The Progression of Leukemia: Most Old People Have Some of the Necessary Mutations in Blood Cells

Here is an interesting look at the progression and prevalence of DNA damage leading to leukemia, cancers of bone marrow and white blood cells. Cancer is an age-related disease because its proximate cause is DNA damage and we accumulate ever more of this damage as time goes on. DNA repair systems in our cells and destruction of precancerous cells by the immune system are highly efficient but not perfect, and falter with age due to other forms of accumulating damage. The development of a robust suite of effective cancer treatments is an essential part of progress towards effective treatments for degenerative aging, and perhaps so is a means of DNA repair as well:

It is almost inevitable that we will develop genetic mutations associated with leukaemia as we age. Based on a study of 4,219 people without any evidence of blood cancer, scientists estimate that up to 20 per cent of people aged 50-60 and more than 70 per cent of people over 90 have blood cells with the same gene changes as found in leukaemia. Scientists investigating the earliest stages of cancer development used an exquisitely sensitive sequencing method capable of detecting DNA mutations present in as few as 1.6 per cent of blood cells, to analyse 15 locations in the genome, which are known to be altered in leukaemia. By comparing their findings with other research conducted with a lower degree of sensitivity over whole exomes, the scientists were able to conclude that the incidence of pre-leukaemic cells in the general population is much higher than previously thought and increases dramatically with age.

The pre-leukaemic mutations studied appear to give a growth advantage to the cells carrying them and this starts a process in which cells with these mutations dominate blood making. As they increase in number, the likelihood that one or more of them will acquire more mutations becomes greater, something that could eventually lead to leukaemia and leukaemia-like disorders. Interestingly, the study found that mutations affecting two particular genes, SF3B1 and SRSF2, appeared exclusively in people aged 70, suggesting that these mutations only give a growth benefit later in life, when there is less competition. This finding explains why myelodysplastic syndromes, a group of leukaemia-like conditions associated with these genes, appear almost exclusively in the elderly.

None of the 4219 people studied were found to have a mutation in NPM1, the most common acute leukaemia gene mutated in up to 40 per cent of cases. This unexpected result suggests that mutations in NPM1 behave as gatekeepers for this cancer; once a mutation in this gene occurs in a cell with particular previously accumulated pre-leukaemic mutations, the disease progresses rapidly to become leukaemia. "The significance of mutations in this gene is astonishingly clear from these results: it simply doesn't exist where there is no leukaemia. When it is mutated in the appropriate cell, the floodgates open and leukemia is then very likely to develop. This fits with studies we've conducted in the past in which we found that the gene primes blood stem cells for leukaemic transformation."

Link: http://www.eurekalert.org/pub_releases/2015-02/wtsi-lma022415.php

Comments

Perfect DNA repair is not possible without some kind of master copy. It is not possible to even know if the DNA is damaged unless you have some kind of complicated hashing algorithm that somehow works in a living creature (and even that is not 100% perfect). It's not impossible as in "we can't build it"; it's totally impossible according to basic information logic. To know whether gigabytes of data are bad, you either need to perform some mathematical operation on them or compare them to what they should be. Any nanobots that were tasked with this kind of repair would need to be receiving commands from something that knew exactly where each nanobot is and what it is supposed to be doing and somehow had the power to control them all. Which requires total mastery of chemistry, and it's indefinitely far ahead of where we are now; nobody reading this will ever see it in his lifetime without longevity treatments.

Fortunately, the human body is not a closed system. The way to approach this problem in the near term would be to kill wide swaths of cells on a regular basis and replace them with freshly created stem cells from a known-good (known from sequencing) source.

Posted by: Slicer at February 27th, 2015 10:32 AM

I apologize in advance for a series of layman's questions. First, what would it take to repair or re-synthesize the DNA of a single cell in a "pristine" or even improved condition?

If this were possible, would it then be desirable to create a line of such cells from the single cell and then use them as the basis of cell/replenishment therapies, then target and destroy those cells that weren't a product of this process (perhaps by adding one/a bunch of markers or receptors to the new cells) moreso than trying to develop in vivo DNA repair?

Whatever approach is used, I'm curious about the technical hurdles that remain to restoring an overall youthful state to human DNA.

Posted by: Seth at February 27th, 2015 10:58 AM

Seth, there are two methods of creating a known-good line of stem cells.

The first is reverse sequencing, which has been done (although not to human cells to my knowledge). A lot of cells are sequenced, and straightforward spot-the-differences computer techniques are used to get the correct sequence. The correct sequence goes out of the computer and into the single cell, which is then used as the basis for replenishment therapies. Done. I genuinely hope someone out there is working on this.

The second is to take a lot of stem cells, get a few copies of each, and forward-sequence them all. Do the same differential analysis. Whichever line is closest to the correct sequence is used as the basis for therapies.

Death-to-everything-else biomarkers are a bad idea in everything but one specific case. You can't do it early on; you'd kill the person (all his neurons containing his personality and memories would die) even if his body somehow survived. Apoptosis and replenishment must be done slowly; killed neurons replaced by fresh ones, the fresh ones allowed to have time to learn from the brain's existing structures, then some more old neurons killed off to make room for the new again. Every other body tissue follows the same principle; unless you're simply replacing the entire organ wholesale, you need to let the new cells take their place among the old and gradually replace them, otherwise you wind up with a lot of dead organs. The only time biomarker cell genocide would work is near the end of this process, to kill off a few last holdouts after dozens of rounds of replenishment. And then, when those replenished cells started getting a high error proportion, you'd need a whole new biomarker...

Posted by: Slicer at February 27th, 2015 11:26 AM

Another approach would be replacement of blood/Plasma every so often to stimulate a more youthful environment. This would boost the immune system and make the T-Cells in theory more efficient at clearing out unwanted cells as well as other rejuvenating effects which have been observed in various mouse experiments.

I believe most damage could be mitigated if the body can be taught how to revert to a more youthful environment and thus its repair mechanisms would remain efficient.

Posted by: Steve H at February 27th, 2015 11:45 AM

Steve, a youthful environment might reduce the rate of mutations and interrupt the feedback mechanisms that make things get worse more quickly (the "growth advantage" talked about here), and it might even kill off certain types of mutated cells, but it's not going to fix all the DNA damage already there.

Posted by: Slicer at February 27th, 2015 11:53 AM

Yes of course fooling the body to revert to a more youthful environment is not going to cure all the damage. A lot of DNA damage is caused by Telomere attrition so you could use a transient therapy to restore them using hTERT combined with Plasma therapy in theory to mitigate a large amount of damage and rejuvenate tissues/organs. A hTERT AAV could do this and whilst it wont help the blood cells themselves it should help the cells producing them.

Of course no single therapy is going to fix the aging issue but a youthful environment is a big step towards mitigating damage.The body knows how to repair itself it just needs to be encouraged to do so.

Posted by: Steve H at February 27th, 2015 12:12 PM

"The body knows how to repair itself"

Not completely. Make no mistake, everything you suggested is useful, but at some point you have to bring in cells from outside. Even the healthiest, longest-lived life forms on Earth do not have the innate ability to completely error-correct DNA. There are simply no mechanisms that can determine when a cell has damaged peptides; any repair mechanism is based on certain results of that damage, and those mechanisms are not perfect (making them anywhere near perfect would require fundamental, all-encompassing alterations that could only be described as transhuman). Even young people in young bodies accumulate DNA damage; old people in young bodies would still be accumulating it.

Posted by: Slicer at February 27th, 2015 12:26 PM

Also, just to be clear, I'm talking about DNA damage as mutations, not structural damage.

Posted by: Slicer at February 27th, 2015 12:52 PM

Yes you of course correct Slicer however Plasma rejuvenation is easily within our grasp for practical use now, its safety approved and would be an excellent step towards gaining public support. SENS is even investigating this I note and funds research into it according to their newsletter. Definatly think there is huge mileage to be gained from this therapy which is why I am involved in getting a HPE Plasma trial started.

Cells brought in from outside is certainly feasible and thankfully Stem Cell research is very well funded generally. I think that is a solution to that issue, it also depends how fast mutants develop and how fast would they develop if you reverted the body back to a youthful environment? Presumably the mutation rate would be somewhat mitigated by a youthful phenotype?

Posted by: Steve H at February 27th, 2015 1:09 PM

I don't know if youthful environment and telomere repair would contribute to a lower mutation rate, but I do know that mutations accumulate at least in part due to oxidative stress, replication errors, chemical and radiation-induced lesions, and the pure chance of base tautomerization.

Restoring the youthful environment is certainly an avenue to be pursued, but it will not make some of these mutagenic influences disappear or even slow down.

Posted by: Seth at February 27th, 2015 1:24 PM

Seth, and especially Slicer: thank you for weighing in to address both obvious general issues and Steve H's questions.

Posted by: Michael at February 27th, 2015 5:40 PM

Is there any indication that Telomere length is increased with the introduction of a younger environment? I have read most of the Parabiosis and plasma exchange studies and I dont think anyone measured that.

I am aware that telomere length can fluctuate so was wondering if any such change was observed? This would mean telomere length has some plasticity within its environment and is influenced by more than just Telomerase activation.

Posted by: Steve H at February 28th, 2015 6:15 AM

True = Accumulated damage results in premature death

Not true = Perfect repair mechanisms prevents death

Therefore, aging research has said nothing interesting so far besides stating the obvious.

Posted by: rdg at March 1st, 2015 2:27 AM

Michael: You're welcome. I try.

rdg: Cars can crash, so what's the point of taking your car to a mechanic? Especially if it's a really old car that you keep restored?

Posted by: Slicer at March 1st, 2015 1:32 PM

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