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Regulating Cell Cycle

ImageCell cycle progression is regulated by the interplay of two major types of proteins. One protein promotes cell cycle progression (i.e. its effect is to push cells through the checkpoints); the other type of protein inhibits cell cycle progression. Together, these proteins establish a balance that permits cell cycle progression under typical conditions  – where there is no DNA damage. However, if there is DNA damage, proteins that sense this damage will turn on proteins that inhibit cell cycle and also those that are responsible for repairing the damage.

If all goes well and the damage is repaired, then the delaying proteins turn off and cell cycle is allowed to proceed. If the damage is NOT repaired, then the cell is instructed to commit suicide by apoptosis (cell death without inflammation).

The proteins that push cells through cycle are called proto-Oncogenes. The ones that inhibit cell cycle are called tumor suppressors.

That’s how things work when cell cycle is being regulated properly. But sometimes, the DNA damage may affect the genes for these two types of proteins specifically. When this happens, cell cycle regulation may be compromised. When that happens, cancer can develop.

Why? Because cancer is a disease of cell cycle regulation. The basic problem in cancer is that cells have ceased to have their cell cycle regulated properly and are dividing out of control. Remember, multicellular organisms like us thrive because we have delegated different behaviors to different cells / tissues / organs and all the cells are co-operating in a way that promotes the health of the individual organism ahead of the health of each individual cell.

So, what kind of mutation causes this to happen? Well, it depends upon which protein has been mutated. If pro to-oncogenes have a ‘gain of function’ mutation, this will make them work extra hard to push cells through cell cycle checkpoints – even when there are signals to prevent this. (Think of a gas pedal that gets stuck to the floor. It doesn’t matter if you hit the brakes, you’re still moving forward) If this same protein undergoes a ‘loss of function’ mutation, then the cell can never enter cell cycle and will probably die off.

Contra-wise, if tumor suppressor proteins have a ‘gain of function’ mutation, then cell cycle cannot proceed and the cell will probably die. (In a car analogy, tumor suppressor proteins are the brake pedal. If the break is always on, then you can never go forward. If the tumor suppressor protein has a ‘loss of function’ mutation, then cell cycle can never stop (our brakes are broken).

So, each type of protein has to have a specific type of mutation to lead to unregulated cell cycle.

Keep in mind, that the purpose of cell cycle regulation is to protect the integrity of the genome (all the DNA of the cell). If this regulation breaks, then more and more mutations can occur over time.

 
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Posted by on October 15, 2012 in Uncategorized

 

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Cell Cycle and Cancer

Cell Cycle in intimately connected to cancer because, in essence, cancer is a disease of cell cycle dysregulation. The purpose of regulating the cell cycle is to maintain genomic integrity, therefore the checkpoints of cell cycle progression specifically interrogate the DNA’s suitability to replicate, to divide and to be assorted into new, ‘daughter’ cells.

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If a cell replicates DNA when there is damage to the DNA, then poor copies are perpetuated. If a cell commits to division when there is DNA damage, the same result might ensue – i.e. daughter cells may receive poor copies of the DNA. If a cell divides when chromosomes are not properly assorted then neither cell is healthy.

All three mechanisms have the same goal: ensure high fidelity copying.

With cell cycle checkpoints intact, cells can only pass when their DNA is in good condition or when chromosomes are being handled properly. The result is one healthy cell gives rise to two healthy cells. If a cell reaches a checkpoint and damage is detected, then the cell ‘arrests’ cycle progression for a short period of time. During this arrest, the cell has the opportunity to rescue the DNA and resume cycling. If this does not happen, then the cell is triggered to commit apoptosis –  cellular suicide. In this was, the cell gives its life for the good of the organism.

In this way, the cell is very analogous to a bee stinging an intruder. Although the bee will die now, it has contributed to the good of the colony in its sacrifice. After all, the worker bee cannot reproduce herself, her genetic heritage is intimately tied to the fate of the colony and its queen. Similarly, the cell dies to preserve the organism against what might be a harmful alteration / mutation. And, like the bee, this cell likely could not reproduce by itself anyway, it’s genetic heritage is tied to that of a larger body where only the gonads produce reproductive cells.

When cell cycle checkpoints are not functional, poor copies of DNA / cells get through. Furthermore, these cells are now inherently unstable because they have a compromised checkpoint, and additional errors may accumulate. Sometimes these errors disrupt other regulators of cell cycle, leading to a compounded problem. Over time, these cells may develop into cancerous cells.

The other point of cell cycle regulation is in the midst of mitosis, during metaphase. At this time, the cell has bound the chromosomes with spindle fibers that attempt to shorten and pull the chromosomes to a flat plane in the middle of the cell called the metaphase plate. The checkpoint here is to find out whether every single chromosome has attached to each side and each daughter cell will get the correct number. If this fails, cells will have incorrect distributions of the chromosomes and are unlikely to survive. Further, if these cells did survive, they would never be able to correct the error.

Here, the bee analogy would be too strained to continue, but it is not too difficult to see that when a cell disentangles itself from preserving the health of the body and instead looks only after its own short-sighted interests that these cells will grow and compete directly against the rest of the body for space and resources. Initially, when a tumor is small, this may have little consequence, but as a tumor becomes larger or more dispersed in the body, this selfishness can severely impact the larger organism, ironically (for the cancer cell) undermining even the tumor’s self interest.

 
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Posted by on October 14, 2012 in Education, Uncategorized

 

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Returning from the reality holiday

I’ve been on a break from reality for … well, it depends on how you measure it… three years? nine years? 

In 2002 I got laid off from a biotech company where I had been making monoclonal antibodies that we used for delivering vaccines to the cells that kick-start the strongest immune response. Antibodies are the proteins that some immune cells (B cell) make to clog up, block and make tasty meals out of any foreign substance that gets into your body. The idea was that we could make antibodies that would home in on just the right cells, stick to them, and deliver a ‘package’ of vaccine target protein to these cells just as they were cranking up. It’s an idea that works fairly well and is being used by a company called Celldex to make vaccines against a variety of undesirable ailments (this trick is most suited for cancer, because that’s a condition that develops from your own cells, and the body has a tough time seeing it as a bad, foreign entity)

Anyway, I left that company and got a job at the university. This was a good move for me because I wanted to go back to school anyway and it gave me the opportunity to meet and talk with the people who would make the decision about admissions. About 9 months later I was starting grad school and working towards a PhD. That was the longest, most grueling process of my life. The only way to handle it is to focus on what’s in front of you and not get too distracted by all the years of your life you just signed away or talks and presentations that you might dread giving. Nevertheless, by late 2009, I was free and clear. The whole thing was over and I knew more about immunology and B cells than I ever thought I’d want to.

I’ve whined a lot about how this was a terrible time to come out of grad school – people were getting laid off again, not hired! I’d spent an entire economic cycle locked in the ivory tower and missed the good years in between. But, one door closes… right?

After school, and in a mighty difficult transition, our family moved to the midwest for a great opportunity my wife had. I also took the opportunity to re-invent myself and started teaching. I simply love teaching, it’s a great way to keep learning and (for blabbermouths like me) talk all day to a captive audience. I’ve been teaching as an adjunct for three years now and I feel like I’ve got things pretty much in hand, but adjunct means part time. And part-time means crappy salary and no real job you can sink your full-time working teeth into (you see, if nothing else, grad school teaches you that you can only be happy if you are working hard all the time). So, to speak plainly, it’s not enough work for me.

So, problem solved: start a company. Did that, produced a couple diddly little apps for the iPhone, but I have the creative ideas, not the programming talent. After almost a year of chasing that dream and not finding any partners to put as much into it as I have, my company has been morphing. That’s actually the story that this blog is supposed to be following, but often that’s not the case…

My latest idea has been to make iBooks – I’ve written about some of those ideas here too. And, to be fair, I think it’s come along really well. I have one and 3/4 books finished and only waiting on illustration before they will be published and a couple more on the way.

But, in the course of making this change and getting to the start of another school year, my wife and I had the talk. The talk that includes such phrases as “is this really what you want to do?” and “I think it’s great, but it’s not a job”. And, you know what, that’s spot on.  It’s about time that I take the bull by the horns and stop trying to ‘creative’ my way out of under-employment and start finding an honest 9-5 (or more).

Please cross your fingers for me. I’m hoping to be able to keep up with everything, but I know how that goes. And, if any of you know some good work for a motivated immunologist / teacher / writer / game designer in the Kansas City area (or anywhere, honestly), then point them my way.

 

 

 
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Posted by on August 20, 2012 in Uncategorized

 

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