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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FDA and 23andMe change their Facebook status to ‘in a relationship’

In 2007, 23andMe launched their personal genome scan, a SNP-based test that offered consumers an estimate (some might say a guess) as to how certain elements of their genotype might contribute to their likelihood of having an array of traits and diseases. It was a great success, if success was to be measured in ink and column inches rather than actual dollars. Anne Wojcicki’s company quickly came to represent the embodiment of direct-to-consumer genetic testing, an icon of what was more a movement than an industry.

 

For that reason, six years later, when the FDA surprised 23andMe with a cease and desist order for their genome scan, it could reasonably be taken as a rejection of not only one company but the entire DTC ethos. At the time, many canny observers pointed out that the FDA’s drastic move seemed to have more to do with 23andMe’s attitude than it did with any specific risk posed by testing. As Duke University genetic professor and trenchant observer Misha Angrist was quoted as saying at the time, the FDA missive read “like the letter of a jilted lover…‘We went on fourteen dates! We exchanged all these e-mails! We held hands in the park! Now you’re telling me, “Fuck you,” and kicking me to the curb.’ ”

 

In response, a chastened 23andMe kept a toe in the DTC puddle by offering testing for ancestry and non-medical traits like sleep patterns and eye color while negotiating a slow courtship of the regulatory body. Eventually they got flowers back from the FDA – or rather a single flower, permission to offer just one carrier test, for the aptly named Bloom syndrome. But this blossom, like many others, was freighted with greater significance, and now that they were friends again the FDA decided that other DTC carrier tests would no longer require individual premarket approval, allowing 23andMe to add back a layer of medical testing to their business model.

 

The FDA drew a line between giving out information on carrier status (okay) and giving out information that was diagnostic (not okay). This created the odd situation where 23andMe could tell a customer if he or she had, for example, one CF-causing variant but was forbidden to inform them if they had two, since that was a presumptive diagnosis. Let’s leave aside how confusing this all gets, since sometimes people can have two disease-causing variants and remain healthy, and sometimes carriers can have medical complications. I’m not even going to mention that. See how I didn’t mention that? The bottom line was that 23andMe could inform you of a risk for something that might happen, but only if it was a mere possibility and not if it was certain or highly likely.

 

Two years later, the FDA has come out with another announcement – this time I assume that 23andMe is less surprised than the rest of us – that will expand the universe of what is available through DTC testing. The company will now be allowed to provide testing for susceptibility to 10 diseases and conditions with significant health implications, including late-onset Alzheimers disease, Parkinson’s. celiac, Gaucher’s disease type 1, hemochromatosis, and others. Again, this isn’t just a bouquet of flowers being handed out to a patient suitor. It signifies a change in thinking at the FDA about the value of DTC genetic testing, which they noted in their press release “may help to make decisions about lifestyle choices or to inform discussions with a health care professional.”

 

No but really this is getting embarrassing get a room you two.

 

The FDA announcement indicated that these 10 diseases were merely a beginning. In the future, 23andMe and other trusted practitioners will be able to introduce tests with less regulatory scrutiny. The FDA’s commitment to a streamlined and less burdensome process demonstrates a new interest in making DTC genetic testing widely available.

 

The important thing, emphasized Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health, was that consumers did not come away believing that genetics was destiny. “…it is important that people understand that genetic risk is just one piece of the bigger puzzle, it does not mean they will or won’t ultimately develop a disease.” For this reason, the FDA has doubled down on it’s practice of differentiating between susceptibility and diagnosis.

 

Conceptually, this makes sense. Practically, in some cases, it creates a situation where DTC customers can access the sort of probabilistic information that we are generally loathe to give out in a clinical setting – like their chance of getting late-onset Alzheimer’s disease – but are blocked from getting exactly the sort of definitive, actionable information we value the most.

 

Possibly, this might serve to differentiate the realm of DTC testing from the kingdom of clinical medicine. Genetic counselors, often DTC skeptics, might feel more comfortable adopting a live and let live approach if areas central to GC practice like susceptibility for cancer and heart disease were reserved for the clinic. Still, when it comes to ApoE, it is a bit of a paradox that the solution to information deemed too hot to handle by counselors is to give it out with no counseling at all. The impact, I am inclined to believe, will be to speed the integration of probabilistic testing into genetic practice. In the meantime, it will almost certainly herald a period of rapid expansion of health and wellness testing in the DTC space.

 

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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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Will H.R. 1313 Allow Wellness Programs to Undermine Your Rights Under GINA? Inquiring Constituents Want to Know…

It’s 2017, and it’s hard to keep track of the reasons to be outraged, but here’s one with special relevance to the genetics community: H.R. 1313, the Preserving Employee Wellness Programs Act (alternatively entitled H.R. 666, the Unfortunate Erosion of GINA Act).

There are two main questions we should be asking about H.R. 1313. One, what does it do? And two, why does it exist? For the first, what the law would do (if passed) is allow so-called wellness programs to circumvent the limitations on data collection by employers set out in the genetic non-discrimination act (GINA) and the Americans with disabilities act (ADA). I say so-called wellness programs because in point of fact they have not generally been demonstrated to make people, shall we say, well-er. Which raises the question of why Congress is so keen to make sure they are maintained, but we will get into that later.

Under GINA, employers are not allowed to purchase, request or require genetic information from their employees. The assumption behind this point of law is that employers who had that information might be tempted to try and reduce their exposure to risk by discriminating against those in their risk pool (or their dependents) with increased susceptibility. Alternatively, they might try and use genetic information as a part of decision-making about promotions or assignments. Some of the people attacking the bill have pointed out that attempts to use predictive genetic information are at present likely to be absurdly ineffective and misguided, but this only makes the acts of discrimination more random, not more (or less) nefarious. If they could do it with pinpoint accuracy, it would still be unfair.

Exceptions for wellness programs already exist under GINA, to allow these programs to ask the participant about genetic conditions or genetic testing. As the law stands, the employee must participate voluntarily, and individual identifying information must be collected by a licensed or certified health professional (including, specifically, a genetic counselor) and cannot be shared with the employer except in the aggregate. As for voluntariness, H.R. 1313 would alter this dynamic by sleight of hand – employers are not allowed to charge people more for insurance if they don’t participate, but they are allowed to offer incentives for employees who do participate, and those incentives can be up to 30-50% of their total healthcare contributions. Got that? We’re not charging you more, people who don’t give us your genetic information, we are simply charging the other people less.

 (Sidebar: perhaps we can get corporations to introduce wellness programs that require employees who participate to vaccinate their kids, while the ones who do not pay thousands of dollars more per year in health insurance costs. Vaccines, after all, are the best validated wellness program that we have. Just a thought.)

 The second and most serious charge that has been made about H.R. 1313 is that it would eliminate privacy protections that exist under GINA, and give your employer access to genetic information about employees and their family members. This has been reported in a number of places (in the NY Times here and in STAT here) but is disputed by the NSGC fact sheet circulated on, forebodingly, the ides of March. The bill doesn’t refer to the issue of sharing genetic information specifically, and it seems reasonable to assume that those protections you have under GINA would be in force unless specifically taken away, HOWEVER, there’s obviously room for doubt, given all the doubt. Take home point: the bill should be amended to include a clear message that genetic information is private and cannot be shared with employers (or, for that matter, sold – as commonly happens with wellness programs today).

Which brings me to my second question: why does this bill exist? Identifying the beneficiaries might shed some light on what it is intended to do. Employers might like the bill, if they see it as allowing them to shift health care costs to non-participants via the incentive system (lower costs for some being alternately described as higher costs for others). If we are being pie-eyed optimists, we could imagine that employers are just determined to see you healthy, although in that case they might be put off by the absence of any compelling evidence that these programs work. If we are being conspiracy theorists, we might wonder if some employers see an opportunity to obtain information on the health and health risks of employees and their dependents to which they are denied access under GINA.

Obviously the law is a boon to the ‘wellness’ industry, which Congress is nurturing with this sack of high quality manure while asking in return only that the wellness program not be “highly suspect” as a method to “promote health or prevent disease.” Ah, the old, ‘not highly suspect’ standard.

Perhaps, say you, another beneficiary of the law is the employee who receives a rebate for being healthier. Yes. I’m all for lower health care costs. But since the wellness programs don’t actually make employees healthier, but may identify employees (and their dependents) with more health risks, their benefits come by chasing people who need insurance out of their insurance pool. Companies could keep their own overall costs the same by dropping everyone’s premiums by some intermediate amount, which would help all employees with the added benefit of not being a human rights violation. Food for thought.

On March 8th, the American Society of Human Genetics (ASHG) came out with a strong statement opposing H.R. 1313, quoting director of science policy Derek Scholes as saying that “If enacted, this bill would force Americans to choose between access to affordable healthcare and keeping their personal genetic and health information private….Employers would be able to coerce employees into providing their genetic and health information and that of their families, even their children.”

The response from NSGC has been more nuanced, prefacing a statement on their concerns about H.R. 1313 with the caveat that “NSGC supports the collection of family health history information.” Without taking an official position on the bill, NSGC has indicated concern about voluntariness and privacy protections, proposing that in its final version, “the bill should explicitly reaffirm the GINA discrimination protections, roll back penalty language altogether, and limit rewards, among others. NSGC would also support further study of the value of wellness programs, and their focus to ensure the programs can indeed positively impact health.

Privately and publicly, I have heard comments from members of the genetic counseling community who are concerned about H.R. 1313. This bill has gathered a fair amount of negative attention and there is a good chance it does not move forward, at least not in its current form. I don’t say this to discourage grass roots activism; in fact it’s the opposite – evidence suggests that public pressure is having an impact. So call your Member of Congress! (we all have our elected representatives on speed dial by now, right?). Here’s a quick summary of three points worth making:

  1. Participation in any program that includes gathering genetic or family health history information on the participant and/or family members should be truly voluntary, and should not be associated with substantial rebates or incentives.
  1. Wellness programs should be explicitly required to conform with the privacy protections for genetic and family health history information that have been established by GINA and the ADA. Congress should pass no laws that erode or diminish these important civil rights protections.
  1. Laws creating special exemptions or accommodations for wellness programs should include a standard for wellness programs based on an objectively assessed, documented record of improved health outcomes.

 

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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.

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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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