SNPs and radiation sensitivity

SNP_260x260What would you think about a simple genetic test that could tell you exactly how sensitive you are to radiation? Something, say, as simple as a cholesterol test that could tell you whether you are extraordinarily sensitive to radiation, exceptionally resistant to radiation damage, or pretty much normal – how great would that be?

Consider a cancer patient whose oncologist is recommending radiation therapy – it would be helpful to be able to sort out the patients who are likely (or unlikely) to suffer complications to healthy tissue. Such knowledge could help doctors better plan treatments and to tailor them according to a patient’s individual genetic profile. This is the sort of work being undertaken by Dr. Barry Rosenstein, a radiation biologist at New York City’s Mount Sinai Medical Center.

What Rosenstein and those in his laboratory look for are single-nucleotide polymorphisms, abbreviated SNP (and pronounced “snip”). The DNA molecule is made of a series of nucleotides (adenine, thymine, guanine, and cytosine – abbreviated A, T, G, and C); these nucleotides are arranged along the chromosome in sets of three (called codons), and the sequence of codons along the chromosome tells the cell how to assemble a protein. My mental image of this process is of a pile of Lego blocks and each DNA codon tells the cell which brick goes where to assemble whatever protein the gene codes for. But what happens when this code gets changed slightly? And that’s what a SNP is – a very limited change to the DNA sequence that can change the function of a single gene.

One possibility is that nothing will happen – if I swap a red brick for a white one in a wall of Legos then whatever I’m building will work pretty much the same, provided the bricks are the same size and shape. Similarly, it’s possible to make some changes to the DNA without really affecting the health of the cell (or the organism) at all. But this sort of change isn’t what most interests Rosenstein – of more interest is what happens when a SNP causes a structural change in a protein; especially when the protein is one that contributes towards a cell’s sensitivity to radiation. This would be the equivalent to, say, replacing a 6-peg Lego block with a 4-peg block – a single such change might not make much of a difference, but accumulate enough of these changes and the structure grows increasingly prone to stress.

Each of our cells has well over 100 genes that help make it more or less sensitive to radiation damage. What Rosenstein and his colleagues were curious about was whether or not it is possible to identify specific SNPs that could help predict which patients might react more strongly to radiation therapy – while every effort is made to spare excessive radiation dose to healthy tissues, sometimes damage happens anyhow. This sort of collateral damage is certainly better than dying of cancer, but it would still be nice to try to minimize it. At this point I should also stress that this is still very much work in progress – I just learned of it last week and I’m looking forward to following the work as it continues.

But let’s consider this a little further – let’s assume that this research pans out and that it’s one day possible to assemble a genetic profile that helps us to better understand each individual’s sensitivity to radiation damage. How could something like this be used?

One obvious application might be in the workplace – what if a nuclear power plant (or an airline or a hospital for that matter) could test prospective employees to see who might be more susceptible to the elevated radiation levels they’d be exposed to on the job. Would it be ethical to give someone a job involving elevated levels of radiation exposure if their SNP inventory showed they were less able to repair DNA damage? After all, how can you justify letting your employees be exposed to a potential hazard that you’ve found out is more dangerous to them than to the average person?

But on the other hand, is this the company’s responsibility or the responsibility of the workers? Let’s face it, workers voluntarily accept risks all the time – think of police and firefighters – shouldn’t it be up to the worker to decide whether or not to accept a risk? This is certainly the approach that has been taken with pregnant women – a company cannot dictate whether or not a pregnant woman can be exposed to potential reproductive hazards; only the woman can make this choice. Similarly, it may be inappropriate for a company to limit a worker’s opportunities based on a genetic test showing a higher sensitivity to radiation – it could be that this decision should only be made by the worker.

On the other hand, companies make decisions about where someone can work all the time and many of these decisions are based on a person’s physiology, much of which can be the result of genetics. A former job required that I have a valid driver’s license – in order to be hired I had to meet all of the physical requirements to legally drive. Not only that, but I also had to be able to lift up to 50 pounds and more and I had to be mentally sound – there are genetic factors that play into all of these. Other jobs also have physical and/or genetic requirements: fighter pilots can’t be colorblind and can’t be too tall to fit into the cockpit, firefighters have to be able to carry equipment and hoses up ladders, and so forth. So if the colorblind are excluded from flying fighter jets, why not exclude the genetically sensitive from working with radiation?

There are court decisions and laws that prohibit discriminating against an individual because of their genetic profile. But isn’t excluding the colorblind from flying fighter jets a form of genetic discrimination? Colorblindness is, after all, a genetic disorder – how can we legally say that a person with this particular genetic ailment can’t fly a high-performance jet?

Part of the explanation is the difference between what might and what will come to pass and how this can affect safety or job performance. Fighter pilots, for example, have to be able to tell the difference between red, green, and white lights in the cockpit. Colorblindness may be genetically determined, but it is something that has already happened and it has a measurable impact on a pilot’s safety and performance. But radiation sensitivity is different – it affects the likelihood that somebody might develop cancer from a given dose of radiation. The risk of developing colorblindness is 100% – in a colorblind person the genes controlling it have been expressed and the affliction has already appeared. And not only that, but it can affect safety. On the other hand, a genetic predisposition to radiation damage is only a predisposition – we cannot say with any degree of certainty that a certain genetic sequence will (or will not) cause a person to develop cancer. So we can discriminate against the certainty of a physical trait that affects one’s ability to do our jobs safely and effectively, even when that trait is genetically determined. But we cannot discriminate against a person who simply has a higher possibility of having an adverse effect.

Putting this all together, the possibility of using genetic analysis to help make more informed medical decisions is both promising and exciting. But let’s hope that, as these techniques become better refined and more prevalent, they are not used inappropriately or discriminatorily.

One Response to “SNPs and radiation sensitivity”

  1. Arthur Weissbach July 16, 2013 at 11:51 AM #

    I’ve just read your April 22 comments on SNP’s and radiation sensitivity. I’m late to the discussions as usual. I would just comment that focusing on radiaition damage to DNA is bit old fashioned since one knows that insults , such as radiation, oxidative damage , and other insults can affect other macromolecules such as RNA or proteins just as easily. Since the status of the DNA involves all of the above, the number of genes involved in repair or even carcinogenesis is probably in the thousands and there are some shotgun experiments that hi-lite the incredible complexity of the interactions (cf. Moses & O’Malley, J.Biol. Chem., 2012, 287, p.23266-23270).There are guys who spend their whole careers trying to understand just protein repair.
    In any event, the actual mechanisms in low level radiation effects in cells have been simplified to the point where it is useless, in my opinion. as a teaching tool.
    My apologies for being redundant but, folks, this is chemistry at work not physics.
    Art Weissbach (July 16, 2013)

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