefits of calorie restriction or exercise, I look forward to a way to demonstrate this unequivocally.

In any case, in recent years the measurement of patterns of DNA methylation has shown promise as a potential biomarker of aging. DNA methylation is a part of the process of epigenetic changes that take place in response to circumstances, altering levels of proteins produced by cells. Our biology is essentially an assembly of fluid machines in which the controlling switches and levers are the levels of various proteins in circulation. Everything reacts to everything else, in a complex never resting dance of overlapping feedback loops at every level. From this, however, patterns emerge. Aging takes a broadly similar path for all of us, and thus there are some broadly similar reactions to its damage in our cells. The trick is having enough computational power and the right tools of biotechnology to be able to pull out those patterns from the thousands of unrelated variations in DNA methylation that exist in all our tissues.

This is a popular science piece, but still has some interesting information on how things are going with the DNA methylation approach to generating a biomarker of aging that might prove useful as a measure of the effectiveness of future treatments for aging:

Biomarkers and ageing: The clock-watcher

Horvath's clock emerges from epigenetics, the study of chemical and structural modifications made to the genome that do not alter the DNA sequence but that are passed along as cells divide and can influence how genes are expressed. As cells age, the pattern of epigenetic alterations shifts, and some of the changes seem to mark time. To determine a person's age, Horvath explores data for hundreds of far-flung positions on DNA from a sample of cells and notes how often those positions are methylated - that is, have a methyl group attached.

He has discovered an algorithm, based on the methylation status of a set of these genomic positions, that provides a remarkably accurate age estimate - not of the cells, but of the person the cells inhabit. White blood cells, for example, which may be just a few days or weeks old, will carry the signature of the 50-year-old donor they came from, plus or minus a few years. The same is true for DNA extracted from a cheek swab, the brain, the colon and numerous other organs. This sets the method apart from tests that rely on biomarkers of age that work in only one or two tissues, including the gold-standard dating procedure, aspartic acid racemization, which analyses proteins that are locked away for a lifetime in tooth or bone.

Others began downloading the epigenetic-clock program from Horvath's website to test it on their own data. Marco Boks at the University Medical Centre Utrecht in the Netherlands applied it to blood samples collected from 96 Dutch veterans of the war in Afghanistan aged between 18 and 53. The correlation between predicted and actual ages was 99.7%, with a median error measured in months. At Zymo Research, a biotechnology company in Irvine, California, Wei Guo and Kevin Bryant wondered whether the program would work on a set of urine samples Zymo had collected from 11 men and women aged between 28 and 72. The correlation was 98%, with a standard error of just 2.7 years.

[Researchers] expect that the most interesting use of the clock will be to detect 'age acceleration': discrepancies between a person's epigenetic and chronological ages, either overall or in one particular part of their body. Horvath says that recent work has found that people with HIV who have detectable viral loads appear older, epigenetically, than healthy people or those with HIV who have suppressed the virus. Another study, not yet published, observes that some tissues show significant age acceleration in morbidly obese people.

What is Robust Mouse Rejuvenation, and Why Should We Care?
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SENS, the Strategies for Engineered Negligible Senescence is a detailed research plan for developing the means to prevent and reverse degenerative aging by repairing its causes. SENS assembles the list of causes from the present scientific consensus on fundamental differences between old and young tissues, differences that are not known to be caused by any lower-level process. The potential repair therapies are also assembled from the best and latest of research strategies in a range of fields: stem cell therapies, targeted cell destruction, engineered enzymes to break down unwanted biomolecules, immune therapies, and so forth. SENS as a program is shepherded by the SENS Research Foundation but has growing support in the broader scientific community, and far from every last relevant research program is actually initiated by, funded by, or even known to the Foundation.

Robust mouse rejuvenation (RMR) has been the first long term milestone for SENS since its proposal and initial development by Aubrey de Grey. No new technology arrives fully formed, and it is understood that the first versions will be flaky, expensive, and generally much less effective than the later refinements. But in the case of rejuvenation treatments, this may not matter all that much, as even a somewhat effective form of rejuvenation provides the patient more time in which to wait on those refinements - or perhaps even assist in their development. So robust mouse rejuvenation as originally outlined means a full enough implementation of SENS to be capable of doubling the remaining life expectancy of an elderly mouse, demonstrated and then replicated in rigorous laboratory studies. It doesn't mean an absolutely complete implementation, and it doesn't mean full and absolute rejuvenation: it is a first pass to demonstrate greater benefits than any other approach to date.

It is important to note that when I talk about implementation of SENS in the laboratory, I am almost always talking about robust mouse rejuvenation. I do not mean clinical translation of this result, and neither do I mean a complete and fully effective suite of rejuvenation treatments. The path from robust mouse rejuvenation to the clinic might be decades long in the highly regulated US and Europe, but first generation SENS treatments will hopefully jump into clinics in other parts of the world just as rapidly as did first generation stem cell therapies. Medical tourism is a wonderful thing, and will probably one day save your life.

SENS is presently divided into seven general categories of damage that cause aging, each of which seems largely independent from one another and requires a very different approach to repair: a whole different line of research, no doubt running in different labs and organized by different research groups. We may see the seven categories split further in the years ahead if any of the subcategories prove to be either much harder or more important to aging than is presently assumed. For example, if I were writing SENS from scratch I might put immune system aging in its own bucket rather than lumping it under the general category of death-resistant cells. But that's just my view.

It is presently thought that each category of age-related damage in SENS is enough to kill you in roughly a human life span or a little longer even if all of the others are defeated. This may or many not turn out to be the case, but the evidence for this viewpoint is compelling, as each of the SENS categories of damage has at least one fatal age-related condition associated with it, and for which it is the primary known driver. This is in fact how these forms of damage were first categorized and investigated by the research community, as researchers work backwards from the visible and deadly consequences of aging in search of the mechanisms by which they unfold. The assumption that all aspects of SENS must be at least partially addressed in order to prevent aging and extend healthy life is why robust mouse rejuvenation is marked as a goal: get every category of repair treatment in the SENS portfolio working to at least the level of a proof of concept.

How long remains between now and the implementation of robust mouse rejuvenation? Ah well, there's the rub. How long is a piece of string? It is very hard to predict timelines for research when funding is at a low ebb, even research like SENS wherein it is fairly clear as to what the researchers should be working on, which lines of work are most promising, and where the end goals lie. If there was a good level of funding for SENS, say at the level of $100 million a year, then we could fall back to planning estimates of a decade or so to get to robust mouse regeneration. We could do that because with that much money there can be many irons in the fire, and the law of averages begins to smooth out random chance: some projects fail, some do very well and come in early, surprise advances sometimes happen, and some projects take far longer than they were expected to. When there is comparatively little funding then progress in research is uncertain, and I would be surprised to learn that there was more than about $10 million devoted to directly SENS-related work outside the stem cell and cancer research communities this year given that the SENS Research Foundation's yearly budget is around $5 million at the moment.

The glass half full way of looking at this is to see that people like you and I can make a large difference to the level of funding just through ordinary fundraisers, like those that raised $20,000 and $60,000 for SENS research projects last year.

But I think it is worth bearing in mind that robust mouse rejuvenation is not a coordinated single point in time at which all parts of SENS will suddenly become available at once. Different areas of SENS research stand at very different stages of readiness and progress, and some will clearly be done first, and perhaps considerably in advance of the others. The best candidates at this point for early success are, I think, breaking of glucosepane cross-links and mitochondrial repair of some form. If a method of breaking down the predominant form of cross-links in human tissues is demonstrated to produce benefits, will the world sit around waiting for robust mouse rejuvenation in order to develop it? Of course not. In fact, I'd wager that robust mouse rejuvenation will probably be contemporary with medical tourism for first generation treatments based on the more easily developed parts of the SENS rejuvenation toolkit.

You may still get nailed by one of the other forms of age-related damage on roughly the same time scale as a normal human life span, but it is hard to argue that you will not find improvements to health and function through repair of only one or two forms of age-related damage. If you can undergo a treatment to remove glucosepane cross-links to improve function of skin and blood vessels, then I'd argue that your life is better as a result even though all of the other forms of damage are gnawing away at your health in their own ways. Robust mouse rejuvenation is an aspirational goal, but it isn't a dividing line. Results will be more piecemeal and staggered, and any result with significant merit will probably be rapidly developed as a treatment in less regulated parts of the world. Until research funding for SENS and SENS-like research grows greatly, the pace of progress towards rejuvenation will remain variable and uncertain.

Commercial Blood Factories Lie Ahead
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A number of competing lines of research aim at producing large volumes of blood to order, with an eye to eventually eliminating the need for blood donors and all of the shortcomings inherent in donated blood - the need for screening and other expenses in the donation process, the short shelf-life of blood outside the body, and so forth. Firstly there is the approach of creating synthetic blood substitutes, which will be most likely restricted to short-term use in trauma cases for the near future as the intent is to provide the critical function of oxygen transport and little else. Then there are the varied efforts to grow blood from stem cells, some of which are coming closer to clinical trials, an initial step on the way to commercialization. A decade from now blood factories will be established in much the same way as skin factories are a going concern at present: there will likely be some mix of generic blood types produced in bulk from known lineages alongside the ability to create blood to order from a specific patient's cells.

A few years back the researchers involved in the work quoted below estimated that blood derived from stem cells would be in trials by now. They are presently looking at starting small trials in 2016 at the earliest, which perhaps illustrates why scientists are usually cautious about putting timelines on the table, especially in an environment of heavy government regulation, where new delays and new expenses are ever on the menu.

First volunteers to receive blood cultured from stem cells in 2016

The consortium will be using pluripotent stem cells, which are able to form any other cell in the body. The team will guide these cells in the lab to multiply and become fresh red blood cells for use in humans, with the hope of making the process scalable for manufacture on a commercial scale. The team hopes to start the first-in-man trial by late 2016.

Blood transfusions play a critical role in current clinical practice, with over 90m red blood cell transfusions taking place each year worldwide. Transfusions are currently made possible by blood donation programmes, but supplies are insufficient in many countries globally. Blood donations also bring a range of challenges with them, including the risk of transmitting infections, the potential for incompatibility with the recipient's immune system and the possibility of iron overload. The use of cultured red blood cells in transfusions could avoid these risks and provide fresh, younger cells that may have a clinical advantage by surviving longer and performing better.

Professor Marc Turner, Principal Investigator, said: "Producing a cellular therapy which is of the scale, quality and safety required for human clinical trials is a very significant challenge, but if we can achieve success with this first-in-man clinical study it will be an important step forward to enable populations all over the world to benefit from blood transfusions. These developments will also provide information of value to other researchers working on the development of cellular therapies."

Artificial blood 'will be manufactured in factories'

Prof Turner has devised a technique to culture red blood cells from induced pluripotent stem (iPS) cells - cells that have been taken from humans and 'rewound' into stem cells. Biochemical conditions similar to those in the human body are then recreated to induce the iPS cells to mature into red blood cells - of the rare universal blood type O.

There are plans in place for the trial to be concluded by late 2016 or early 2017, he said. It will most likely involve the treatment of three patients with Thalassaemia, a blood disorder requiring regular transfusions. The behaviour of the manufactured blood cells will then be monitored.

This sort of pace of development will likely be beaten to the end goal of commercial blood manufacture by less constrained and more ambitious commercial development in East Asia, I'd imagine. That has been the pattern so far in the development of applied stem cell technologies, at least.

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