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Oncogenes & Ontology

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Someone recently said to me that telomerase wasn’t oncogenic. And in one sense, they were exactly right: the gene that produces telomerase is not recognized as an oncogene. In the other sense however, they were wrong: the reactivation of telomerase (or ALT) is a necessary step in the route to a malignant neoplasm, known as oncogenesis. This is one of the reasons I have never liked the “oncogene” designation. It’s fuzzy and a little misleading. Moreover, I think this fuzzyness is related to some of our misconceptions about cancer.

When we look at disease, we tend to look at it in terms of cause and effect. E.g. influenza causes flu, pneumocystis causes pneumonia, etc. And this schema works really well when you a are dealing with pathogens. Charge in, antibiotics and antivirals blazing, remove the cause, and the disease goes away (usually, although if it doesn’t then you probably have just not removed the cause well enough, as is the case with latent HIV). However, cancer and genetic diseases are often a different story. People ask: “Why haven’t we cured cancer yet?” and I have seen at least one paranoid documentary claiming we could obviously cure cancer at any time and just don’t because evil corporations profit off of it. Ideas like these are the result of the misconception that cancer has simple causes and simple solutions.

Misconception concerning oncogenes is a primary culprit in the current confusion, and (as I talked about in an older post) why we tend to hear a lot these days about “the X cancer gene”. These ideas are absurd. There are two mistakes working together here: (1) That oncogenes are genes whose only purpose is to cause cancer; (2) That oncogenes are sufficient to cause cancer.

(1) In truth, oncogenes have a variety of roles in the body, it is their constitutive over-expression that drives the growth component of cancer. Many oncogenes are lethal if knocked out, which is to say they are vital to development and survival of the whole organism. It is just that there is actually to much of a good thing.

(2) This is where things really begin to go off the rails. An oncogene alone is no more a cause of cancer than active telomerase or the lack of a tumor suppression gene. The development of a neoplasm is a stepwise process and no one step is sufficient while all of them are necessary. Generally it requires three mutations for a benign neoplasm and five for a malignant one (certain conditions, like a genetic predisposition for retinoblastoma or infections with an oncovirus take this number down by one). And while these mutations need to perform similar functions (cause growth, remove reproduction limits, direct angiogenesis, alter metabolism, etc), they can occur in any of a multitude of individual genes.

With a system so complex, it should be apparent why the old schema doesn’t work. There is no one single cause of cancer and no one single cure. There is no one “X cancer gene”. Cancer is a large spectrum of conditions the battle against which will rage on well into the future. While we might find ways to cure specific cases and deal with specific oncoviruses and genetic predispositions we will never cure ‘cancer’. To do so would mean to remove all mutation and make ourselves essentially genetically static. I hope I don’t have to explain why that would be a bad thing.

Sources & Further Readings

  • I don’t really have a whole lot on oncogenes lying around at the moment, but a nice place to get an introduction might be Geoffrey M. Cooper’s textbook on the subject. It’s short and pretty straightforward.

Written by Caudoviral

02/13/2011 at 14:41

Posted in Biology, Cancer

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Who wants to live forever?

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So, I actually had something planned for today. I was going to talk about that Italian paper I mentioned in one of my posts last week. But that got bumped down the list because I read Cracked. Yeah…that’s a shameful admission. (probably not the only one I am making this week if I stick to my tentative schedule). Anyway, they posted up an article about entitled 5 Ways Science Could Make Us Immortal. So I pop it open expecting some delightfully fanciful conjecture involving Robocop and maybe Ras al Ghul’s Lazarus pits. And honestly? #4-1 on their list are exactly that: Some wishful thinking mixed with a seed of scientific basis with a few minor flaws, some humour, and the realistic realisation that most of these are long shots (although notably there is a lab at my university working on a crude implementation of #3). But #5…I hate #5. And I don’t blame Cracked for that. I hear this repeated constantly even by very bright people. The reason for that is that it is another one of those things that seems to make sense on a cursory glance, but then completely falls to pieces when thought through (and as I have mentioned before, a lot of people are a lot more willing to do the first than to do the second).

This is the myth that telomere degradation is the primary cause of aging and that reactivating telomerase will help us immortals.

To understand why this is an appealing and to understand why it is a mistake, we need to do some background. A telomere is a repetitive sequence of DNA found at the ends of your chromosomes. Bacteria have this nice system going where there DNA is circularised and replicated bi-directionally and nice enzymes choreograph the splitting and splicing point in an elegant X fashion and in the end you have two circular genomes. We eukaryotes have a bit more of a sloppy approach. See, our DNA is arranged in linear chromosomes, and the enzymes that replicate our DNA are not flawless. They cannot run all the way to the end of the chromosome, and so with each replication we knock off more and more of the repetitive, non-coding sequences in the telomeres. They essentially work like a buffer. I am sure by now you have spotted what the original telomere researchers did. If each replication loses a little more telomere, then there must be a finite limit to the number of replications any particular cell strain can have. There is also an enzyme called telomerase (or TERT, Telomerase Reverse Transcriptase, if you want to be pedantic). It replenishes telomeres and one of the characteristics of immortal cell lines is the presence of activated telomerase.

What all this means is: telomeres are the cause of cellular aging. Cellular aging, known as senesence, describes the process by which cells stop dividing after a certain number of replications. This number is known as the M1 or Hayflick limit. If cells are forced to continue to replicate beyond the Hayflick limit (which, for instance, certain viruses can force them to do) then their telomeres degrade fully, this is known as the M2 limit. At the M2 limit genetic damage results as continual wear begins to lop off the ends of genes. It’s messy and generally leads to cell death. However, if telomerase is active, then the cells never reach either limit and become immortal.

It is really quite tempting to assume that as it is in the micro it would be in the macro. And many people these days read about telomeres and cellular aging, and try to claim that the aging process of the entire organism stems from the same phenomenon. Indeed, some scientists have even proposed research into mechanisms to reactivate human telomerase as a way to stave off aging. There is both a serious flaw in the principle and a serious flaw in the plan itself.

The flaw in the principle is this: there is no actual causative link that has been shown between telomere length and life span. As a for instance, the average mouse has telomeres three times yours in length and higher levels of active telomerase, yet a lifespan of about three years. Further, experiments with mice have shown conflicting results: inhibiting the enzyme itself has little effect, inhibiting the gene that produces it entirely causes decrepitude (It should also be noted that wholesale inhibition of telomerase does not in fact provide a proper model of the human situation. Even we keep telomerase active in multiple systems, most notably our immune system and reproductive system). Studies in humans have shown only a correlation between age and shortened telomeres, which confirms the theory that telomeres shorten over time and repeated replications but does not provide a causative link between age and telomere length.

However, there is one thing that reactivated telomerase is causatively associated with, and it leads us to the flaw in the plan to reactivate it. Survival is good. Life will go to amazing lengths to survive and reproduce, and immortality sounds like a pretty sweet gig for a genetic line. So if we have this delightful little enzyme floating around, why don’t we have it active in higher levels? Why hasn’t evolution done for us what some scientists are proposing to do? It is a highly conserved enzyme and must have been around for ages. Well, truth be told, people with highly active telomerase are selected against. This is because they get cancer significantly faster than the rest of us.

The cancer biologist’s rule of thumb is that it takes about three mutations to get a benign neoplasm and about five mutations to get a malignant one. One of these mutations is always the reactivation of telomerase or the activation of so called ALT (Alternate mechanism for Lengthening Telomeres). See, cellular aging thing isn’t just a sad accident consigning us to mortality, rather it is a defence against tumours. Cancer cells replicate a lot. And mutations are relatively rare occurrences (~10^-8 per nucleotide per generation). So the average cell that starts replicating out of control will hit the M2 limit signalling a process of controlled cell death to start. Unless it mutates and upregulates telomerase (or activates ALT). To have constitutively active telomerase would increase the chance of any cell becoming cancerous by multiple orders of magnitude. Advocates say that perhaps we could activate telomerase temporarily to replenish things and then turn it of again, but haven’t really provided mechanisms for that (nor even established that the underlying principle is correct).

Besides, myopic focus on telomerase takes attention away from the other clear causes of aging: like accrued replication errors in DNA, and the ever present threat of oxidative stress from by-products in cellular metabolism (Protip: this second one is what is actually going to kill you, not even evolution can beat physics and build a perfect engine). If we can eek a few more years out of reactivating telomerase while simultaneusly dodging increased cancer risk, I am all for it. But it won’t be immortality. Aging is a global process and there are just too many things that don’t work quite efficiently enough to keep us going forever.

This article written with many much thanks and respect to Nobel laureates Elizabeth Blackburn, Carol Greider, and Jack Szostak who managed to solve the problem of how the hell linear chromosomes work anyway and who have opened up a fascinating field of telomere research.

And now, the musical stylings of Freddie Mercury and Brian May.

Written by Caudoviral

01/17/2011 at 17:11

Posted in Biology, Cancer, Health

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Sympathy for the Devils

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You and I are different. I am guessing you had noticed this. But have you really given thought to why? And I don’t mean that in a philosophical/psychological sense. The concept of “self” and “other” is coded into our very cells. This is why we have to check blood type before doing transfusions. This is why people have to be matched with specific organ donors. And there is a very good reason.

A vital part of the immune system are major histocompatability complexes. MHC genes generate MHC molecules. MHC molecules are what differentiate your cellular “self” from a cellular “other”. Thus, should a virus infect your cells, it is the MHC molecules that will take the viral proteins and present them to your immune system. Think of them as raising the alarm when invaders come to call. Now, because there are an awful lot of pathogens and those pathogens are constantly evolving, there must also be great variation in the MHC molecules to be able to keep up. In fact, there is so much variation that the MHC molecules from your body are so different from those in my body, that mine would not recognise yours and would in fact identify yours as harmful invaders.

We should be very thankful for that. Not everyone is so lucky.

The above is a Tasmanian devil (Sarcophilus harrisii). There are approximately 10,000 of them left. If estimates are accurate there will be 0 left by approximately 2035. All because of their MHC.

See, if your cells mix with mine, mine will identify yours as an invader. This isn’t the case with Tasmanian devils. If cells from one devil mix with those from another, there is no immune response. So even though there are 10,000 of them left, there is no more diversity in their immune responses than if there were one.

Normally this would mean that the entire species would be at risk of being wiped out by an epidemic to which they could not generate an immune response. However, when that epidemic arrived, its nature proved to be uniquely disturbing. They die of contagious cancer. Not an oncogenic virus, not a cancer generated by a common carcinogen in their environment. This is essentially a cancer that can metastasise from individual to individual. Because, at the cellular level, they aren’t individuals. So when the cells of a healthy devil come into contact with malignant cells from an infected devil (commonly through fighting, copulating, or feeding/drinking from the same source), the malignancy spreads to the new devil in the same way it would spread between organs in a single organism.

Researchers are working to stem the tide of the epidemic, and there are reserve populations of healthy devils in captivity. However, even if this hurdle is overcome the underlying problem is still a quandary: what do you do when a species has lost too much diversity to be viable? Are other endangered species already past that point? Further, this is the third transmissible cancer that we have seen (there is a type which infects dogs and a type that infects hamsters). I doubt it will be the last.

I know that species rise and fall, but I really don’t want to see these little guys go. And really, Tasmania just doesn’t need another extinction, I still miss the Thylacine.

I was going to put in a picture of a devil suffering from the disease here, but in the end it just broke my heart. I dislike indulging in an over-abundance of sentiment, but in this case I feel it is better to just place a link here, those who are interested can follow it. Devil Facial Tumor Disease

Further Reading

Allograft theory: Transmission of devil facial-tumour disease. (Pearse & Swift 2006)

Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial. (Siddle, et al. 2007)

Tasmanian devil facial tumor disease: insights into reduced tumor surveillance from an unusual malignancy. (O’Neill 2010)

It should also be noted that the wonderful blog ERV has several posts on the subject and is where I first heard about this crisis a couple of years ago. Check it out.

[in article image source: By Prince Roy from Taipei (Tasman Peninsula) [CC-BY-2.0], via Wikimedia Commons]

Written by Caudoviral

01/14/2011 at 23:40

Posted in Biology, Cancer

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