Wednesday, March 1, 2017

Your Thoughts?


I have included my latest mystery/thriller - A CURE FOR THE LIVING - to my manuscripts page.
Thank you for your input to date on THE DAEDALUS PROJECT. All comments are very much appreciated.

Thanks,
Bill.

Friday, February 3, 2017

Epigenetic Markers for Cellular Ageing

While there have been many hypotheses on the causes of ageing, the precise mechanism of cellular ageing, and how it can be measured, remains unclear.

A study in 2016 (1) has illuminated the differences between various measurements and possible mechanisms of cellular senescence and ageing.

One widely-reported association between telomere length and ageing has been proven to be inconsistent. Over-expression of oncogene, and DNA damage, have also been seen as contributing to cellular ageing. But the oncogene-induced senescence is really a tumor-suppressive mechanism. Oncogenes, which cause abnormal DNA replication, as well as short telomere length, are both detected by cellular mechanisms as damaged DNA and then initiate senescence of the cell.

Another change related to ageing is the level of methylation at some CpG sites. This has been developed by the authors as a tool for estimating chronological age. The study shows that this “epigenetic clock” measurement is much more accurate in measuring chronological age than telomere length, and correlates well with physical factors in the elderly.

The conclusion of this study is that epigenetic and chronological cellular ageing, as measured by CpG methylation, are independent of cellular senescence caused by telomere length or DNA damage. The results of this and other studies show that even if telomere length is artificially maintained by telomerase, the cell continues to age. The telomeres act as a mechanism for restricting the number of cellular divisions, not for preventing ageing. Cellular senescence, due to DNA damage, telomere shortening, oncogenes, or whatever, is merely a mechanism for removing cells that are seen as damaged, while the rest of the cells continue to age naturally. Cellular ageing “is an intrinsic mechanism that exists from the birth of the cell and continues” throughout its life. 

Which brings us to the larger questions of what causes cellular ageing. Do the methylation markers cause ageing, or does ageing from another source cause the methylation? It is known that methylation is a mechanism for turning certain genes on or off. Since each species has a specific life span, it is clear (at least to me), that each species has evolved a genetic mechanism for ageing and death at a precise moment. Methylation may be a mechanism for directing the cell to begin ageing.

One hypothesis for the specific rate of ageing of each species is that each species, in order to adapt to the rate of change of the environment in the niche it inhabits, developed at optimal time of reproduction. If the environment (food and water supply, weather, temperature, predators, etc.) changes quickly, the organism must adapt to reproduce quickly. It evolves a rapid rate of development to quickly reach sexual maturity and produce offspring with mutations better able to withstand the changes in the environment. Once reproductive maturity is reached, evolution can no longer exert an influence to keep the parent organism alive. In fact, there may even be evolutionary pressure for the parents to die off quickly in order to minimize competition with the offspring and thus increase their survival rate.

It is unclear to me, then, why so much money is currently being spent on researching what appear to be the consequences of ageing rather than focusing on the genetic process itself. DNA is a code, a very complicated code, but a code, nonetheless. Why not focus on breaking this code, and finding the obviously predetermined genetic cellular ageing mechanisms and limits on lifespan that each species has evolved?

We age and die because evolution could not function otherwise. But now we have reached a stage in our development where we no longer have to rely on natural evolution. Soon, hopefully, we will understand our genome to the extent that we will be able to control how we develop (and age). We will no longer be an evolving species, but a self-creating one. Of course, once we reach a stage where we no longer age, other problems will arise (reproductive, social, economic, political, psychological, etc.), as I have discussed in previous posts.


1.     Lowe, D. et al., Epigenetic clock analyses of cellular senescence and ageing, Oncotarget. 2016 Feb 23; 7(8): 8524–8531, https://dx.doi.org/10.18632%2Foncotarget.7383

Wednesday, June 8, 2016

Earth: One Of The Early Civilizations In The Universe

A paper in Monthly Notices of the Royal Astronomical Society in 2015 (1), based on data collected by NASA's Hubble Space Telescope and the Kepler space observatory, has arrived at some unexpected conclusions. The analysis suggests that earth was quite early in its formation as a habitable planet compared to all the habitable planets the universe will eventually produce.

Kepler's planet survey indicates that there are about 1 billion Earth-sized planets in the Milky Way galaxy at present. If you include the 100 billion galaxies in the observable universe, the number of Earth-like planets becomes exponentially larger. The Hubble volume (the volume of space containing all objects traveling away less than the speed of light due to the expanding universe) is estimated to contain about 10^20 Earth-like planets.

Calculations suggest that our solar system formed after 80% of the existing Earth-like planets in the Universe and the Milky Way had already formed. However, if the existing gas in the Universe continues to condense to form stars and planets, the analysis shows that the Earth formed before 92 per cent of similar Earth-like planets are expected to ever form in the future. In other words, there is less than an 8% chance that we are the only civilization the Universe will ever have.

But if we assume that the Milky Way today contains just one other civilization, calculations show that it is likely that Earth would be at least the ten billionth planet with a civilization in the observable Universe. The observable Universe would eventually contain at least one hundred billion civilizations.

If the calculations are right and most of the Earth-like planets in the Universe will form in the distant future, a civilization a trillion years from now will have a very difficult time in learning how the universe began and formed since most of the evidence for the big bang will have dissipated due to the accelerating expansion of the Universe. We may then consider ourselves lucky in being one of the “early” civilizations to form. 

If we are an early civilization, perhaps the only civilization in the Milky Way until now, though many more will eventually form, it might explain Fermi’s paradox, in which Enrico Fermi famously asked “Where is everybody?” in referring to why signs of extraterrestrial life haven’t yet been found. In the distant future we will be the the ones contacting their early civilizations, our own UFOs to be seen in their skies, and we will be imparting our knowledge of how the Universe formed since they would have no way of knowing.


1.     Peter Behroozi and Molly Peeples. On The History and Future of Cosmic Planet Formation. Monthly Notices of the Royal Astronomical Society, 2015 DOI: 10.1093/mnras/stv1817








Tuesday, November 24, 2015

Young Blood Can Reverse Aging

The quest for stopping and even reversing the aging process has entered a new phase over the past few years. A few scientists have investigated the phenomenon of administering the blood of young mice to old mice, an experiment that has a long but not a very illustrious history. As far back as the 1600s renowned figures such Andreas Libavius and Robert Boyle (of Boyle’s Law fame) proposed that transfusions of the blood of the young might rejuvenate the old, but the experiment was a catastrophe since, at the time, there was no knowledge of blood groups. 

In recent years several scientists have returned to the experiment. In 2005 Conboy et al published a paper in Nature (1) in which they used a procedure called parabiosis where they surgically combined the circulatory systems of young and old mice. Together with a later study, (2) they found that the exposure of old mice to young blood restored proliferation and the regenerative capacity of satellite cells (skeletal muscle stem cells) as well as hepatocytes (liver cells) by re-activating molecular signaling. In 2011 Villeda et al (3) demonstrated that young blood can increase regeneration of brain cells in old mice and that old blood can inhibit regeneration in young mice. This and later studies (4) showed that certain proteins in old blood decrease regeneration of brain cells in young mice and impair cognition. Specifically, they found that beta-2 microglobulin is elevated in the blood of old mice and if injected systemically, or locally in the hippocampus, impairs cognitive function and neurogenesis in young mice. The same group (5) further showed that injecting plasma of young mice into old mice can increase regeneration of cells in the hippocampus and increase cognitive function.

It is known that TGF-b1, a multi-functional cytokine, becomes elevated with age in several organs, including muscle and brain (6). Hanadie et al. (7) demonstrated that TGF-b-1 inhibition enhances neurogenesis and muscle regeneration in old mice, as well as decreasing inflammation. Sinha et al. (8) published results showing that increasing GDF-11 levels in aged mice causes increased genomic integrity of muscle stem cells and restores the structure and function of muscle cells and brain (9), though the effects of GDF-11 have recently been challenged (10). In yet another study (11), researchers found that, unlike previous theories, mitochondrial DNA is not degraded in older mice and by changing the regulation of two genes, CGAT and SHMT2, that control glycine production, they could restore mitochondrial function in fibroblast cell lines to that of young cells.

Whatever the specific molecules turn out to be, and there will eventually be several, the exciting point of all these findings is that there are elevated levels of substances in the plasma of old mice that inhibit stem cells in various organs studied, and there are other substances that are increased in young mice which promote these same stem cells. Furthermore, the stem cells of old mice can be induced to act like those of young mice by administering the correct plasma substances. If it turns out that aging can be thus reversed by common pathways in all organs systems, the cure for aging may not be far away.

But even if we isolate all these products, the question will still arise as to what genetic pathway controls their production and the aging process. It is not enough to simply administer these products to aged individuals, for practical reasons if nothing else. It will be necessary to eventually change the genome of the human species to actually make it ageless, if that is our goal. It is not a coincidence that these products are produced to induce aging. It is clear that aging, and the pace of aging, is a genetic process, since each species ages at different rates and has its own unique lifespan. Each species is programmed to self destruct after a specific period, probably related to its unique requirement to mature and reproduce at a specific rate according to its evolutionary niche (the rate at which its own unique environment changes). If the environment changes quickly – the number of predators, food supply, weather, etc.—it has to reproduce quickly, and age quickly, for its offspring to produce the mutations to adapt. Since evolution always acts through mutations on the next generation, death is a necessary evolutionary trait. The survival of the new generation, and thus the species, is greatly enhanced if the parents no longer compete for natural resources, etc. after reaching sexual maturity. For those who object by saying that few animals in the wild die of old age but rather by predation or lack of food, I ask who does the predator most likely capture? The very young are normally protected by the herd while the old and slow are the stragglers who end up as prey. Furthermore, the very young are usually fed by the parents until they are able to find food while the grandparents are left to fend for themselves. The species is programmed for the new generation to mutate into a more adapted organism and for the old, which are no longer as suited to the new environment, to die off.

If we continue on this path to cure the disease of aging, we should consider the consequences of success. Some of the positive and negative effects of creating an ageless species are obvious, and some are not. In earlier postings, I have reviewed some of these considerations, but it might be time to revisit the topic since science is moving at such a rapid rate. It seems that few people are actually discussing the practical, societal, psychological and moral issues that will inevitably arise when the cure is found.








1.     Conboy I. M. et al. Nature (2005) 433, 760-764 doi:10.1038/nature03260
2.     Brack AS, et al. Science. (2007) 317 807-810.
3.     Villeda SA, et al. (2011) Nature 477: 90-94.
4.     Smith LK, et al. (2015) Nature Medicine 21, 932-937.
5.     Villeda SA. et al. (2014) Nature Medicine 20:659-663.
6.     Carlson ME, et al. (2009) Aging cell 8:676-689.
7.     Hanadie Y. et al. (2015) Oncotarget, Vol. 6, No. 14. pp. 11959-11978
8.     Sinha M. et al. Science 9 May 2014: Vol. 344 no. 6184 pp. 649-652 DOI: 10.1126/science.1251152
9.     Katsimpardi L. Science 9 May 2014: Vol. 344 no. 6184 pp. 630-634
DOI: 10.1126/science.1251141
10.  Egerman MA et al. Cell Metabolism, May 2015 22: pp 164-174.
11.  Hashizume O. et al. Scientific Reports, 2015; 5: 10434 DOI: 10.1038/srep10434


Friday, January 30, 2015

Is Only 7% of the Human Genome Functionally Important?

ENCODE studies in 2012 (1) concluded that about 1% of the human genome codes for proteins and that about 80% of the genome is “biochemically active, and likely involved in regulating the expression of nearby genes.” These findings have produced a great deal of controversy and much hypothesizing among the scientific community. But a recent paper published in Nature Genetics (2,3) sheds doubt on those findings.

Researchers at Cold Springs Harbor created a computational method called fitCons which analyzes the changes in DNA letters that have occurred during long evolutionary periods across different species as well as during shorter periods between human individuals. In this way they hoped to identify which parts of the human genome were preserved and thus functionally important.

The present study showed that only about 7% of the letters in the human genome were preserved and are functionally important. Their conclusion is that “most of the sequences designated as ‘biochemically active’ by ENCODE are probably not evolutionarily important in humans,” and that “the much larger ENCODE-based estimates can’t be explained by gains of new functional sequences on the human lineage.”

Among the ENCODE papers, Kellis showed that 5% of the noncoding DNA is conserved across mammals and that an additional 4% is conserved among humans.

An obvious question that immediately arises if these findings are correct is what the activity shown by ENCODE in the other 73% of the genome that is not preserved by evolution is doing. Some of the critics of the ENCODE data have suggested that much of the ‘biochemical activity’ detected by their methodology is spurious and insignificant.

1.     Massachusetts Institute of Technology. "Biochemical functions for most of human genome identified: New map finds genetic regulatory elements account for 80 percent of our DNA." ScienceDaily. ScienceDaily, 5 September 2012. www.sciencedaily.com/releases/2012/09/120905154823.htm
2.     Cold Spring Harbor Laboratory. "Which 'letters' in the human genome are functionally important?." ScienceDaily. ScienceDaily, 20 January 2015. www.sciencedaily.com/releases/2015/01/150120160323.htm

3.     Brad Gulko, Melissa J Hubisz, Ilan Gronau, Adam Siepel. A method for calculating probabilities of fitness consequences for point mutations across the human genome. Nature Genetics, 2015; DOI: 10.1038/ng.3196