Category Archives: Robert Resta

Why Me?

“We tell ourselves stories in order to live.” – Joan Didion

Even after decades of clinical experience I am still struck by the sometimes random and sometimes cruel nature of the occurrence of genetic and congenital conditions. You meet a family with 3 successive children with a profoundly serious recessive condition and the next carrier couple that you see have 6 unaffected children. A grandmother watches her husband, son, and grandchildren die from Li-Fraumeni cancers, and then you encounter a TP53 mutation in a young woman with breast cancer and a family history devoid of other cancers. A gene panel reveals that a woman has dodged a BRCA1 mutation in a pedigree overflowing with breast cancer – but she has a pathogenic APC mutation and not a single relative with colon cancer or polyposis. An adopted woman learns she is pregnant the same day she is contacted for the first time by her biological family and told that her biological father just died of Huntington disease.

We consult the Codex of OMIM or the Oracle of Bayes, and then tell scientific stories of skewed mendelian ratios or stochastic processes (Literal translation: Shit happens), stories as much for ourselves as for our patients. My favorite (non)explanatory story is “a multifactorial combination of genetic and environmental factors.” Come on, please. What human trait is not the result of a combination of genetic and environmental factors? We can wind up committing the original sin of genetic counseling – responding only with cold, meaningless facts to patients’ cris de coeur for comfort, validation and acknowledgment of their emotional states, their quest for a psychologically meaningful understanding and acceptance of their situation, and the need to make sense of their suddenly upturned lives. We should be forgiven though. Genetic counselors are only human and who among us is without sin? None of us were immaculately conceived.**

Patients will fill this void with their own stories. It was that stress in my life. They used to spray insecticide all the time in my neighborhood and now every house on my block has someone with cancer. Then there are the somewhat morally judgmental plaints – I am a vegan, I exercise daily, and put no poisons in my body; my sister eats only fast food, smokes, drinks, and has a new boyfriend every weekend, but I am the one who gets cancer and it’s just not fair. Or it must have been the manufacturing plant down the road with that awful chemical smell (How come no one ever lays the blame on pleasing aromas like cinnamon buns in the oven, freshly roasted coffee, or the sensual curry infused scent of an Indian kitchen?).

If Joseph Campbell was right, mythopoesis is as innate as erythropoiesis. Our minds can’t help but tell stories like our marrow can’t help but make blood. So let me offer my own mythological explanation of the epidemiology and distribution of genetic and congenital disorders – Pedigrus Rex, the god and ruler of pedigrees. Pedigrus is definitely  in the classic Greco-Roman tradition of a powerful god ready to unleash his power at a mere whim or perception of insult, without the slightest thought to consequences. As much Zeus as Trickster.

Pedigrus rex

Sometimes he is benevolent. Let’s see, I will render that woman pregnant after she has given up, exhausted from years of unsuccessful fertility treatments. Sometimes he is terribly unkind (Pedigrus Wrecks?). Hmmm, I think I will give a tetralogy of Fallot to that baby with severe ichthyosis. Hey, why not introduce yet another common mutation in another gene to the Ashkenazim? Sometimes he is astonishingly trivial in his malevolence, like making my pedigree software malfunction after having entered a hugely complex family history. Usually, though, he is emotionally indifferent, just going about his business of indiscriminately sowing the seeds of sadness, joy, shock, and love into the soil of human reproduction. We may try to appease him with sacrifices in our temples or try to understand his motives by consulting seers and prophets in our clinics. Mostly, though, he is beyond comprehension and placation.

This is not to lessen the importance of providing medical and scientific explanations. Many patients want technical information and often that is why they come to us. The beam of knowledge sheds some light for them but does not fully illuminate. They will integrate the scientific story into their own narrative – but on their own terms. It is only part of what they are seeking. Our duty to patients is not discharged once we have given them a recurrence risk or a name to their child’s condition. We need to help them create a psychologically meaningful narrative, a life story, that helps them cope and adapt to their situations, to grow and move on.

The Greek tragedies teach us that we have the ability transform sadness into love, shock into acceptance, fragility into strength, denial into hope. Suffering (pathos) turns into recognition (anagnorisis) and reversal (peripeteia). Humanity trumps divinity by telling stories that work emotional miracles. We can all be greater than gods.

“Mythology, in other words, is psychology misread as biography, history, and cosmology.”
― Joseph Campbell, The Hero With a Thousand Faces

Thanks to Emily Singh for help with the graphics.


** Let me digress here and correct a common “mythconception” about the term Immaculate Conception. Most people use the term to describe a conception that occurred without the benefit of sexual intercourse. This is quite incorrect; this is confusing Immaculate Conception with Divine Conception. Immaculate Conception refers to Mary, the mother of Jesus, and not to the conception of Jesus. In Roman Catholic doctrine, Mary, who was the product of conjugal relations between her parents Joachim and Anne after years of infertility, was the only human ever conceived without Original Sin on her soul, i.e., she was immaculately conceived. Jesus, on the other hand, was the product of Divine Conception by the Holy Spirit. He could not have been conceived in the usual style because that would have tainted him with Original Sin, a trait he would have inherited from Mary’ s husband Joseph. Mary learned of her pregnancy at The Annunciation, traditionally 9 months before Christmas on March 25th, when the Angel Gabriel announced to her that “the Holy Spirit would come upon thee” resulting in the miracle of divine conception in Mary’s virginal womb that was unblemished by sin or sex, and without Joseph’s, er, assistance (Joseph had his own visit from an angel who sort of explained the situation to him. So you  might understand why Joseph was deserving of sainthood.).

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Barriers or Filters?

 

Both good and bad can be said about Direct to Consumer (DTC) genetic testing. Some of the tests offered are probably better labeled Dreck To Consumer. Please, somebody, issue a cease and desist order for MTHFR testing. Or better yet, make it a criminal offense, punishable by sentencing to hard time at the Clockwork Orange Folic Acid Supplementation Rehabilitation and Penal Colony.

On the other hand, I am betting that established labs that currently offer clinically useful genetic testing will be migrating toward a greater presence in some form in the DTC market. This trend will be driven, by among other things, the demand on the part of some patients because of the convenience factor, the increasing uptake of BRCA testing by unaffected women, and by the potential income source it would create for labs. Whether clinicians like it or not, some form of DTC testing will probably play an increasing role in patient care in the near future. We will need to adapt to it, even if it makes some of us feel uneasy. My prediction is that we will initially see the most significant inroads in the area of DTC germline testing for cancer predisposition gene panels that include BRCA, Lynch, and their kindred.

Another  factor that could drive DTC testing is that genetic counselors are sometimes viewed by clinicians, labs, and consumers as barriers to genetic testing. For patients, just finding the time in their busy lives for an hour long appointment and verifying insurance coverage for the consultation is no mean feat. Then there is the genetic counseling ethos of nondirectiveness and genetic counselors’ obsessive urge to (over?)educate patients, which can result in some patients coming out of the session saying No Thank You to genetic testing for now, much to the chagrin of their referring care providers. Not to mention the lack of genetic counseling manpower in some parts of the country. From this perspective, you start to understand why some critics claim there can be a reduced uptake of genetic testing when a genetic counselor is an intermediary between patient and laboratory.

Genetic counselors might cringe at the thought of patients entering the genetic testing pathway without having worked through the emotional implications, and possibly partially blind to the clinical and personal implications of positive, negative, and uncertain results. We somewhat paternalistically view ourselves as guardians of our patients’ medical and emotional well being. While genetic testing may be important for patients, at least for unaffected patients genetic testing is rarely an urgent matter. It can take place today, next week, a few months, next year, or at some point in the vague future. Perhaps that is not so terrible because a test result delivered at the wrong moment might backfire by causing the patient to go into a psychological tailspin and possibly wind up avoiding risk reducing and screening strategies. In this way, genetic counselors are more like filters than barriers, helping ensure that nobody takes a deep dive into their gene pool without first pausing and taking a deep breath.

This response may be partially and subconsciously influenced by the fact that our jobs depend on the steady stream of patients seeking genetic testing. DTC also takes away some of the “gatekeeper” power inherent in our positions. Conflict of interest affects us in ways that can make us too uncomfortable to acknowledge that it might it shape our beliefs and attitudes.

Enter DTC into this drama, stage right. If you are a patient who has a few hundred bucks to spare, you can avoid carving a chunk of precious time out of your busy schedule to set up a genetic counseling appointment (and maybe 2 or 3 appointments, depending on the provider’s policy of requiring separate appointments for counseling, test, and results disclosure), avoid those incomprehensible (non)explanations of benefits from health insurers, and with saliva testing skip the unpleasantness of a blood draw (although saliva collection has its own icky issues). Those forward-thinking online genetic counseling services that are unaffiliated with specific labs may help mitigate some of these perceived barriers, but maybe not enough for the majority of patients. DTC labs make it pretty easy to sign up for genetic testing, no muss, no fuss, never needs ironing. If I am honest with myself, in some situations – and maybe more often than I am willing to acknowledge – the “hassles” of genetic counseling may very well serve to discourage a goodly number of patients from undergoing genetic testing.

One concern about DTC is the way that labs may try to portray their tests to patients. Labs typically strive to act in patients’ best interests and try to make sure that patients get the genetic testing they need. By and large I find them to be just as committed as I am to providing excellent patient care. But at the end of the day they are businesses, and even if they have noble aspirations, it is in their best interests for as many patients as possible to undergo genetic testing. This can subtly influence their advertising under the rubrics of patient education and patient empowerment.

The best example I can think of to illustrate this point is the websites of many labs that offer cancer genetic testing, DTC or otherwise, which often cite the high end of disease risks in hereditary cancer syndromes. Labs aren’t lying to patients when they quote 80-90% lifetime breast cancer risks or whatever. But it certainly makes their genetic tests look more clinically critical than, say, the 40-50% risks found in some studies. It’s not that the 40-50% risk is necessarily closer to the “true” risk than 80-90%. The point is that there a range of risk estimates out there and which risks one chooses to present can be influenced by many factors.

Here is one lesson I have learned from ~34 years of genetic counseling with about a jillion patients: Nobody undergoes genetic testing until they are emotionally ready. Sometimes that readiness is thrust upon the patient, such as when a patient is diagnosed with cancer and has to make treatment choices fairly quickly. But for unaffected patients, some emotional triggering event(s) needs to occur before they make a genetic counseling appointment. Examples of triggering events might include reaching an age when the patient’s own parent was diagnosed with cancer or when their own child reaches the age the patient was when the patient’s parent was diagnosed; having a false positive “scare” on a mammogram; a recent cancer diagnosis in a loved one; a media celebrity such as Angelina Jolie sharing a personal cancer story; reaching a certain stage in life where, as one patient put it, “It was time to start acting like an adult” (which I suspect for many people is the incipient stages of facing their own mortality); having a grandchild; or gazing at your child one day and realizing that you might want to be around for your kindergartener’s college graduation.

If my observation about what leads patients to genetic testing is correct, it will be interesting to see if affordable, convenient, DTC genetic testing will itself become the trigger event that nudges patients into undergoing genetic testing. Would this be good or bad? Will we see a rapid proliferation of genetic testing for hereditary cancer or other syndromes if DTC testing becomes widely available? Will this translate into clinical gains that are also economically cost effective, such as increased uptake of risk-reducing surgery and high risk screening? Who will watchdog labs to assure that they offer a quality, uniform, and trustworthy product that patients can depend on without first doing in depth research about depth of coverage, variant calls, and the other arcana of genetic testing? If recent calls for cancer genetic testing for essentially everyone, such as the proposal by Dr. Mary-Claire King or Canada’s Screen Project, become widely embraced, will DTC be the most efficient way to deliver the service? Will life insurers start requiring genetic testing before a consumer is eligible for a policy? How often will untrained care providers and patients misinterpret test results? Will it turn out that genetic counselors are barriers to genetic testing or are they filters who help ensure that the appropriate patients get the appropriate testing at the appropriate time in their lives? Will genetic counselors wind up largely becoming, as I have predicted for years, phenotype counselors who meet with patients after genetic testing?

Nobody knows the answer to these questions, although a lack of data has never been a barrier to strong opinions. This is the time to plan research studies that can help address them. The genetic counseling profession needs to continuously adapt and evolve. But it needs to do so without losing its soul.

 

Thanks again to Emily Singh for help with realizing the graphics.

 

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Am I Man Or Am I A Microbe?

For several decades, it was commonly believed that bacterial cells constituted ~90% of the cells in the human body. You could casually slip this eyebrow-raising fact into a dinner party conversation or a philosophical debate about human identity and the discussion would pause while everyone chewed over that attention-grabber. If we are 90% bacteria then you could argue that humans are basically a minor evolutionary appendage to a seething microbial mass. It was humbling and downright embarrassing, from a species pride viewpoint.

However, about a year ago, researchers from the Weizmann Institute of Science in Israel re-evaluated the data and assumptions behind this eyebrow-raising factoid and poured a pitcher of cold water on it when they concluded that the number bacterial cells in our bodies was only ~30% greater than the number of human cells. Stripping this fact of most of its dignity, the authors pointed out that about 25-30% of bacteria are lost with an average bowel movement, or as they wryly commented “Indeed, the numbers are similar enough that each defecation event may flip the ratio to favor human cells over bacteria.” If that is true then I was at my most human when I underwent a colonoscopy.

But a half-human/half-bacteria hybrid evokes an image of a cheesy monster from a 1950s Grade B sci-fi movie forbidden planet that orbited around my developing childhood psyche. It was a blow to my pride in my species. I am a human, damn it, and I have my biological dignity. I am not some primitive blobby affair that obtains its food by absorbing dead organic material or some thermophile sucking sulfur from a deep Pacific hydrothermal vent. I go to a supermarket to hunt and gather my food like a man! Yeah! That’s what I’m talkin’ about! No foreign species is going to dominate my body!

The lying left wing scientific media got it wrong again. So I pondered how I might further trivialize my bacterial component and fully regain pride in my species. How could I write a scientifically based executive order using alternative biological facts that could ban all foreign species from my native body? And then I hit on the right-in-front-of-me-all-the-time ruby slippers solution: click my heels together three times for DNA, the very currency of evolution! There’s no species like Homo, there’s no species like Homo, there’s no species like Homo. So I asked myself “Hey Bob, you Wizard of Odds genetics specialist, tell me, how much bacterial DNA does the human body contain compared to human DNA?”

The Assumptions

  • The analysis of the Weizmann Institute paper is reasonably accurate.
  • I used Ecoli K-12 as the model organism. Several hundred types of bacteria reside in the human body and some have more or less DNA than E. coli, but E. coli is the predominant bacterial strain in humans.
  • The total number of non-bacterial organisms  in human – viruses, archaea, fungi – are several orders of magnitude less common than bacteria and are essentially a rounding error of the human microbial makeup.
  • The E. coli genome is fairly compact, containing little in the way of introns or non-coding DNA.
  • Each E. coli bacterium contains 4,377 genes and 4,639,221 base pairs, which I rounded off to 4.4×103, amid ~4.6×106 DNA base pairs.
  • The reference person is a 170cm tall male who weighs 70 kg (Sorry for the sexist bias here, but this is the model used in the published papers. Proportionally though, the ratios here probably apply to all genders, whichever bathroom they choose to use, except in North Carolina).
  • Per the updated estimates, the human body contains ~4×1013 bacteria.
  • Our bodies contain ~3×1013 human cells. However, per the Weizmann Institute paper, about 90% of those cells are enucleated blood cells. Thus the vast majority of cells in an adult do not contain nuclear or mitochondrial DNA. Ergo, the total number of human cells that contain DNA is on the order of ~3×1012.
  • Each nucleated diploid human cell has about 20,000 genes (2×104) and 6,000,000 (6×109) DNA base pairs (though see Addendum below). The number of haploid sperm and egg cells are small enough to ignore for these calculations.
  • The total amount of mitochondrial genes and DNA in humans is minor compared to nuclear DNA and can also be ignored for these calculations.
  • Unlike bacterial DNA, the vast majority of human DNA is non-coding, resulting in a far higher ratio of DNA to gene in humans compared to bacteria.

 

The Calculations^

What is the total number of bacterial genes in the human body?

This is calculated by multiplying the number of genes in each bacterium by the number of bacteria in the human body:

(4.4×103) x (4×1013) ≅ 1.7×1017 bacterial genes in the human body

 

What is the total amount of bacterial DNA in the human body?

This is calculated by multiplying the number of DNA base pairs in each bacterium by the total number of bacteria in the human body:

(4.6×106) x (4×1013) ≅ 1.8×1020 base pairs of bacterial DNA in the human body

 

What is the total number of human genes in the human body?

This is calculated by multiplying the number of genes in the human body by the number of nucleated cells:

(2×104) x (3×1012) ≅ 6×1016 genes in the human body

 

What is the total amount of human DNA in the human body?

This is calculated by multiplying the number of DNA base pairs per cell by the total number of nucleated cells:

(6×109) x (3×1012) ≅ 1.8×1022 DNA base pairs in the human body

 

So to summarize:

Organism Total Number of Genes In Human Body Total Number of Base Pairs in Human Body
Bacteria ~1.7×1017 ~1.8×1020
Human ~6×1016 ~1.8×1022

 

This analysis demonstrates that there are far more bacterial genes in the human body than human genes. The preponderance of bacterial genes is not significantly altered by a “defecation event” or even a colonoscopy prep. The best I can say is that any genetic superiority humans might have over bacteria comes from our “junk” DNA. Not much solace there.

To throw a little salt in the psychic wound, the human genome contains about 150 non-human genes that have insinuated themselves into our double helices. Even some of our human genes ain’t so human. A bit less than 1% of the total, but enough to strike a symbolic blow to the human ego. Homo bacteriensis, I guess. Bacteria rule.

Addendum (Added 3/19/2017)

Actually, in thinking about this for a few more days, I realized that the number of human genes in each diploid cell is ~40,000 since each cell has ~20,000 maternal genes and ~20,000 paternal genes, so the number of human genes in the body is (4×104) x (3×1012) = 1.2×1017. This is getting closer to the number of bacterial genes in the human body, give or take a few quadrillion genes. Likewise, the amount of human DNA in each diploid cell is actually (1.2×1010) x (3×1012) ≅ 3.6×1022 DNA base pairs in the human body. Bacteria, being haploid organisms, only have a single copy of each gene, except just prior to binary fission when their DNA content is doubled. So the bacteria/human differences are greater if you limit the assumption to the number of human genes, not the number of human alleles.

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Thanks to my good friend Tom Wolfe for pointing out to me the revised estimates of bacterial and human cells.

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^ – I freely admit that these calculations and assumptions may not be error free. I ran them several times and kept coming up with different answers. It has been a long time since I multiplied and added exponents. Please check my calculations .

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Are We Ready For This?

Recent advances in genetic testing technology have us poised on the brink of a new paradigm of prenatal diagnosis – prenatal screening for all genetic and chromosomal conditions. Okay, not all disorders, but lots. Non-invasive Prenatal Testing (NIPT), whole exome sequencing, and expanded carrier screening are close to being available and affordable to a large proportion of the population. This is the culmination of a trend that began with the introduction of amniocentesis in the late 1960s, followed by ultrasonography, maternal serum screening, microarrays, and cell free placental DNA in maternal serum. From a strictly technical standpoint, each technology, while far from perfect, was an improvement on its predecessors in terms of accuracy, detection, false positive rates, and the range of  detectable genetic conditions.

On the surface, this sounds like progress, and it is, in many ways. These technologies can contribute to the reduction of the incidence genetic conditions, some of which are pretty serious, a long-standing goal of medical genetics since its inception, as Nathaniel Comfort has pointed out. But technological advances often outstrip the ethical and social means with which to appropriately assess, modify, and utilize them in fair, just, and meaningful ways. So I ask these questions of the sage and thoughtful readers of The DNA Exchange: Just because we can perform prenatal screening for nearly everything genetic, should we? Who should be making this decision?

There are many competing and intertwined narratives about the history of prenatal diagnosis. Let me offer one such narrative to provide ethical and historical angles. During the 1970s and early 1980s, amniocentesis was primarily offered to women of “advanced maternal age” because of the well-documented increase in the incidence of trisomy with maternal age. At the time, in the US women 35 and older represented about 5% of the pregnant population, and this group accounted for about 20% of pregnancies with Down syndrome (this statistic has since changed considerably). While such a policy could be viewed as discriminatory and prejudicial against people with disabilities, the goal of the policy did not seem to be the elimination of genetic disability. Rather, the effect and likely the intent of the policy was to level the reproductive playing field for “older” mothers. During the 1970s, women made great strides in expanding their social and economic opportunities and in taking some measure of control over their reproductive lives with birth control and the availability of safe, legal abortion. Women could now readily attend most colleges and graduate schools, had more career opportunities, and did not feel as much social pressure to retire to motherhood after high school. However, one of the perceived obstacles for delayed childbearing was the greater risk of Down syndrome and other trisomies. Amniocentesis removed this perceived obstacle and consequently women felt freer to delay childbearing until such time as they felt that they and their partners were ready.

Over the decades, mission creep worked its way into prenatal screening. With the gradual incorporation of ultrasound and maternal serum screening into most pregnancies, regardless of maternal age, the detection rate for Down syndrome increased, and critics of prenatal diagnosis raised the specter of the theoretical elimination of all people with Down syndrome. While such an outcome never seemed likely for a variety of social, cultural, individual, and economic reasons, that could be viewed as the intent of prenatal screening. But still, aneuploidy represents only a small portion of all genetic and congenital disorders.

But it is a qualitatively different ethical story with universal NIPT and the expanding number of conditions it can screen for, the prospect of carrier screening for hundreds of genetic conditions for all couples, and talk of whole exome screening of fetuses. That is making quite a profound statement to and about people with a wide range of physical and developmental abilities.

We tacitly assume that the majority of pregnant women want such screening at the same time that we offer it to them. Many patients will  assume that because we are offering it, it must be a good thing. Because genetic counselors’ jobs can depend on the offer and uptake of such services, it affects our views and actions in ways that we often cannot fully appreciate or grasp. To some extent, we offer new testing because labs are offering it and because genetic counselors tend to be early adopters of new genetic tests. As much as we like to think that we are objective assessors of genetic technology who always put the best interests of patients first, the complicated human psyche makes for a messier reality. Our perspectives are distorted by being in the center of the storm. Go ahead and disagree with me if you want, but you are by and large wrong. That’s not me trying to sound superior; motivated blindness is a basic foundational principal of human psychology.

Psychological complexity aside, think of this. The medical profession is already doing a less than stellar job of presenting a realistic and unbiased picture of Down syndrome to parents. Remember, too, that more and more prenatal genetic testing happens without the involvement of a board certified genetic counselor and that parents are often not educated about these conditions until after they have received an abnormal test result. Not exactly the best time to seek out and weigh complicated information. Add a few hundred more conditions less common and familiar than Down syndrome, and you can see the makings of a goddamn mess.

So can there ever be an ethical justification for universal prenatal screening of (theoretically) all genetic and chromosomal diseases? Let me offer some suggestions that could serve as a starting point to address this question. One can argue that this framework or one like it should have been in place decades ago. I agree, it should have. I recognize that for people who are opposed to termination of pregnancy under any condition or for some of the staunchest disability advocates, prenatal screening will never be acceptable unless it somehow improves the lives of people with different abilities and their families. But I ask all sides to at least hear me out.

First, many parties should be involved in the discussion about wide scale prenatal testing, à la Cyprus and thalassemia screening. Prospective users, clinicians, labs, ethicists, religious leaders, legal experts, legislators, and most especially the community of people who are affected directly by the conditions in question (let me add “and others” since no doubt I am forgetting some important stakeholders). You will never get everyone to agree on all of the details, but there should be at least broad consensus about the most critical issues among the majority.

Second, more resources need to be devoted to improving the lives of people with genetic conditions and their families. Every newborn should  be able to live full, rewarding, loving, and enjoyable lives as much as humanly possible. This involves large-scale medical, technological, and social innovations and changes. Improving the social attitudes toward disability is a long, slow, frustrating journey but that should not deter us.

Third, related to the above, prenatal genetic testing should also offer some benefit people with the conditions in questions and their families, other than letting them have the same option as everyone else to terminate pregnancies. Right now, people with disabilities and their families get essentially zero benefit from prenatal screening. Or more accurately, very little research has been done to show any benefits.

Fourth, any new technology or test needs to be vetted by those who do not have a vested professional, financial, or personal interest in the technology or test. Intellectual, research, and financial conflicts of interest have ways of distorting our views in subtle ways that we are incapable of appreciating. This is extraordinarily difficult for us to understand and acknowledge (vide supra motivated blindness).

Fifth, better resources need to be developed for parents to become educated about the medical implications of genetic diagnoses, the range of developmental outcomes, the resources available to manage the condition, and the impact on families, particularly in lower socio-economic populations.

Sixth, this information needs to be provided to parents before they decide to enter the cascade of prenatal screening, not after they receive an abnormal test result. Parents have to carefully decide which if any condition(s) is important to their reproductive and family planning.

If all of these recommendations are in place, this will allow parents to make informed choices about whether or not they wish to go down the prenatal screening pathway and for which conditions. For parents who would never consider a termination under any conditions, they should have the option of screening only for those conditions for which prenatal knowledge can help the child and family, with better medical, psychological, or adaptational outcomes. For parents who have carefully weighed these issues and feel that there are certain conditions that they will choose to avoid if they can, then they should be supported in their decisions with safe, legal, and non-judgmental abortion services. For parents who are not interested in prenatal screening, they should be supported in their decision rather than being made to feel like they are sub-standard parents.

We can ignore my plea, just sit back and see what happens. But this would be a big mistake. Although genetic counselors obviously cannot address this issue by themselves, we are in the ideal position to take the lead in organizing, coordinating, and spearheading the discussion. We owe it to ourselves and to our patients.

 

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No Great Shakes

Cooties. That dread disease for which there is no effective vaccination. A microbe resistant to all known antibiotics and antivirals. A fourth biological domain – archaea, bacteria, eukarya, and cootia. Cootiensis trumpii, in formal Linnaean taxonomy, is the sole representative of this branch of life. A highly contagious cause of a wide range of medical, social, and psychological ills. The Dreaded Lurgi, to our UK colleagues and Spike Milligan fans. Etymologically, cootie may be derived from kutu, a term for a biting insect in the Austronesian language family, attesting to its pandemic nature. Cooties appear to thrive in certain foods, icky substances like mystery spills on hospital floors, and dropped food not picked up for a few dangerous seconds too long. In the sometimes cruel world of childhood, an unfortunate socially awkward child may be super-infected. During my pre-pubescent years, I was fairly certain that most girls my age were cootie hosts. My sisters sure thought I was a cootie reservoir.

cootie2

Two virulent strains of Cootiensis trumpii, viewed through an electron microscope.

Cooties may be as old as humanity. Some paleoanthropologists believe that the hand impressions common in many Paleolithic caves actually represent ritual attempts to purify the hands of cooties acquired by the ancestors of modern humans after they interacted with Neanderthals and Denisovans, who in fact may have been wiped out by a devastating cootie plague rather than having been out-competed by our early ancestors (Okay, I admit I just made that up about paleocooties and early humans. But nowadays it is apparently okay to make up facts, just as long as they serve one’s agenda.).

Paleolithic cootie purification rituals?

Paleolithic cootie purification rituals?

All of which brings me to how I greet patients at my cancer genetics clinic. About a decade ago it dawned on me that many of my patients are immunocompromised from their cancer treatment. The last thing they need is to acquire an infectious disease from me. Handshakes have long been known to be a source of microbe transfer between people. So I decided that I would stop shaking hands with my patients when I greeted them in the waiting room. After all, we are supposed to make them healthier, not sicker.

No, I don’t know the likelihood of passing along infectious disease cooties via handshake in an outpatient setting but it is probably not trivial. Yes, I use a hand gel sanitizer but many people use them inadequately. Besides, I bet all that hand sanitizing is selecting for super-resistant cootie strains. Evolution is far more resourceful and clever than we can ever hope to be. Soap and water may be more effective than alcohol gels in eliminating microbes but, honestly, how many of us will sing “Happy Birthday” twice while thoroughly soaping up between genetic counseling sessions? No, I am not a germophobe. Regular exposure to microbial organisms is a good way of keeping my immune system cocked and loaded. Yes, my hospital has policies on minimizing contagion in out-patient settings. For example, the plants in my office must be a minimum distance from patients.

The potential cootie host in my office.

Which is why it strikes me as odd that guidelines do not include a hand-shaking ban; my guess is that hand clasping is at least as likely a source of nosocomial infection as the big old plant in my office. On top of that, many employees come in to work when they are sick with some crud, trying to be conscientious, not inconvenience co-workers, and not screw up patient schedules. “Oh, it’s just a cold and I am past the infectious stage, I am sure” they will unconvincingly say between coughing fits. The road to an office-wide flu epidemic is paved with their good intentions. And not uncommonly there are unstated conflicting tensions between hospital policies encouraging employees to use their sick days and the attitudes of mid-level management who seem to view sick days as abuse of a privilege bestowed by God and only to be used when you are near death or beyond.

I recognize the social importance of the handshake in establishing a trusting relationship between strangers. So I have replaced it with a simple wave and a pleasant smile, which is probably at least as socially effective and friendly as a handshake. Some patients look at me quizzically when I state my no handshaking policy. However, the vast majority become very appreciative of the policy once I explain its basis and most people say “That’s a good idea. I wonder why most healthcare providers don’t do it?” Good question. I think it actually enhances the trust between provider and patient, and communicates that I care about them far more concretely than those hospital advertising slogans that proclaim patients always come first. And for patients who still think I am peculiar after my explanation, well, tough noogies, as we used to say when I was a kid (extreme situations called for the more forceful “Tough noogies on your boogies!”).

Call me old-fashioned, but other forms of greeting, like the fist bump or its two-knuckle modified version called a cruise tap, seem inappropriate in the hospital setting and still involve some degree of skin-to-skin contact. Wearing gloves to shake hands would be just plain old wrong. There are other greetings that do not involve skin contact – the wai in Thailand, eyebrow flashing, sticking out your tongue (Tibet), the Japanese bow, the namaskar of India, the  jumping greeting dance of the Maasai, or particularly among men in Western cultures, that barely perceptible slightly angled up-tilt of the head between two bro’s who sort of recognize each other. But unless you work primarily with specialized patient populations, the regular use of such greetings will probably only lead to awkward misunderstandings between clinicians and patients.

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Inspector Clouseau (wanting to know if your dog bites) and Professor Quincy Adams Wagstaff (addressing the faculty of Huxley College) were both frequent users of the flashed eyebrow greeting.

I admit that it felt odd when I first started my no-handshake policy. I sometimes held my hands behind my back to fight the instinctive urge to shake hands. Deeply embedded cultural practices don’t disappear overnight. But after a few months, it became quite natural and I found myself recoiling in concerned surprise when I would see other providers shaking hands with patients. I have even begun minimizing handshaking outside of work; there is always “that bug that’s going around” that I prefer to avoid if I can. The no-handshake policy should not be limited to the cancer clinic. We need to minimize the risk that any patient will get sick from a visit to a medical office, whether or not they might be immunocompromised. No one deserves the cooties!

no-germs

Thanks yet again to Emily Singh for help with graphics

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What Is Genetic Counseling?

Until recently, I have felt pretty comfortable calling myself a genetic counselor. I have a graduate degree in genetic counseling, passed a long and difficult certification exam, and I am licensed by the great state of Washington to practice genetic counseling. It’s on my business card, the directory of my office building, and it is my official job title. I have been providing genetic counseling to patients for 33 years. I had not lost a wink of sleep worrying over what to call myself until about two years ago when I started to develop a nagging identity crisis when, on this very web site, my fellow DNA Ex’er Allie Janson Hazell suggested that maybe it is time to re-think if we should be calling ourselves genetic counselors. It was a minor itch at first. But now it’s grown into a persistent problem that I can’t stop trying to scratch, like the mysterious treatment-resistant, psychologically rooted foot disease that afflicted the John Turturro character in the recent HBO mini-series The Night Of.

But let me pose the question differently than Allie did. Why give up a good and beloved name? And I don’t even want to begin to think about the bureaucratic nightmare of rewriting state licensure laws. Instead, maybe, just maybe, it is time to debate whether we should redefine genetic counseling and the genetic counselor’s scope of practice. After all, genetic counseling is what genetic counselors do. If many of the daily activities of genetic counselors are not captured by the current definition of genetic counseling, then perhaps it is time to rethink it.

I acknowledge some personal resistance and intellectual conflict of interest – fellow DNA Ex’er Michelle Strecker and I were part of the National Society of Genetic Counseling Task Force that wrote the modern definition of genetic counseling in 2oo5 and published in 2006 (the first formal definition was published by the American Society of Human Genetics in 1975 ):

Genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This process integrates the following:

• Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence.

• Education about inheritance, testing, management, prevention, resources and research.

• Counseling to promote informed choices and adaptation to the risk or condition.

 

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I like that definition, with its integration of clinical, educational, and, most critically, psychological aspects of genetic counseling. I am not sure I want to see it relegated to a historical footnote. Paradoxically, it could be that I am subconsciously trying to unconvince myself about the need for a new definition as much I am trying to convince the blog’s readership that it is time to consider updating it.

But I have to admit that maybe the modern definition is not so modern anymore. Genetic testing has become, in some instances, downright cheap. Everybody and their cousins are offering genetic testing. You can even obtain genetic testing, for all intents and purposes, without the involvement of a physician, genetic counselor, or any other health care provider. Roughly one in five genetic counselors works in a laboratory setting. Genetic counselors work as test interpreters, policy advisors, genetic ancestry specialists, insurance advisers, laboratory managers, account managers, sales staff, mutation database curators, laboratory liaisons, report signers, educators, and researchers. There are probably genetic counselors who are performing activities that I can’t even think of or grasp. Although for now we are still largely anchored in the clinic, we are drifting on a professional tide away from it. The definition probably still reflects the activities of many genetic counselors, but it also may not capture what a lot of genetic counselors do in their practice.

Here is the scope of practice for genetic counselors from the website of the National Society of Genetic Counselors (a more detailed listing of genetic counseling competencies can be found at the Accreditation Council For Genetic Counseling):

Genetic Counselor Scope of Practice:

a) obtain and evaluate individual, family, and medical histories to determine genetic risk for genetic/medical conditions and diseases in a patient, his/her offspring, and other family members;

b) discuss the features, natural history, means of diagnosis, genetic and environmental factors, and management of risk for genetic/medical conditions and diseases;

c) identify and coordinate genetic laboratory tests and other diagnostic studies as appropriate for the genetic assessment;

d) integrate genetic laboratory test results and other diagnostic studies with personal and family medical history to assess and communicate risk factors for genetic/medical conditions and diseases;

e) explain the clinical implications of genetic laboratory tests and other diagnostic studies and their results;

f) evaluate the client’s or family’s responses to the condition or risk of recurrence and provide client-centered counseling and anticipatory guidance;

g) identify and utilize community resources that provide medical, educational, financial, and psychosocial support and advocacy; and

h) provide written documentation of medical, genetic, and counseling information for families and health care professionals.

Some of the core questions and issues are, as I see them:

  1. Do the definition of genetic counseling and the scope of practice accurately reflect what goes on in clinics and in other work settings?
  2. Should the definition be broadened such that the very act of genetic counseling incorporates some of the newer activities of genetic counselors? This would suggest that the definition of genetic counseling could include some practices that are not involved with direct patient interaction.
  3. Is the definition still adequate but the scope of practice needs to be reworked? Or is the scope of practice adequate but the definition needs some sprucing up?
  4. How do we not lose sight of the psychological component to genetic counseling?
  5. Distinguishing between genetic counselors (roughly equal to the scope of practice) and genetic counseling (roughly equal to the definition).
  6. Remembering that genetic counseling ≠ genetic testing.
  7. Any definition will have an implicit ethos that needs to be carefully considered. The current definition is clearly centered on the psychological and physical well-being of patients.

Perhaps it is time to create another task force to address these questions and issues. I second Allie Janson Hazell’s suggestion that any such group should be international in scope; North America does not have a monopoly on genetic counseling. Of course, that could lead to an ungodly large committee; Resta’s Rule Of Committees is that a committee’s effectiveness is inversely proportional to its size. Decades of experience have taught me that the maximal effective committee size is five (no, I did not arrive at that number by a rigorous scientific process; it’s just a natural fact revealed to me in a trance one day).

I suggest a tiered process. A small task force, ideally international, investigates these questions and issues, and if the definition and/or scope of practice are found wanting, then they draft a new definition and/or scope of practice. This would then be passed on to a larger committee consisting of several representatives of the major international genetic counseling organizations, who could then choose whether to pass it on to their larger membership for comment.

The task force should include a clinical person, a lab person, and two or three other genetic counselor specialties. Grizzled veterans like me should be kept off this committee. We may unknowingly be too caught up in the old vision, too self-convinced that dammit, we do genetic counseling the right way. This project needs counselors who are early mid-career to late mid-career, the group who are the natural successors to us silverbacks, ancient shamans, and village elder wise women.

The scope of practice does not have to be particularly terse. But the definition should not be too wordy; think of how convoluted and awkward the old ASHG genetic counseling definition was. The current definition is about the right length, and, practically speaking, the definition can stand on the first sentence alone without the bullet points below it. I think that it is a tough act to follow, but sometimes the show must go on.

Oh, and while they are at it, they really should consider changing the wording to the more grammatically correct genetics counselor and genetics counseling. And let me interject another curmudgeonly opinion. I think that there are valid points made by both sides of the “Are they patients or are they clients?” debate, and I personally go back and forth freely. But I pray to God that we never use the phrase “consumers of genomic medicine.” I don’t care what you tell me about the business side of genetics and medicine; we should never label people as primarily income generating entities.

What do the Good Readers of The DNA Exchange think about this? Complete the very unscientific poll below, and share your thoughts in the Comments section.

The NSGC Annual Education Conference – only 2 weeks away – will be an ideal venue to further this discussion. And speaking of the AEC, note the announcement just below the poll about an opportunity to meet some of your favorite DNA Exchange bloggers at the upcoming Annual Education Conference in Seattle.

 

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GCs Got Talent! A Genetic Counseling Talent Show/Benefit For The Genetic Support Foundation At The NSGC Annual Education Conference in Seattle Friday, September 30 at 8:00 PM

An Evening of Music, Comedy, Dance, Storytelling, Arts and Crafts As Performed By Our Very Own Genetic Counseling Colleagues

Meet Some of Your Favorite DNA Exchange Bloggers, Judges Laura Hercher & Michelle Strecker, And The Evening’s Emcee, Yours Truly, Kool Papa Bob!

gcgottalent_final

rap-boy

 Illustrations by genetic counselor Dena Goldberg – “Dena DNA

Do you have a good story to tell or a talent to put on display? We would love to hear from you. There are still a few slots available. Story tellers and performers should email talent@geneticsupportfoundation.org to learn more.

 

For more information about the event, and ticketing, visit https://www.geneticsupportfoundation.org/gcs-got-talent-the-comic

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Miracles, Monsters, And Do-Re-Mi: A Variant Cultural History of The Word “Mutation”


None of us can cast stones for we are all fellow mutants together.

– Herman Muller (1950)

Until relatively recently, mutations were thought to be uncommon events that irregularly popped up around the genome, save for a few hotspots here and there. Unless exposed to a mutagen, DNA was conceptualized as a fairly stable molecule and the individual genome tolerated only a limited amount of variation. But large-scale DNA sequencing has demonstrated that gene mutations are pretty much the norm rather than the occasional exception. For example, a recent as yet unpublished study by Craig Ventner’s team of 10,545 deeply sequenced  human genomes found that each genome contributes on average 8,579 novel variants and uncovered more than 150 million variants in the coding and non-coding regions. If you run a complex genetic test and you don’t find a mutation of some sort, then there is probably something wrong with your sequencing technology. Of course, not all gene mutations are bad. Some are disease associated, some may confer biological advantage, some are neutral, and some are difficult to pin down. Differentiating among the good, the bad, and the neither-good-nor-bad has become a bête noire for anyone faced with interpreting the clinical significance of genetic test results for patients, especially when classifications differ among labs.

Although the word mutation carries some potently negative connotations, its definition implies objective scientific neutrality – “An alteration in the nucleotide sequence of DNA,” in its simplest form. But of necessity this is only a recent, post-Watson and Crick wording that itself has mutated over the centuries and that has often had some not-so-neutral musical, psychological, biological, pop culture, sociological, and religious ramifications. A hop, skip, and a jump through the history of the word reveals the richness and variety of its usage – as well as its darker sides.

According to the Oxford English Dictionary, one of the earliest recorded occurrences of the word goes back seven centuries to – who else? – Chaucer who used it in the sense of a change or alteration and whose Middle English rendered it as mutaycouns (“mutaycouns of fortune” from his translation of The Consolation of Philosophy by the Roman philosopher Boethius). Shakespeare used it similarly when, in King Lear, Edgar cries that the misfortunes of fate shorten our lives “World, World, O World! But that thy strange mutations make us hate thee, Life would not yield to age.”

Mutation was also used to describe the key Catholic belief in the transubstantiation of bread and wine into the body and blood of Jesus Christ during the sacrament of Communion. In the 1426 translation by John Lydgate of the French Cistercian monk Guilaume de Deguileville’s Pilgrimage of the Life of Man, a popular devotional book of the Middle Ages, we read about “That marvelous mutacion, Bred into flesshe, wyn into blood.”  This “marvelous mutacion” is a critical distinction between Protestant and Catholic theology, two religions that seemed to be at war with each other for most of the Middle Ages. Catholics believed that the Eucharist wafer dipped in wine transubstantiates into the actual body and blood of Christ whereas Protestants viewed it as a symbolic and ritual re-enactment of the Last Supper. Presaging future genetic connections between monsters and mutations, Martin Luther referred to transubstantiation as “a monstrous word for a monstrous idea.” During my Catholic school years, I remember joyously singing “Eat His Body, Drink His Blood, and we’ll sing a song of love. Allelu-Allelu-Alleluia!” Leonard Cohen does not have a thing over the Catholic hymnal.

Musically, mutation is the exchange of one syllable for another in an ascending note scale, as in solmization, i.e., associating a musical note with a human sound. Think do-re-mi-fa-so-la-ti-do. Mutation is also used in music to describe changes in singing voice that occur with age and gender, particularly the change that occur in boys’ voices as they transition to puberty, much to the chagrin of many choirmasters of Medieval Europe’s churches (a curiously coincidental link between religion and mutation). Choir boys were faced with a Sophie’s Choice of either genital mutilation or mutation.

Mutation also bridges musical and genetic definitions when DNA sequences are transformed into musical notes. For a couple of hundred bucks you can upload your 23andMe DNA sequence and have it translated into a piano solo, dance music, or a fully scored orchestral work. It’s a little bit funny, but the thing is what I really mean is that it gives new meaning to Elton John and Bernie Taupin’s 1970 hit single Your Song. As a leading candidate for the award of The World’s Worst Dancer, my daughters shudder to think what my DNA would sound like if it were translated into dance music and performed in public. No doubt it would contain many nonsense mutations although my daughters would hope it contains a very early premature stop codon. In a darkly comic coincidence that bridges modern music, Herman Muller’s above quote, and DNA, the musician Frank Zappa named his official fan club United Mutations, supposedly after reading his weird fan mail (think of how unusual the mail must have been if Zappa found it strange). And in another odd connection between mutation’s musical and biological connections, Zappa sounded like Darwin when he proclaimed “Without deviation from the norm, progress is not possible.”

The earliest reference I could find to the use of the word mutation in the context of evolution was in the 1869 publication Die Formenreihe des Ammonites subradiatus by Wilhelm Heinrich Waagen, a German paleontologist and geologist (no doubt somebody used the word before Waagen; there is always somebody else who was “really the first”). Based on his observations of fossil ammonites in the Punjabi Salt Range, Waagen proposed that evolution occurred slowly through minute mutations in a definite direction and that could be observed by careful examination of successive fossil strata, resulting in the eventual emergence of new species (though I think  he was thinking of mutations as anatomic rather than strictly genetic phenomena). Waagen was a devout Catholic who opposed Darwin’s evolutionary model and who tried to reconcile the fossil record with Genesis, suggesting that new species arose through new acts of divine creation

Mutation in its more modern sense arose with the re-discovery of Mendel’s work by de Vries, Correns, and Tschermak-Seysenegg and the flowering of modern genetics and evolutionary theory in 1900. de Vries in particular emphasized the importance of mutations to evolution in his magnum opus The Mutation Theory (1901-03). Gene mutations were now understood to be the engine that drove evolutionary change and chromosomes were thought to somehow carry genes. But the physical nature of mutations remained a mystery that was not resolved until the early 1950s when Alfred Hershey and Martha Chase identified DNA as the “hereditary material” and Watson and Crick famously resolved the structure and self-replicating mechanism of DNA.

Mutations could be adaptive or non-adaptive, though the presumption was that most mutations were evolutionary dead-ends and natural selection genetically purified the population (one can see the natural jump to eugenic ideologies). Creatures that were very different from their contemporaries presumably from underlying gene mutations were sometimes called, in the vocabulary of Richard Goldschmidt, “Hopeful Monsters,” evolutionary opportunities for saltatory speciation through chromosomal level mutations (Hopeful Monster and Hopeful Monsters are also the names of two different musical bands, as well as the title of 1990 novel by Nicholas Moseley). Others thought that hopeful monsters were only hopeful ideas and that speciation occurred through a more gradual dynamic balancing of winnowing and selection of small effect mutations.

Early 20th century eugenicists took the notion that mutations were largely negative and ran with it down some dark ethical alleyways. The “defective germ plasm” of immigrants from anywhere other than certain parts of northern and western Europe, people dwelling in the lower socio-economic rungs, the feeble-minded, and other undesirables made them genetic threats to the hereditarily healthy population. The solution to avoid becoming awash in defective germ plasm was to coercively or non-coercively discourage such genetic riff-raff from producing offspring. Eugenicists also encouraged genetically desirable people to have more offspring but such genetic hopefuls were not said to carry good mutations, just good genes.

The early 1930s saw the introduction of the far more neutral term allele, derived from allelomorph, which was itself introduced in 1902 by William Bateson, who also gave us the word “genetics.” Essentially alleles were versions of the same gene that differed on a DNA level. Although allele is in genetic publications, it has never really entered into the wider public vocabulary and discussion around genetic variation.

The geneticist Herman Muller had a career-long interest in genetic mutations, starting with his work with Drosophila in Thomas Hunt Morgan’s Fly Room at Columbia University and continuing with his Nobel-winning work on radiation induced mutations. His work, perhaps more than any other, was critical in the development of the idea that mutations were primarily harmful. In his influential 1950 American Journal of Human Genetics paper “Our Load of Mutations,” he viewed mutations as a “load” that the human species had to bear. However, he thought that most mutations were only slightly disadvantageous, and that each of us carries 8 slightly harmful mutations. Each mutation carried a selective disadvantage of 2.5%, and thus on average each person has a 20% chance of death or reproductive inefficiency as a result, under the assumption that humans were still living in the Neolithic. Muller worried that the comforts of the modern world allowed more maladaptive mutations to survive and increase, and that environmental exposure to ionizing radiation increased the frequency of  new mutations. This problem could be ameliorated by reducing the amount of man-made ionizing radiation and discouraging reproduction among those who carried the most mutations, “only” 3.5% of the population in his reckoning. Theodosius Dobzhansky served as a counter-point to Muller, arguing that variation was mostly adaptive and we should embrace the social and genetic diversity brought about by mutations (Muller’s paper and his disagreements with Dobzhansky are thoughtfully discussed in historian of biology Diane Paul’s 1987 paper “Our Load of Mutations” Revisited and is my primary source here).

Thus until about 60 years ago, with a few exceptions, mutations were largely viewed as having negative effects, while recognizing that some portion must be positive to allow adaptation and evolution to occur. Other than synonymous mutations in which the amino acid sequence is not altered, the notion that a mutation could have no phenotypic effect was not seriously discussed because mutations could only be inferred by their phenotypic effects. But in the 1960s, Motoo Kimura, among others, suggested that, based on studies of protein evolution, the rate of nucleotide substitutions was so high that it was difficult to believe they all had a positive or negative phenotypic effect. He felt that most mutations were neutral, that is, they have no measurable phenotypic effect and genetic variations among populations were largely the result of genetic drift, influenced by population size and dynamics. Mutations are like algae floating in the gene pool, pulled by the stochastic and unpredictable tides of populations

In Pop Culture, public fear of mutation arose in the context of the post World War II threat of nuclear war and the potential subsequent widespread exposure to ionizing radiation. Mutants in the public conception were typically monsters or super-humans with special powers that could be a blessing and/or a curse. Godzilla, The X-Men, the backwoods Southerners of  Deliverance, certain zombies (though apparently there are some finely nuanced arguments about the distinction between mutants and zombies), Spiderman, and the Hulk all owe their unique characteristics to mutations induced by radiation or inbreeding. For the most part, you don’t want to be these creatures. While it would be pretty cool to web-sling through the upper reaches of Manhattan’s skyscrapers, hulk-out to frighten off bad guys, or maybe even level a city or two, the message is almost always that being a mutant comes with the Faustian price of giving up the soul of your humanity. In conversation, to label someone a mutant is to suggest that they are very different, and usually in not such a good way. Even when used in a sort of positive context to describe super-athletes who seem to function on a different level than their competitors such as LeBron James, Diana Taurasi, Babe Didrikson Zaharias, Babe Ruth, Wayne Gretzky, Florence Joyner, Michael Phelps, or Diana Nyad, its use suggests that they are a different species from the rest of us, “freaks of nature” (ironically echoing the centuries old terminology “sports of nature” to describe biological specimens whose anatomy deviated significantly from the species type).

Not surprisingly, for many patients in genetics clinics, discovering that they carry a mutation, even in a recessive form, can be a narcissistic ego blow and affect desirability as a mate. If you carry a mutation you are implicitly a mutant. Connotations of the word mutation contribute to fears of having children with disabilities. Currently in medical genetics, and probably for the better, mutation is falling out of favor and there is a trend to replace it with a more neutral, or least less negative, terminology. Mutations are now described as variants that are categorized by qualifiers – benign polymorphism, uncertain significance, deleterious/pathogenic, etc. Although this nicely delineates the multiple effects and uncertainties of mutations, it doesn’t necessarily suggest that carrying a mutation is a good or normal state of affairs. And carrying a pathogenic variant, even a likely pathogenic variant, usually doesn’t make you feel too good about yourself when you wake up each morning and look at yourself in the mirror.

Mutations also cause much fretting and hand-wringing on the societal level. Witness the controversy around genetically modified organisms and worries that Frankenstein-like plants or animals will take over the environment like some real-life mutation, er, variant, of Day of The Triffids. Even CRISPR-Cas9 and other gene editing systems, which are intended to fix mutations, are criticized because of fears that they may unknowingly induce undesirable mutations in non-targeted parts of the genome.

At the end of the day, mutations are part of our biological identity. They are literally etched into our DNA, although we would be ignorant of the existence of most of them in the absence of DNA sequencing technology. None of us are Wild Types and all of us are Wild Types. We should embrace mutations, not reject them (well, at least most of them). Mutation is the norm for life, not the exception. Despite their typical neutrality, fear of mutations has been used to justify religious wars, castration of pre-pubescent boys, sterilization of the “unfit,” and to engender deep-rooted psychological fears in parents and in societies. Muller and Zappa were both right – we are all mutants and we should be united. But it turns out that being a mutant is usually not such a bad thing.

For an excellent short review of the concept of mutations in the history of biology, see Mutation: The History of An Idea From Darwin To Genomics by Elof Axel Carlson, Cold Spring Harbor Laboratory Press, 2011. Once again thanks to Emily Singh for help with graphics. 

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