Interesting Comments by George Church
George Church is an important figure in the development of modern genomics and genetic engineering. Like a number of luminaries in the medical life sciences, in recent years he has become much more openly supportive of efforts to treat the causes of aging and extend healthy human life spans. You might recall the keynote he gave at the SENS6 rejuvenation research conference, and note that Church is a member of the SENS Research Foundation advisory board. With that context, I'll point you to recent remarks made to a journalist:
A Harvard professor says he can cure aging, but is that a good idea?
I mentioned to Church that CRISPR is the kind of work for which Nobels are awarded. He quickly responded that there are more important things in the balance than prizes. There are cures for human diseases, he said. Church thinks that one of the ailments he can cure is aging. When I met him early this year, in his laboratory at Harvard Medical School, where he is professor of genetics, he expressed confidence that in just five or six years he will be able to reverse the aging process in human beings."A scenario is, everyone takes gene therapy - not just curing rare diseases like cystic fibrosis, but diseases that everyone has, like aging," he said. He noted that mice die after 2.5 years but bowhead whales can live to be 180 or 200. "One of our biggest economic disasters right now is our aging population. If we eliminate retirement, then it buys us a couple of decades to straighten out the economies of the world. If all those gray hairs could go back to work and feel healthy and young, then we've averted one of the greatest economic disasters in history. Someone younger at heart should replace you, and that should be you. I'm willing to. I'm willing to become younger. I try to reinvent myself every few years anyway."
So on Tuesday, I asked him if he was still on track to reversing the aging process in the next five years or so. He said yes - and that it's already happening in mice in the laboratory. The best way to predict the future, he said, is to predict things that have already happened.
This is filtered through a layperson with mixed feelings about the whole business of trying to treat aging, so necessary context is lost. Church is big on the application of genetic tools to many present problems, no surprise given his background, and it is true that an entire class of solutions in medicine and other fields can be constructed atop robust, reliable gene therapy of the sort enabled by CRISPR. However, many types of genomic research into aging and longevity are presently taking place, and there are many types of intervention, existing and proposed, that can employ genetic engineering. Sadly, those gathering the greatest attention at the current time are also the least likely to produce meaningful results. Let me divide things up into a couple of categories:
Firstly, we have the search for longevity genes and the idea that we can use drugs, gene therapies, and other tools in the toolkit to adjust metabolism to look more like that of people with specific genetic or epigenetic traits that are linked to longer healthy lives. This covers a broad range of approaches, from calorie restriction and exercise mimetics to analysis of centenarian genomes in search of common factors. This is slow and expensive work, and so far has produced little more than knowledge. There is also the problem that in principle even complete success means tiny gains. What does it mean to have the full set of characteristic differences present in a centenarian's metabolism? It means you have perhaps a 1.5% chance of living to 100 rather than a 1% chance, to pull some numbers out of the air - the real numbers are along these lines. Identified genetic associations with longevity are a matter of a tiny increase in a tiny chance of survival, and if you get there you're still decrepit and age-damaged. The same goes for calorie restriction and exercise mimetics; even if completely recapturing the real thing, that gains a few years of additional life expectancy. You still age, you still die, and the schedule is much the same. This is not a goal worth spending billions and decades on, but it is nonetheless what most researchers are involved in.
Secondly we have classes of compensatory alteration to the genome, or equivalent therapies that change protein levels without changing genes. These are in principle capable of providing benefits that will have greater impact than any presently available option - such as calorie restriction - but they don't directly repair the damage that causes aging, and thus cannot on their own do more than delay the inevitable. In this category you'll find things such as follistatin or myostatin gene therapy to force greater maintenance of muscle mass, increased catalase production in mitochondria to slow their contribution to aging, attempts to mine regenerative and long-lived species for mechanisms that might be ported over to humans one day, and a range of gene and other therapies that spur old stem cells into action, overriding their response to cell and tissue damage, and restoring at least some of the tissue maintenance that falls off with age. The jury is still out on the degree to which these stem cell approaches raise the risk of cancer due to higher levels of damaged stem cell activity in damaged tissues, but so far it is less than expected. The bulk of researchers not involved in the first category above are working on something in the second, and this includes Church. I take his remarks quoted above to refer to the range of rodent studies from past years demonstrating a modest slowing of aging or partial restoration of some narrow set of measures relating to aging via gene therapies and the like.
Thirdly we have the role of gene therapies and genetics in repair therapies after the SENS model, addressing the causes of aging and thus in principle capable of producing indefinite healthy life spans if the repair is good enough and frequent enough. The SENS approach to mitochondrial DNA damage, currently in initial commercial development for inherited mitochondrial disease by Gensight, is a gene therapy, copying altered mitochondrial genes into the cell nucleus as a backup. Similarly forms of clearance of various forms of accumulated gunk - amyloid, lipofuscin, cross-links - that degrade cell and tissue function could well take the form of gene therapies to deliver additional tools needed for the job to cells, though it is more likely we'll see other forms of therapy at first. The SENS vision for preventing cancer may also be a gene therapy in its most complete form, acting to suppress the activity of all mechanisms capable of lengthening telomeres throughout the body. Here again, I suspect other less radical telomere extension blocking approaches will arise at first.
The point here is that genetic engineering and genomics covers a wide range of ground. A lot of it is pointless with respect to aging, at least from any perspective other than the scientific goal of full and complete knowledge of how the decay of the unmodified human machine progresses. Of the rest there are very definite classes of degree for the potential benefit that can be achieved. Not all approaches are the same, and in advance of trying them we can make reasonable predictions of the best possible benefit that could be achieved. We live in an age of rapid, radical progress in biotechnology. We should not be aiming low. I don't believe that slowing aging is good enough, and I don't believe that to be the best possible outcome achievable in the next few decades, were people to support the right lines of research. The weight of scientific evidence backing SENS rejuvenation approaches is compelling, and should be compelling enough to draw anyone away from tinkering with calorie restriction mimetic drugs or longevity-associated genes, lines of research with very limited best possible outcomes when it comes to translation to therapies for aging. Yet it is not, still, and this is why we continue to need advocacy and fundraising to advance the SENS cause, to produce more evidence, and persuade more support, and speed progress towards an end to aging.
Those comments after the article... Sigh.
Are we missing something though? Why are so many people into the genetic approach if there are clearly better ways? People like Church, or Venter can't think it's going to provide almost meaningless results, otherwise they wouldn't be putting so much time, money, and effort into it, right?
One of the things that intrigues me about this is for example gene p53 which if I remember correctly helps to suppress Cancer by means of forcing cells to undergo apoptosis. So if the cancer cells have disabled p53 somehow then why can't we just use whatever protein or miRNA is associated with p53 as a treatment?
Likewise, can't we produce some kind of protein and/or miRNA as a treatment for aging?
And of course, yes, obviously organ and tissue replacement, fast-grown outside the body....
I'm skeptical of the SENS idea that moving mitochondrial genes into the nucleus will work. Mitochondria are already pretty cut down and it's likely that what few genes they have that remain are in the mitochondria for a reason. I suspect it's because Nick Lane is right about how mitochondria enabled the growth of Eukaryotes.
It seems George Church has suggested less conservative approaches to anti-aging (banking on iPSC technology), and they do repair damage by basically regrowing cells:
http://www.sens.org/videos/new-epigenome-analysis-and-engineering-technologies-reversal-aging-george-church
http://www.economist.com/news/technology-quarterly/21615029-george-church-genetics-pioneer-whose-research-spans-treating-diseases-altering
“We’ve taken my 60-year-old fibroblast [connective tissue] cells, changed them into a different form and then back to fibroblasts and they’re young again, most of the time. Turning that into a whole body therapy is another leap but my point is that we can do it.”
@Ham: Maybe it's because, if all you have is a hammer, everything looks like a nail.
@xdb:
p53 gene therapy would kill any cell we would apply it to. What is needed is a tool to tell apart cancerous cells from non-cancerous cells. Once you have that, you can kill them in many ways, not only with p53. There is a lot of research about this. Search for targeted cancer therapy news.
Indeed, the 13 mitochondrial genes remain there for a reason: the proteins they produce are very hydrophobic. That is already addressed by MitoSENS.
George Church is on the advisory board of a company I am involved with and I must say his work is grounded and he has very good reasons for saying what he has. Church is nothing like Venter though as Church believes we can do something about aging and Venter recently suggested longevity was socially irresponsible.
"Venter said the billionaires of the world may be attracted to the idea of living significantly longer, potentially even for 120 years or more, but that’s “socially irresponsible” and would further deplete the world’s resources"
http://ww2.kqed.org/futureofyou/2015/10/02/longevity-pioneer-its-irresponsible-for-humans-to-live-forever/
Not the first time he has said this sort of thing. Church believes we can do something about aging and his gene drives and tests are very much heading that direction.
Steve,
Interesting on the Venter comments. I did not know that he felt that way. I read articles about him wanting to make 100 the new 60, etc. unless he's drawing the imaginary line in the sand at 120, which I don't think is the case either.
To add,
The person he founded HLI with (Diamandis) seems to be pretty pro longevity, last time I looked. Or at least it seemed that way.
@XTB/GTR - Regarding mitochondrial genes needing to be in the mitochondria for some unknown reason, and not just because their proteins are hydrophobic... Reason recently said to you on 16-10-15 "If that were true, then the allotopic expression gene therapy for LHON pioneered by Gensight wouldn't work in animal and cell models. But it does."
Hi all,
Note : message is long, skip if too long. Summary : aging gene tinkering can work but some roadblocks ahead.
'' He noted that mice die after 2.5 years but bowhead whales can live to be 180 or 200 ...
So on Tuesday, I asked him if he was still on track to reversing the aging process in the next five years or so. He said yes - and that it's already happening in mice in the laboratory. ''
Until they reverse aging in a mouse to continuously live on and on above it's 3 years, it's mostly not going to be strong in effect; make a mouse live the life of NMR (35 years old) and then, I will be Sold; especially when they make a 'eternal mouse' who lives as a long a human centenarian. Gene tinkering so far is about 20-40% in potency effect and all of these pathways have been worked/tried/tested on to find some way to increase the potency; meaning that there is interconnection redundancy and the entire body is a Yin-Yang homeostatic/osmostic system that will auto-regulation itself depending on context/situation and what we do to it by gene tinkering. Hence why certain therapies in mices and insects have no translatability in long-lived humans.
I suggest him (and others) to focus on long-lived species too; there is little in regards to long-lived models. Just random observations but very little tangible. Bowhead whales are a good start; they though us that the IIS(Insulin)/Nrf2/ARE/Redox/Telomeres is the major responsible pathways to remaining healthy for many years and live longer while abating damage accumulation, mutational load and gene network dysfunction.
I was looking for papers made by this scientist and found out a very good one that supports his claims. And, I especially can't wait he brings back wolly mammoths from extinction (via mammoth DNA from Russian mummified mammoth cadaver combined into adult mother elephant that would birth a mammoth) to the north here in northern Artic Canada and in US Alaska territory (he said bringing back certain cool extinct species, which seems counterintuitive as they are gone for a reason, can save us from global warming future as they will transform it yet again by their repopulating consequence effect on North).
Albeit, I have slight hold of self against his ageing claims from reading this paper and the next one :
Meta-analysis of age-related gene expression profiles identifies common signatures of aging João Pedro de Magalhães1,∗,†, João Curado2 and George M. Church1
'' Our results suggest an overexpression of genes related to lysosomes, such as cathepsins (CTSS, CTSH and CTSZ), and the lysosomal membrane. Lysosomes degrade many macromolecules, including proteins, and biochemical changes in these organelles have been described with aging (Cuervo and Dice, 2000). One hypothesis is that the overexpression of genes associated with lysosomal function, as well as that of genes related to phagocytosis, is a cellular response to the accumulation of abnormal proteins with age. In this context, adaptive aging gene expression changes could help pinpoint changes at other levels. We also found an overexpression with age of anti-apoptotic genes and cell-cycle ...
regulators like granulin (GRN) and annexins. It is possible that some of these genes are not upregulated due to their role in apoptosis but rather as a part of other functions. For example, clusterin (CLU) is an extracellular chaperone that could curtail the effects of misfolding and aggregation of proteins (Kumita et al., 2007) ...
The upregulation of p21 with age was previously validated by western blot in muscle (Edwards et al., 2007) and could be related to an increased proportion of senescent or growth arrested cells with age, an area of extensive other studies and interest (de Magalhaes and Faragher, 2008) ...
These results suggest that senescent biomarkers detected in vitro may be important biomarkers during mammalian aging in vivo. Considering that inflammatory processes can induce senescence and that senescent cells can secrete inflammatory cytokines ...
An underexpression of collagen genes and of genes associated with energy metabolism, particularly mitochondrial genes, as well as alterations in the expression of genes related to apoptosis, cell cycle and cellular senescence biomarkers, were also observed. ''
Elevated Coding Mutation Rate During the Reprogramming of Human Somatic Cells into Induced Pluripotent Stem Cells†‡§
Junfeng Ji1, Siemon H. Ng1, Vivek Sharma1, Dante Neculai1, Samer Hussein2, Michelle Sam1, Quang Trinh1, George M. Church3, ...
Elevation of p21 and lysosomal cathepsin with aging is proof that inflammation if going on and the proteasome/lysosome/etc are trying their best to mitigate that by degrading the junk. Other studies have tinkered with these genes and elements with slight results; p21 is a tumor inhibitor and oncogene marker; but also a oxidative stress marker. Cathepsins directly relate to lipofuscins accumulation degradation and other destroyed molecules. What I'm getting at is that the gene reprogramming way could hit certain stumbling blocks that I thought we could overcome. Mostly what Reason and others have said; damages but espeically Irreversible damages such as crosslinks (thanks Florin for killing my hope ;D jk I'm back in the damage camp! lol) that are truly chemically irreversible; if the proteasome and lysosome/cathepsin/peptidase and other degrading systems are having all the difficulty removing this; including undegradable lipofuscins and crosslinks from damage accumulation; how the hell can gene reprogrammation overcome this ? That puzzles me. I still think of the foetus skin descarrification a possible geneting process that removes all damages (including crosslinks) and that complements George Church's findings of reversal of his own fibroblasts' aging (fibroblasts are responsible from skin ECM matrix formation; yet studies that show fibroblasts age reversal show reversal of lipofuscin content (or stabilization) in FACS electron scans; so really the damage accumulation* is greatly frozen somehow (proteasome must find a way to clear it because these damage end residues impede proteasome, phagosome and lyososome/contribute to lysosomal mass; thus difficulty of degradation/DNA junk clearance).
Reverse aging of his 60-year old fibroblasts and here seeing mutational load changes in iPSCs...
Gene tinkering is becoming more and more as sort of a crapshoot (sometimes it does miracles and most of the time it doesn't, it's a degree thing and hitting the right gene combo) and as reprogrammation of iPSCs shows (high telomeres, reversal of damages ?, stem cells anew); and some other told me (Irreversibility* of certain damages will be the new word), it will be interesting to see if these findings can be applied to Every cell, tissue and organ in the entire body from head to toe (that's the crux of it, and most likely we will stumble on new unforeseen dead ends). Fingers crossed.
1. http://www.ncbi.nlm.nih.gov/pubmed/19189975
2. http://onlinelibrary.wiley.com/doi/10.1002/stem.1011/full
@xdb: In addition to hydrophobicity, mentioned by Antonio, there is the even more profound problem of code disparity: the "key" by which RNA is translated into amino acids is different in mitos from the nucleus because (it's thought) of their having originally evolved as separate organisms, so instead of coding for tryptophan the sequence UGA encodes a STOP codon, truncating the protein. This is trivial for genetic engineers to fix, but a very hard problem for evolution. (Hydrophobicity is somewhat harder for engineers, and much easier for evolution relative to the code disparity problem but still very difficult).
All the remaining laggards in the mitochondrion appear to suffer one or the other or both of these problems. Various possible additional explanations are addressed in this paper by Dr. de Grey:
de Grey ADNJ. Forces maintaining organellar genomes: is any as strong as genetic code disparity or hydrophobicity? BioEssays 2005;27(4):436-446. PubMed: 15770678. Categories: MitoSENS
As Jim relays from Reason, existing cases of engineered "backup copies" of mitochondrial genes refute the idea that in situ expression is necessary to function.