OncoSENS: Making cancerous mutations harmless

 
Two types of damage accumulate in our genes as we age: mutations and epimutations. Mutations are damage to the DNA sequence itself, whereas epimutations are damage to the “scaffolding” of that DNA, which controls how and when genes get turned on in the cell. For practical purposes, both mutations and epimutations ultimately harm us in the same way: by causing abnormal gene expression, whether it’s by increasing or decreasing the amount of a protein encoded by a gene being produced, by altering in the conditions under which that production is activated, or by altering the structure and function of the ensuing protein itself. Because of their similar effects, an approach that prevents the negative consequences of these changes in gene expression can be used to make both kinds of damage harmless, despite the fact that the molecular basis of mutations and epimutations are quite different.
 
So what kind of harm can the changes in gene expression resulting from (epi)mutations cause? The one that most people know about is cancer, which is the result of a series of (epi)mutations that happen in sequence in the cell, leading to its uncontrolled growth. Other kinds of (epi)mutations also occur in our cells over time, and some scientists have worried that these non-cancer-causing (epi)mutations might also contribute in different ways to age-related disease and disability. But there is good reason to believe that there aren’t enough such mutations to actually have a meaningful impact on our health. This is because the threat of cancer from even a single (epi)mutation is so great that it forces the body to develop defenses against (epi)mutations that far exceed what would be needed to prevent a meaningful burden of non-cancer (epi)mutations  from occurring.
 
In addition, studies performed across the lifespan in the tissues of mice appear to confirm that mutations do not accumulate substantially during the aging process per se in most tissues. In fact, the great bulk of mutations that will ever occur in the body occur during embryonic and childhood development, because a growing body requires rapid cell division, and cell division requires error-prone DNA replication. But we emerge from this high-growth, high-(epi)mutation period in the prime health of young adulthood. So the small number of additional mutations that occur over the course of the rest of the lifespan, when the degenerative aging process is clearly taking root in our cells, can’t plausibly be contributing much to age-related ill-health – except, again, for those (epi)mutations that lead to cancer.
 
There are a few cases where non-cancerous (epi)mutations can cause a disproportionate effect on tissue health. One such case is (epi)mutations that cause cells adopt a “senescent” metabolic state that makes them toxic to their neighbors, so that damage to just a few isolated cells causes problems to normal, unmutated cells around them. But because a cardinal feature of such cells is that they don’t reproduce themselves, the threat posed by the (epi)mutations that cause the is still very precisely centered in the individual cells themselves – and can be eliminated by destroying the senescent cells themselves
 
A second kind of (epi)mutation that may cause a disproportionate amount of harm even though it is confined to an individual cell is when the (epi)mutations kills or disables a cell in a tissue where the total number of cells is very few, and the cells are very critical. In such tissues, the loss of even a few cells represents a substantial blow to tissue function. Again, however, the solution to this problem does not require the direct repair of the underlying (epi)mutations, but in simply replacing the missing cells using cell therapy. (Note that this is a general feature of the damage-repair heuristic of rejuvenation biotechnology. It doesn’t matter that some cells are lost because of mutations, others because of “programmed cell death” (apoptosis) in response to stress, others because of loss of oxygen supply, and so on: the damage can be repaired once it has occurred, irrespective of the metabolic causes of that damage).
 
A Halfway Solution: Drugs that Inhibit Telomerase
The fact that cancer appears to be the only way that age-related (epi)mutations actually harm our health simplifies matters a great deal: it means that if we can develop a sufficiently-strong rejuvenation biotechnology to protect us from cancer, we will effectively have the (epi)mutation problem licked. In other words: if cancer were completely taken off the table as a cause of age-related ill health, then the impact of (epi)mutations on our lives would be nil, and would continue to be negligible for many decades longer than the current human lifespan.
 
Fortunately, a strategy to achieve extremely strong protection against cancer does exist, although its implementation is extremely challenging. This strategy is based on the one inescapable vulnerability that all cancer cells share in common: their absolute need to renew their telomeres. Telomeres, as you may know, are long stretches of DNA at the ends of our chromosomes that don’t actually contain any genetic instructions for making proteins, but are instead there to provide a protective “cap” to the rest of the chromosome. In an oft-used metaphor, telomeres act like the nibs that keep the tips of your shoelaces from unraveling, protecting your chromosomes from becoming frayed by metabolic and other damage. But just as shoelace nibs do slowly get worn down over time, so too a cell’s telomeres are worn down a little each time it reproduces itself; and when a cell runs out of telomeres, it quickly self-destructs. 
 
Because cancer cells reproduce at a furious pace, they quickly reach the ends of their telomeric “ropes,” and need to find a way to lengthen them again in order to keep going. Successful cancer cells are the ones that have evolved mutations that exploit one of the cell’s two systems for renewing telomeres: either a primary system called telomerase, or in a few cases an “alternative” system appropriately called Alternative Lengthening of Telomeres (ALT). If a nascent cancer can’t find a way to seize hold of the telomerase-lengthening machinery, their telomeres will run down, their chromosomes will fray, and the cell will be destroyed before it can kill us. 
 
So despite their diversity, all cancer cells share one critical thing in common: they are absolutely dependent for their survival on their ability to hijack telomerase (or, less frequently, ALT). This fact has led the search drugs that inhibit telomerase activity in cancer cells to become one of the hottest areas of cancer research today. 
 
There is certainly promise in this approach, but the effectiveness of telomerase-inhibiting drugs would be limited by two factors. The first is the fact that some cancers use the ALT mechanism instead of telomerase to keep their telomeres long. Strongly inhibiting telomerase will do nothing to thwart ALT-exploiting cancers – and even in cancers that are initially taking advantage of telomerase, inhibiting the enzyme would still leave ALT in their back pocket. 
 
The second limit on the long-term effectiveness of telomerase-inhibiting drugs is the fact that cancer is an extremely devious disease. Cancer cells are constantly reproducing themselves at a breakneck speed, but their genetic code is wildly unstable, so that novel mutations are constantly appearing in cells within the tumor. As a result, they are continuously throwing out new lines of cancer cells, each of which has a slightly different genetic code and distinct properties. This allows the tumor to harness the power of evolution to overcome drugs and therapies that are thrown at it: while a drug or other therapy may be very effective at killing or disabling the great majority of cells in the tumor, there are usually a few cells lurking somewhere in the tumor with a mutation that allows them to survive the attack. These cells are then able to grow back unimpeded by an otherwise effective-seeming therapy. 
 
This is why so many people with cancer initially respond well to chemotherapy and beat the disease into remission, only to have it come roaring back many months later, in a new form that has evolved resistance to the drug that earlier seemed to defeat it. Through such evolutionary processes, a drug that targets telomerase could seem effective at first, only to be defeated by the cancer cell line if it can (for instance) more effectively break the drug down, or prevent the drug from entering its cells, or put out the biological equivalents of the “chaff” and flares that are used by fighter jets to ward off the targeting systems of hostile missiles. Sooner or later, then, a drug that simply inhibits telomerase activity is likely to stop working.
 
Researchers should certainly continue researching telomerase-inhibiting drugs, and any that work should bepushed to their limits. But limits there will be.
 
The Solution: WILT
By contrast, there is one last-resort OncoSENS strategy that would defeat all cancer – utterly, and permanently. It begins from the same key facts: the absolute need of all cancers for a way to lengthen out their telomeres, and the inherent evolutionary edge that cancer has in defeating drugs that work by killing cancer cells or by altering their metabolism. This strategy (which was the topic of the third SENS Roundtable) has been termed “WILT,” which stands for Whole-body Interdiction of Lengthening of Telomeres. The idea is simple, and bold: instead of merely trying to inhibit the telomere-lengthening machinery of cancer cells, doctors would pre-emptively remove the genes for the telomere-lengthening machinery altogether. Simply put, cancer can’t exploit telomerase and ALT to keep itself alive, if the genes that encode their machinery doesn’t exist! This would make it impossible for cancers to continue growing unless they manage to create a whole new telomerase or ALT gene out of thin air – a vanishingly unlikely possibility.
 
There are two potential deal-breakers for this solution. The first is that although most of our cells never use telomerase, some of them – especially stem cells – do, and removing the gene for it would eventually mean that these healthy cells would run out of telomeric backstop. That would mean that our stem cells would no longer be able to produce new cells to replenish our tissues, and those tissues would begin to atrophy prematurely.  Indeed, this is exactly what happens in dyskeratosis congenita, a disease associated with inadequate telomere maintenance. But there is a way around this problem. The telomere reserve of our stem cells appears to be enough to keep normal cells going for about a decade. So to support the ability of our tissues to renew themselves indefinitely, it would be enough to replace those failing stem cell reserves with new cells once a decade or so. And by engineering these fresh stem cells to have no telomerase or ALT genes of their own, but to have telomeres that are long enough when they are first transplanted into a person to last for a decade on the strength of those original telomeres, our tissues would always have the functional stem cells they need for maintenance, but the stem cells present in the tissue at any given time would be simply incapable of developing into life-threatening cancers.
 
The other potential challenge to the WILT strategy would be if telomerase or ALT had some essential function other than the lengthening of telomeres, so that deleting the genes for their machinery would also compromise some other, essential function. There have been some studies suggesting the existence of such a secondary function, but mostly these studies have been carried out under very artificial conditions. And the most rigorous study to test this question strongly suggests that there are no non-telomere-lengthening functions of telomerase.
 
Will an approach to cancer as drastic as WILT really be necessary to give us the same kind of strong control over cancer that rejuvenation biotechnologies will deliver over other age-related diseases? We do not know: other approaches can, and should, be tried. But precisely because it WILT is so ambitious and challenging an approach, it will take a long time to develop  – so the research that will be needed to give us the option of using the WILT strategy to save lives must begin now.
 
OncoSENS Research Funded by SENS Research Foundation 
 
Current Intramural Research
This project aims to identify targets to eliminate the ALT mechanism. This is especially important, because the ALT machinery is not well-understood, even though it is the telomere-lengthening mechanism exploited by nearly 10% of all cancers. Identifying the machinery underlying ALT, and disrupting it safely and effectively, would keep even telomerase-independent cancers from endlessly dividing, and deny telomerase-using cancers a fallback system as well.
 
Funded Research in Outside Centers
As we discussed above, whereas  mutations are damage in the DNA itself, epimutations are permanent damage to the structures that the cell uses to turn genes on and off. There are very good data showing that the rate at which non-cancer-causing mutations appear in aging tissues is too low to be a plausible cause of age-related disease and disability, but the picture is somewhat less clear for epimutations. SENS Research Foundation is funding research at Albert Einstein College of Medicine to put new methods to use in determining the rate at which epimutations occur in aging mouse tissues more definitively. If, as predicted, the rate at which cells in different tissues suffer epimutations over the adult lifespan is as low as is the case for mutations, it will provide further support that the WILT strategy for OncoSENS will be a comprehensive solution to the problem of both mutations and epimutations in aging.
 
Resources
For a more in-depth account of mutations and epimutations in the nuclear DNA during aging, and how the WILT strategy can make them harmless for the foreseeable future, see the chapter “Nuclear Mutations and the Total Defeat of Cancer” in  Ending Aging.