Until a few years ago, it was known that one of the principle chemical processes of epigenetics was to add a small chemical modification to genes. The process is called methylation, which adds a cluster (group) of methyl (an organic carbon, CH2) to the DNA base cytosine. The chemical name is 5-methylcytosine – 5mC. Adding 5mC to a gene turns it off; removing it turns the gene on. This is fundamental to the way cells dynamically alter the expression of DNA to adapt to the environment.

Just a few years ago it was discovered that there is another form of methylation, this time including a water-like molecule known as hydroxyl (OH). The name for this is 5-hydroxymethl-cytosine, the 5-hmC mentioned above. The take-home here isn’t the names or even the chemistry, but the fact this second form of methylation has been shown to be very important in how cells differentiate into different types. This is especially true for stem cells, which to various degrees are ‘blanks’ that epigenetic factors – likely through 5-hmC – are guided to differentiate into adult types of cells such as muscle or nerves.

While it required three paragraphs of preamble to get back to 5-mC and 5-hmC here is the real news: While scientists were aware of these two types of methylation, they had great difficulty in separating them within the cell and on DNA. That’s where the discovery of a new method for distinguishing both types during the sequencing of DNA comes in. The technique was developed in a collaboration between scientists at Cambridge University (Cambridge, UK) and Babraham Institute (Cambridge, UK), and published in the journal Science [26 April 2012, paywalled, Quantitative Sequencing of 5-Methylcytosine and 5-Hydroxymethylcytosine at Single-Base Resolution]. This work represents an important advance of genetic sequencing technology into the realm of epigenetics. By analogy, it is something like creating a new way of using a microscope through which the unknown is penetrated by a different perspective. While in one sense this tehcnique, which has the unmemorable name of oxidative bisulfite sequencing, is not ‘big news’ for the wider world, it could very well be one of those ‘keystone’ techniques that makes it possible to (eventually) answer questions such as “How do stem cells become adult cells?” or “How does the genetics of cancer cells go off the rails?” The field of epigenetics is in its infancy, this kind of advance in technique and technology gives it a lot more room to grow.

This new type of DNA is, for one thing, distinguished by existing outside the chromosome. Finding bits and pieces of DNA separated from the chromosome, in itself, isn’t too surprising. It’s a bit like finding flotsam along the shoreline; you expect some loose bits of material to be floating around in the cell. However, what scientists now call an extra-chromosomal circular DNA (eccDNA) may be something more significant.

One type of eccDNA, dubbed microDNA and recently discovered by scientists at the University of Virginia (USA) and the University of North Carolina (USA), is found in great numbers of relatively short strands (200-400 base pairs – the combinations of Guanine-Cytosine and Adenine-Thymine) in non-repeating sequences. Their finding has just been published in Science [08 March 2012, paywalled, Extrachromosomal MicroDNAs and Chromosomal Microdeletions in Normal Tissues]. Where these ‘pieces’ of DNA come from has not been verified, but geneticists think it could be from cutting bits of chromosomal DNA (excision), replication of short DNA sequences, or reverse transcription of certain RNA. The research tends to show that microDNA mostly comes from deletions, which would indicate they are part of the repair and maintenance process for DNA.

The big question is what – if anything – are microDNA pieces for? Do they play an active role in the repair process, or are they the result (detritus) of that process? They do seem to be associated with gene variation between different types of cells. So far the researchers have found microDNA in human and mouse cells, but it may not be universal. At this point there are more questions than answers, although the pattern in genetic discovery tends to lead from the simple toward the complex. It is possible that microDNA and other eccDNAs have an important role in the genome – or not. It’s these kinds of questions that keep geneticists on their toes.

As is often the case with a medical advance surrounded with hype, there are doubts and concerns. A major new study by Johns Hopkins medical research in Science Translational Medicine [02 April 2012, paywalled, The Predictive Capacity of Personal Genome Sequencing] involving thousands of identical twins is outspoken about the failure of personal genomic analysis to identify a person’s risk for most common diseases. In fact, it flat out warns people not to uncritically accept negative genome test results.

Since the personal genome sequencing business is turning into a major growth industry and the stake of research on the links between genes and disease is enormous, this study is bound to be not only something of a knowledge-bomb, but also instantly controversial.

The basis of the study is recorded data on thousands of identical twins in the registries of Sweden, Denmark, Finland, and Norway along with the Twins Registry of the American National Academy of Science. Because identical twins are thought to share identical genomes, it should follow that if one twin presents a genetic based disease, statistics should indicate a prevalence of the same disease in the identical twin. The researchers used information on 24 diseases (cancer, autoimmune, cardiovascular, genitourinary, neurological and obesity-associated). Statistical models were created to predict the risk of each disease based on typical doctors’ diagnosis.

The results need a careful reading: A whole genome sequencing could indicate an increased risk of at least one disease, but most people would get negative test results for the majority of diseases in the study. Put another way, even for diseases with links to a genetic foundation, the presence of those genes in one individual is not a satisfactory predictor for another individual. Statistically, for example, if 2% of women show a genetic predisposition for ovarian cancer, it does not mean that the other 98% who test negative for the gene won’t get ovarian cancer.

You may have noticed that this is not a blanket denial of genomic analysis. The researchers are careful to say that genomic information can be very helpful for people with families who have a strong history of a particular disease. In addition, certain diseases that are shown to be particularly related to genetic variation such as coronary heart disease in men, thyroid autoimmunity, type 1 diabetes and Alzheimer’s disease are more likely to be accurately predicted by genomic analysis. This list is likely to grow as medical research advances.

However, in the broader perspective the ability of genomic analysis to predict a limited set of diseases leaves most people and most diseases unpredictable by this method. For example, while some hereditary cancers are gene influenced, hereditary cancer is rare. Most cancer is caused by genetic mutations acquired by environmental exposure, lifestyle choices (like smoking) and random errors in genes that occur during cell division. As one of the lead researchers, Bert Vogelstein of Johns Hopkins Kimmel Cancer Center (Maryland, USA) puts it:

We believe that genomic tests will not be substitutes for current disease prevention strategies. Prudent screening, early diagnosis and prevention strategies, such as not smoking and removing early cancers, will be the keys to cutting disease death rates.
[Source: EurekAlert]

Research by Philip Awadalla, University of Montreal (Canada) and Matt Hurles, Wellcome Trust Sanger Institute (Cambridge, UK) and published in Nature Science [12 June 2011, paywalled, Variation in genome-wide mutation rates within and between human families], indicates that the actual number of mutations we receive from our parents is about 60 – roughly a third of the original estimate. That means, among other things, that the rate of evolution based on genetically inheritable mutations is much slower than thought.

The research also indicates that the number of mutations provided by the mother and father varies. In one case the father provided 92 percent of the mutations, in another case the mother provided 64 percent. Note, however, that these two cases were the only cases in the study. This significant limitation was imposed by the difficulty and cost of sequencing and sorting the genetic information. While these findings are extremely interesting and point to factors based on family or environment, this study must be considered preliminary to hopefully much larger studies in the future.

Given that there are millions of women (and a few men) for whom such hope is paramount, each one of the announcements may be greeted with enthusiasm. Even if each of these discoveries doesn’t turn out to be ‘the cure,’ surely collectively they must indicate progress toward finding a cure? Well, yes they do, but the question has to be, how much progress?

That gets me back to the original problem of knowing more. A team of scientists at Washington University (St. Louis, Missouri USA) led by Matthew Ellis performed a feat of massive computational proportions by sequencing the whole genomes of 50 women with breast cancer. The resulting paper, to be published in Nature magazine was previewed as a news article. [ Fifty genome sequences reveal breast cancer's complexity] The research entailed sequencing 50 genomes from the tumor cells, and 50 genomes from healthy cells and then comparing them, looking for alterations in the genome. They found mutations, lots of them.

They found 1,700 genetic mutations. That might be classified as the good news. The less than good news is that most of the mutations were unique to each woman’s tumor. Only three mutations occurred in 10% or more of the women. The genetic changes also appeared to be the result of almost the entire kit of mutation: Single-nucleotide variations (copy errors, radiation changes); frame shifts (where the boundaries of genes are broken); translocations (genes get moved to the wrong location); and deletions (which sounds like it is).

The positive spin for the study was that three genes were common, sort of: MAP3K1 (10%), PIK3CA (43%) and TP53 (15%). These may represent a toe-hold on correlating genetic mutation and breast cancer. Of course, that leaves over half the women in this study with breast cancers from various configurations of relatively rare mutations. Remember, this study was conducted on a small number of women, who had only one type of breast cancer (estrogen-receptor-positive). The next research will be on a thousand women with different kinds of breast cancer.

How to interpret this? Here’s the opinion of pharmaceutical chemist (and blogger) Derek Lowe:

The Nature piece contains some brave-face material about how this study has uncovered a whole list of new therapeutic targets, but sheesh. What are the odds that any of these will prove to be crucial, even for the low percentage of women who turn out to have them? No, instead of making me yearn for ever-more-personalized targeted therapies, this makes me think that early detection and powerful, walloping chemotherapy (and surgery) must be the way to go for now. I mean, this was still only fifty patients, and uncovered this much complexity: how tangled must the real world be?

[Source: In the Pipeline]

No question the genetic sequencing technology is becoming better by leaps and bounds (and cheaper). No question that studies like this one are racking up a lot of new data correlating genetic change and cancer. It’s possible that one, or a simple combination of genetic mutations could be fingered as the cause for breast cancer – and treatments developed. Unfortunately, studies like this one make it more likely that genetic mutations are part of a much more complex web of causation – probably with elements scientists don’t even know about yet. I can hear scientists like Derek moaning, “We’re not going to test for and make treatment with 1,700 genetic errors!” Like I said, we just need to learn more.

A team of biogeneticists working with David Kingsley at the Howard Hughes Medical Institute and Stanford University (USA) and published in the journal Nature, 9 March 2011, [Human-specific loss of regulatory DNA and the evolution of human-specific traits] used computer techniques to scan the genome of humans, chimpanzees, macaques (monkeys) and mice looking for differences in the genetic sequences. They came up with 510 short segments of DNA that were in the other animals but not in humans. In other words, rather than having extra genes to support human complexity, in this case we are missing genes. This was actually what the researchers expected, having seen similar DNA effects in other experiments with stickleback fish. However, for many biologists the results will be, to put it mildly, surprising. Scientists live for surprises.

There was more: Of the 510 missing DNA segments, only one affected a specific gene directly. That happens to be the gene that prohibits the growth of brain cells. That is powerfully suggestive – although don’t push the connection too hard at this point. More importantly: Of the other 509 DNA segments, all of it is associated with how genes are regulated and expressed. This enters the realm of epigenetics and the so-called ‘junk DNA,’ which concern the 98% of the genome that does not direct the production of specific proteins (what genes do).

I won’t go into lengthy background on epigenetics; here are some posts at SciTechStory:

Small steps toward understanding the epigenome
Oh Daphnia, why so many genes?
New for epigenetics: Active pseudogenes and RNA as gene regulator

After finding the 500+ DNA deletions came the hard part: What are these deletions and what does their absence mean. The researchers opened their work to dozens of specialists, asking them to submit analysis and explanations. The result was identification of a few sequences that were near or known to be related to genetic activity for specific human traits. Kingsley and colleagues then went hunting for these sequences in chimps and mice to see what they did in those animals. Two segments of DNA stood out: One segment I mentioned above that affects cell growth in the brain, the other is associated with what is called the androgen receptor, a transcription factor responsible for expression of male traits (like men have beards). With this segment of DNA missing, human beings (males) lack some traits found in chimps and mice such as facial whiskers and penis spines.

Ah…did you know this is a story about human males not having penis spines? You certainly would think so if you saw most of the coverage, even in science reporting such as Nature News How the penis lost its spikes, the same outfit that published the scientific paper. Sex sells, weird sex sells even better…dontcha know? It’s true that this story about missing elements of DNA includes the fact that somewhere along our evolutionary line human males (and that includes homo sapiens and Neanderthals) dropped a set of sensitive hairs at the end of the penis, which in primates helps trigger rapid ejaculation. Lots of bloggy speculation has flowed from this factoid about human males having more time to establish loving bonds with monogamous mates. It’s a factoid that may be a counterfactual surprise to many women.

As dull as it may sound, the moral of this story is not what humans are missing. It’s that our genetic inheritance is a whole lot more complicated than the DNA code. Some scientists have suspected this for quite a while, now the evidence is mounting. In this case, I think the media release gets it about right:

The finding mirrors accumulating evidence from other species that changes to regulatory regions of DNA – rather than the genes themselves – underlie many of the new features that organisms acquire through evolution.

[Source: EurekAlert]

The findings of this research continue to point in the direction of a re-evaluation of the role of epigenetics in evolution. This is not saying that DNA isn’t important or that the role of DNA in evolution isn’t paramount; but it does say, at the very least, that DNA is not the sole determinant of evolution. There are other factors that mediate between the environment and gene expression – such as the ‘missing’ DNA structures, and of course, those DNA structures that exist but are of unknown purpose – for which a lot more research will be needed to explain. How, when and why did the DNA sequences ‘go missing?’ What are other sequences that help determine human specific traits? Great questions. Scientists love great questions.

This equal sign, =, is about as big the known champion of the gene-filled genome. Little Daphnia pulex, variously labeled a crustacean (like shrimp) or ‘the water flea,’ is the first of its subphylum to have its genome sequenced. Lo and behold: Daphnia’s genome has more genes – about 31,000 – than any other animal with a known sequence. Now here’s the point that gets biologists’ lab coats in a twist: the human being, the most complex creature known to science, has only about 23,000 genes in the genome. Important questions jump to mind. Why does Daphnia have so many genes? The obvious follow-up; how is it that humans have relatively few genes and yet have the most complex biology (mainly, the brain)? The disturbing-stimulating part of these questions? Biologists don’t have the answers.

Back to Daphnia. There’s more to the story than Daphnia having a slew of genes. This is not really a quantitative contest. According to recent studies, Daphnia creates a huge number of gene copies, perhaps as much as thirty percent of the total. This can happen when cells replicate and instead of making an exact DNA copy, there are more (or fewer) genes in the new cell than in the old one. In this case, there are extra copies of some genes, or as the cell biologists say, a copy number variation. Often in most known animal cells a copy number variation is a bad thing, or at least risky. Extra genes are considered a mutation and most mutations don’t work, leading to a dead cell – or worse, the extra genes become part of a cancer process. But this is not apparently the case for Daphnia. Why?

Daphnia pulex is studied intensely. It’s in a select group favored by biologists, which includes the fruit fly (Drosophila melanogaster) and the flatworm (Caenorhabditis elegans). In fact, the Daphnia Genomics Consortium (DGC), sporting a membership of over 450 biologists, has just produced a gaggle of 40 papers on Daphnia, which are highlighted in the journal Science February 2, 2011 [A genome for the environment] and available on the DGC website at the University of Indiana Center for Genomics and Bioinformatics (Bloomington, Indiana).

One of the reasons Daphnia attracts so much attention is its sensitivity to environmental changes. It’s often called the fresh-water equivalent of the ‘canary in the coal mine.’ It’s one of the first organisms affected by minute changes in the chemical makeup of the water it lives in. For the most part, this tiny environmental monitor was observed for visible symptoms – like it dropped dead. Now, with knowledge of its genome and more sophisticated analytical capability, scientists can look for changes in Daphnia’s genetic makeup to pinpoint environmental changes.

However, before that kind of environmental analysis becomes meaningful, the suspected link between the environment and Daphnia’s extraordinary number of gene copies needs to be explained. As Michael Pfrender at the University of Notre Dame (Indiana, USA) puts it:

“We had all assumed that newly copied genes that code for the same proteins would initially have the same functions, and that new functions evolve slowly with age, by acquiring rare beneficial mutations. Instead, we found that half of the newly copied genes had changed their expression very soon, possibly at the time of their origin.”

[Source: EurekAlert]

It seems probable that Daphnia produces so many gene copies in order to have a ready pool of genes reacting to the environment. Somehow it uses the inevitable mutations in such a large gene-pool to achieve very rapid and favorable inheritable genetic changes. Somehow Daphnia’s copied genes interact with the existing genome to incorporate these changes. Evolution, if that’s what this is, has seldom been seen on such a short time-scale.

There’s more. Daphnia isn’t much into sex. Most of the time, in normal environmental conditions, Daphnia is female and reproduces by cloning. Only under environmental stress will it ‘resort’ to creating a male version for reproduction. Again the environmental influence is a key, and underneath must be some dramatic shifting of the genome – this time involving meiosis, the creation of reproductive cells.

And that’s not all. It has been known for a long time that Daphnia will respond to the presence of certain predators by dramatic changes in its phenotype (body shape, among other things), in this case the development of what is known as its ‘helmet,’ ‘neck teeth’ and ‘spikes’ for self-defense. These too occur within a very short period of time but represent a major change in the underlying genome.

A large pool of duplicate genes, environmental selection of gender, and the ability to alter phenotype for self preservation – this is one genetically fascinating creature. One more thing, so far Daphnia has more genes in common with humans than any other animal. Go figure….that’s exactly what biologists and geneticists will be doing for many years.

SciTechStory will keep an eye on little Daphnia, =.

“Obviously we were not designed for outer space. It’s time to hit the drawing boards.” Windman smiled.

Windman meant tissue engineered astronauts. To the assembled rocket scientists, nearly all of them engineers, the concept was unspecific but understandable. Engineers love to change things. Windman was offering the possibility of changing the most intractable problem of space travel – human beings. Windman is a well-known molecular genetics biologist, making him almost as smart as a fluid dynamics engineer, at least.

“You boys don’t need to look cross-eyed. You already pick astronauts according to a very strict physical profile. Genetic selection.” He paused to throw a severe but cursory glance across the audience. “It’s time to become more systematic, and proactive.”

There were nods in the audience. Nods of affirmation, not nodding-off. Windman had their attention, if only because he was saying this meant the ideas had authority. Authority meant there could be action. Something could get done. If Craggy Windman said there were ways to engineer astronauts, then it could be done.

“Let’s do a quick inventory,” said Windman, “Not all the faulty parts, just the ones we know we can fix or replace.” He walked over to the easel and pointed with a finger at an ear.

“Take the inner ear. Please. It’s a mess in space because there is no up and down. All those little cilia wiggling around in the organ of Corti and nowhere to go; their wiggling means absolutely nothing in space. Worse than nothing, the brain gets confused and you feel sick. We can fix that. A few tweaks of DNA and the inner ear will no longer send confusing signals – a much better solution than drugs.”

Several in the room could be seen tugging an ear. The power of suggestion. Windman continued, “Then there’s the microbiome. For example all those wee beasties living in your gut.” This statement elicited a few discrete burps around the room. “We biologists live with the knowledge that you have more bacterial cells in your body than your own cells – by almost ten to one. Just think what we could do if we change the combination of these cells around, alter their genome, make them do things that are beneficial in space. Like not producing body odor!”

Windman laughed. Some in the audience did to. A few, who were astronauts, conspicuously did not laugh. “No such luck with farting though!” Windman laughed again. Smiles all around.

“Ah, yeah. Well, joking aside. We can do things with bacteria. Not right now, but soon…someday soon. There’s one, just for you guys, it’s a bacteria called Deinococcus radiodurans. Tough little critter…can survive radiation doses seven THOUSAND times what you can take. It puts its own DNA back together after radiation blasts it apart. Yours can’t do that. So what we do is snip out the right genes from radiodurans, and we slip them into the human genome. Presto – you can fly through radiation filled space, unharmed. Who knows, maybe you could survive on the surface of Io or Europa?”

Now he had them going. Everyone in that room wanted to go to Europa (the moon of Jupiter, not the old continent). Perhaps a few of them confused the Europas. Windman continued, “Look at that poor forked creature over there…” (pointing at the easel) “…he’s too tall. Bumps his head on the overhead pipes all the time; and he can barely get out the airlock without going feet first. You could lop off a few inches of leg bone – people do that you know – but how much better to get his genes to reduce their expression for height. We don’t make pygmies, mind you, just nicely sized astronauts. The Goldilocks formula, doncha know, not too tall, not too small.”

Windman was on a roll. Visions of NASA funded projects danced in his head…a billion here, a billion there. He could envision banks of genome sequencing machines, humming away, spitting out genomic patterns for almost anything.

His brief reverie was suddenly interrupted when one of the audience stood up and asked, “What about the ethics of human experimentation?” His tone was unfriendly. Several others in the room gasped quietly. Next this fellow might even accuse Windman of playing God. However, Windman was unflappable. He pulled at the lapel of his Armani suit, and then squinted sideways into the audience in the general direction of the accuser. “Well now, young man, I appreciate your concern; but we don’t plan to experiment with people while they’re on Earth. We’ll do it up in space where it’s appropriate…more appropriate…not easy though, it just makes more sense up there.” The words sort of stumbled out.

Windman was not a stupid man. It occurred to him at that moment that he should be careful what he wished for. “Well, there’s a lot you can do to get astronauts better suited to space without tinkering directly with their DNA. Just make more systematic genomic profiles, make them more precise, and then make some selection criteria. They should have just the right DNA for the right physical properties. Of course, they have to propagate…you could select for genes that make them more sexy or virile…or both.”

Now Windman sensed that he had gone too far. The two women in the room were leaving. He thought about adding some good things they might do to the female body, but he held it.

His next words came out somewhat forced, “The day is coming when we’re going to live in space. Like it or not, human beings are built for Earth gravity. That doesn’t work in space. Synthetic biology, tissue engineering, genomic selection, and gene modification – these are tools we will have to use if we want to live in space. The sooner we learn how to use these tools, the better. We need to experiment. Thank you for your attention.”

Windman looked at the easel and thought about taking it with him as he left. He decided to leave it. The applause was finished. So he left as the next speaker was coming in. This speaker’s topic was about replacing astronauts with robots.

It looks like a loose ball of yarn, as in the picture above. In fact, it’s the genome of a common yeast (S. pombe). The human genome spends most of its time in a ball something like this. The familiar “X” shaped chromosomes occur only at the time of cell division. Like almost everything biologists are discovering about the cell, the shape of the genome isn’t arbitrary. A new study, conducted by Ken-ichi Noma and colleagues at the Wistar Institute (Philadelphia, USA) and published in the October 29, 2010 issue of Nucleic Acids Research [ Mapping of long-range associations throughout the fission yeast genome reveals global genome organization linked to transcriptional regulation ] shows that the shape of the yeast genome has real significance.

‘Shape’ in this case means the three-dimensional structure. By (stretched) analogy it’s like the mess on and in your desk. The important stuff is on top. That includes things you need every day and the current things you’re working on. Less important stuff is buried on top, or jammed into drawers where you (mostly) remember where to find them. The genome ball of chromosomes is something like this. Important genes are placed so that they can be more easily reached by transcription factors (RNA material).

To reach this conclusion Noma and his colleagues combined latest-generation DNA sequencing (equipment) with a technique known as chromosome conformation capture (3C – developed in 2002 by Dekker and colleagues at the University of Massachusetts). The 3C technique is tricky, but it does help clarify the conformation (shape); the researchers used this in conjunction with fluorescent probes to locate specific genes through a microscope. From this they were able to ‘map’ three-dimensional computer models of the yeast genome.

The advantage of their new technique is the ability to view genes as they interact with each other. They were able to identify 465 groups of genes that share a similar function (gene ontology groups). The physical relationship of genes in these groups was often significant:

“When the chromosomes come together, they fold into positions that bring genes from different chromosomes near each other,” Noma said. “This positioning allows the processes that dictate how and when genes are read to operate efficiently on multiple genes at once.”

This structure is not merely an accident of chemical attractions within and among the chromosomes – although that is certainly a part of the larger whole – but an arrangement guided by other molecules in the cell to create a mega-structure that dictates genetic function, Noma says. He envisions a scenario where accessory molecules, such as gene-promoting transcription factors, bind to DNA and contribute to the ultimate structure of the genome as the chromosomes fold together.

[Source: Wistar Institute]

Keep in mind that this research was done on the genome of yeast, a relatively simple beasty with only three chromosomes. The human genome presents a more complex challenge. Nevertheless, Noma and other researchers are turning to new techniques that give them a picture of how elements of the genome interact. The physical relationships can tell them a lot about the timing, priority, and chemical activity of various DNA processes – RNA transcription in particular. The real insights will come from future work.

In addition, work in other areas of genome sequencing will undoubtedly influence the research into the importance of genome shape. For example, a study released on the same day as the Wistar paper revealed new information about the amount and versatility of copied genetic sequences [SciTechStory: DNA redundancy: Genetic sequence copies are more prevalent and important than thought] Almost all genes have a copy in the genome, but some are more copied than others. How these copies interact will also have a physical dimension.

Such questions are launching a new field of medicine: genetic risk intervention (or prophylactic risk reduction). If you’re a woman identified with a mutated BRCA1/2 gene, then studies show that over a lifetime you are 56% – 80% more likely to develop breast cancer than women without the gene. These are not long odds. Many women would prefer (or insist) that something be done. That something could be mastectomy (removal of the breasts) or a salpingo-oophorectomy (removal of the fallopian tubes and ovaries). Both are serious procedures with obvious personal implications. Nevertheless, some women are going to see them as justified against the odds of dying from cancer.

A new study, conducted by the University of Pennsylvania, School of Medicine (USA) and published in the Journal of American Medical Association (JAMA, September 1, 2010) indicates that this sort of intervention, specifically prophylactic surgery, works.

The study, which included 2,482 women with BRCA1 or BRCA2 mutations (determined between 1974 and 2008), was conducted at 22 clinical and research genetics centers in Europe and North America. The women were followed up until the end of 2009.

The researchers found that risk-reducing mastectomy was associated with a decreased risk of breast cancer in BRCA1/2 mutation carriers, with no breast cancer events occurring in women who underwent risk-reducing mastectomy during 3 years of prospective follow-up. “In contrast, 7 percent of women without risk-reducing mastectomy over a similar follow-up period were diagnosed with breast cancer,” the researchers write.

[Source: EurekAlert]

This result is not counter-intuitive, but it is not overwhelming. It’s an indicator that this kind of risk intervention has yet to come out of the margins of medical procedures. There are several important and difficult questions yet to be answered:

How accurate and reliable are the genome tests? They are improving, even as they become less expensive, but genome tests are far from infallible.

How certain are the links between having a mutated gene and developing the related medical problem? This is a difficult question because of the many variables that enter in to the steps between having a mutated gene and its expression in some form of disease or disability. Experiments and surveys show a correlation or even a causal relationship between specific genes and certain diseases, but in most cases the conditions for this linkage – the genetic and biochemical details – are unknown.

How effective are the prophylactic measures? The field of genetic risk reduction is so new that statistics are incomplete, at best. It’s almost certain, however, that no procedures will be 100% effective. The risk of failure will have to be part of the consideration.

What, if any, are the risks of interventions? Some of the intervention approaches, such as surgery, carry their own risks. Complications from removal of (any) organs are not uncommon. Beyond the medical procedures there are almost always social and psychological risks.

How much will intervention cost?

This last question – cost – goes to the heart of a common problem in modern medicine: There are many life-prolonging procedures but many of them are very expensive, far beyond the means of an average person and generally beyond the acceptance of health insurance programs. While obviously a mastectomy to prevent the occurrence of breast cancer is not the same as a ‘boob job’ (voluntary cosmetic surgery), it’s still ‘optional.’ Optional in this context will often mean affordable or not affordable. This kicks genetic risk intervention into the arena of rich versus poor, with all its social and political issues.

At the moment risk intervention is mostly defined by surgery, preventive chemotherapy, and lifestyle changes. In the future, interventions will also be carried out on the genome, pre-birth or as an adult. For now, however, our knowledge about links between various genetic markers, the path of disease development, and the measures that could be taken to prevent a disease is, to put it charitably, in its infancy.

Someday scientists and doctors may know enough about the causes of various genetically related diseases to be able to pin down the risk. But that isn’t today or anytime in the near future. Cancer, for instance, is still undergoing a research revolution as molecular biology seeks to discover the underlying organic chemistry. Those discoveries must include understanding how environment and lifestyle play a role in the expression of genetic potentials. Since there are many kinds of cancer and a world full of personal and environmental variables – an accurate and complete understanding of any one person’s risk is going to be difficult to achieve any time soon.

That won’t stop the development of genetic risk intervention. There will be a demand for the procedures, and there will be a market; but genetic risk intervention will undoubtedly be added to the list of controversial and yes, risky, new medical technologies.