If you're a non-vasectomized man, there's a small-but-real chance this little sobriquet will be the most important thing you will ever read while at work. 

Life is about avoiding traps. Avoiding setbacks matters quite a bit, maybe even more than taking steps forward vis-a-vis accomplishments. This is because traps can be HUGE. Make one bad decision about texting and driving and you can find yourself in prison for ten years, only to emerge with a felony on your record. Same for the poor bastard in South Carolina who was put on a sex offenders watch list for the rest of his life after being convicted of public indecency after urinating outdoors. 

Other traps are more pernicious. Some of them can go off without you doing anything wrong per se. To illustrate this, I'd like to share one of my favorite scientific papers. In 2005, Mark Bellis and Co. published a review article (an article that summarizes other original research) on the rates of parental discrepancy. In it, they review virtually every study that's been conducted that aims to answer one simple question: how often is a man caring for a child that he believes is his but, in actuality, is not?

Drum role please... the answer is about four percent, with a confidence interval of 2.7 to 9.6 percent (that means there's a 95 percent chance of the actual number being in that range). 

Frighteningly common, yes? Reading the paper, it seems that the authors (in my opinion) are very, very conservative in their estimate. They toss out studies where a child's true paternity is is suspicious, as well as a few other findings that skew high (incidentally, if you suspect the kid ain't yours, there's a 30 percent chance you're right). The number of "misattributions" seems to fluctuate with societal conditions; one German study taken right after the wall fell found that about 10% of German dads from that period were cuckolds. 

What's the point?

Let's skip/avoid the bitter mysogynistic rant. Men lie. Women lie. Men can be promiscuous douchbags, so too are women. There's a long history of this; the first well-documented example of misattributed paternity I can think of goes back all the way to forty weeks before 0 BC. 

But I digress. The point is, no one seems to care that this is going on WITH REGULARITY. This study was covered by shockingly few members of the media and it is BAFFLING why not. This is a public health problem that affects more young people than virtually any other disease, I reckon.

The other thing is how little people seem to mind the type of inherent blatant dishonesty that this article reveals. Unknowingly saddling a man with a child that isn't theirs seems, to me, one of the greatest injustices you can perpetrate on another person. I think most of us are familiar with objective studies of the emotional, physical and financial costs of parenthood (for those of you who are not, having children has one of the strongest, long-lasting impacts on happiness). To yoke someone into what, for most, is a sort of prison seems unfathomably evil. And yet there's this ill-defined blase attitude that it's somehow unimportant who the father is, because it's all about the child. For that, a man is punished merely for choosing poorly in his choice of mate. Trap, indeed.

For that reason, I propose something that would piss every mombie off: I recommend every man discreetly use the magic of genetic testing to check/confirm whether your kid is actually yours. Even if you like/love the kid, you should be aware of your partner's issues with fidelity. If I ever have a kid, you can be damn sure I'll be doing it. Trust, but verify.

One other thing...

I mentioned earlier that there's this vague favoritism towards the mother when it comes to parental misattribution. Here's a concrete example of it.

Let's explore a hypothetical situation: Imagine you're a man with a kid who's born with autism. Concerned, you take yourself, wife and newborn son to a genetic counselor to discuss the risks of having additional children. They take the DNA from you, your offspring and your wife and do some sequencing work for known autism risk genes. A few weeks later you come back to discuss the results. Before you sit down, the counselor asks to speak with your wife privately. As you sit baffled, they step out into the hall to have a chat. 

Know what's going on? In all likelihood, the counselor subscribes to unilateral disclosure guidelines and, under your very nose, is telling your wife that you are not the father of her child. Based on my understanding, genetic counselors who discover that a child has misattributed paternity (that's a nice term for it, yes?) will generally only reveal that information to the child's mother. In other cases (like this article), universal nondisclosure (i.e., you don't tell the mother that the kid isn't the father's) has been recommended. This is, in my opinion, worse, because there's no private hallway conversation to tip you off. 

Obviously I am a fan of full disclosure. There are valid reasons (that genetic risk stuff cuts both ways, you know), but paternity information is ultimately useful, and the decision what to do with it cannot be made by (or trusted to) an external party. Keeping this vital information private, fellow humans, is a fat sack of bullshit. Even in a worst case scenario where the pregnancy is blameless (e.g., you follow "the lifestyle" and your wife gets knocked up by Lazy Don at a swinger's BBQ) you should still be made aware of it. 

In situations where a misattributed pregnancy might not be excusable (and believe that's the vast majority), a man owes absolutely nothing to either the woman or baby. That might sound harsh, but a baby's a trap that lasts 18 years and will suck a tremendous amount of energy/time/money out of you. I don't know about you, but I'd prefer to invest my limited resources in the ones I fathered. So be it if it makes me a bad person. 

This position can be underscored in the case I've presented. In the genetic counseling example, you've got a kid who is likely going to be a medical nightmare that will likely - let's face it - hand like a boat anchor from your neck for the rest of your life, as well as a (again, barring extenuating circumstance) cheating spouse. You think she's gonna look at you, look at the medical mess she'll be left with and then go ahead and tell you the truth? MMM-hmmm. So remember, if the geneticist wants to speak to your wife privately, it's time for you to take a couple of swabs yourself.    

My gift to new dads everywhere:

Labcorp paternity test link. Not the cheapest, but we use them for outsoucing and they do good work. Two hundred dollars well-spent.  

Tl;dr: Private conference at genetic counselor? Maybe time for a divorce.

Alazheimer's Disease holds a special place in my heart - nearly twenty years ago, I got my start in a lab that studied AD and it launched me on this... interesting trajectory I've experienced. Even though I don't work on AD anymore, I still think about it from time to time. Recently, on one of my sentimental voyages, I learned of the passing of Dr. Mark Smith, the AD researcher from Case Western. I met Mark only once, shortly after starting in bench research as a chubby-cheeked undergraduate assistant who didn't know his ass from his elbow. Mark was a (much more advanced) AD researcher, and he came to Duke to give a talk that was both interesting and accessible to a neophyte like me. I actually still remember parts of his seminar, which is a rare thing indeed considering the coincidence of scientific lectures and napping.

We often hear about how real impact-makers see the world differently. In my estimation, Mark was one of those people.  Hearing about Mark's death inspired me to write a bit about his interesting viewpoint on AD, in hopes it inspired someone out there to think differently. 

OK, let's start with a basic primer. The dominant hypothesis on AD posits that the disease symptoms come from the accumulation of either/both extracellular beta amyloid (a short peptide fragment that's cleaved away from a larger protein) and/or another protein called tau, which acumulates inside brain cells. In some older individuals, these proteins accumulate and are linked together in increasingly large rafts that (it is believed) increasingly frustate normal brain processes, the symptoms of which we see in the form of progressive cognitive decline. In short, beta amyloid and/or tau is the enemy to healthy brain function. 

While this might sound like a relatively clean explanation, there is not a perfect association between pathophysiology and disease in this case - there are patients who are cognitively normal whose brains are full of amyloid and/or tau and AD patients whose brains are relatively clean. Combine this with the fact that diagnostic tests for AD are not very good/reliable, and it becomes difficult to diagnose (much less treat) the disease. The AD lab I worked in attempted to explain this variability through a combination of genetics and environment, specifically the interplay between blood lipid levels (think triglycerides and blood cholesterol) and diet. We studied a gene called apolipoprotein E, which was responsible for removing lipids from the blood. Certain isoforms (or flavors) of the apoE gene seemed to protect their owner from developing AD, while others led towards developing the disease. Our theory was that the gene isoform that preferentially sucked lipid out of the blood resulted in a relatively high level of sugars (which are normally used up first; most of us store the fat in a frosted donut), which could form a sort of glue that would irreversibly connect proteins like beta amyloid and/or tau. This would be particularly true for people who ate high-fat, high-sugar diets like Americans (who, back then, accounted for half the worldwide cases of AD). In the framework of our theory, a cure would stem from either preventing the formation of these protein/sugar moieties (oops, a science word slipped out) or removing them (or getting our diets cleaned up, but we never discussed that. I guess we'd conceded it wasn't going to happen).

As an undergraduate, I knew jack shit about science. Our plan seemed reasonable, and I whole-heartedly (and naively) thought we were on to the ultimate solution. I hadn't considered any other viewpoints. After all, everyone knew that amyloid deposits were bad.  

The I met Mark, who injected a little independent thinking into my along-for-the-ride mentality. During his seminar, it was immediately apparent that Mark wasn't toeing the party line on the whole amyloid thing. While most people viewed amyloid as the villian, he viewed it as a protector, or at least the tombstone of a great battle that raged in our brain. In Mark's view, the ultimate source of AD was oxidative stress stemming from the production of free radicals (dangerously unstable molecules). While Mark wasn't certain of the source, he posited that the brain coped with the stress by. The glycosidic (sugar) linkages between beta amyloid are readily formed in the presence of free radicals. Thus, the amyloid rafts are possible evidence of a native defensive mechanism in which the brain deals with damaging molecules by creating relatively benign proteous structures. The biological principle under which this thesis is derived, Wolff's Law, supports this, stating that a biological system placed under stress will inherent adapt itself to deal with that stress. Thus, the formation of the plaques and tangles we see so often in AD patients could signify the byproducts of a great battle within our gray matter. 

In the majority of research, amyloid has gotten a bad rap, Mark explained. In the field of molecular neurobiology, scientists are often (especially in the late 90s) deprived of real-time observation of this largely invisible world. This can lead to misinterpretation of data. To illustrate this, Mark told the following story: 

"Imagine that you're a member of an alien civilization tasked with studying earth through a large telescope. You know nothing of life on our planet, but are assigned the job of learning about what causes fire. Since you really only have one tool to study the phenomenon, you start by pointing your telescope at a fire every time you spot one. However, every time you see a fire, you also notice that there are little men in yellow coats scurrying around the conflagration, doing something you can't quite distinguish. Over time, you're hard-pressed to even glimpse a fire without the men in yellow coats being there. Furthermore, you see a direct relationship - the bigger the fire, the more men in yellow coats there are. Just to be thorough, you follow some of the yellow men. When they're alone, there are virtually no fires, but suddenly, without warning, they coalesce and and a fire pops up. Confident that there's definitely a relationship between the two things, you sit down and write a manuscript for the intergalactic journal of xenobiology that confidently concludes that firemen cause fires." 

In subsequent years, the role of oxidative stress has become outsized. We now know that there are numerous sources and consequences from oxidative stress - perineuronal net degradation, synaptic bouton formation impairment, and dozens of other science words that you would inevitably skim over. Unfortunately, few people with power listened to Mark at the time he was spreading his message. Drug trials churned away, aimed at targets that would lessen or reverse the deposition of amyloid or, in other cases, remove the accumulations similar to the way the body destroys invading pathogens. 

Many years later, evidence from these same trials increasingly supports Mark's position. Thus far, virtually all of the drugs aimed at preventing and/or removing beta amyloid and tau (and I'm not an expert, so take that with a grain of salt) have been ineffective. 

When a drug fails, it can happen for several reasons, one of which is the drug failing to accomplish the biological function it was intended to perform. However, in many cases, there was ample evidence that the drugs were successful in preventing new accumulation of amyloid/tau, but still failed to reverse the disease (or even prevent it from worsening). This supports (but does not prove) the idea that a cause other than amyloid deposition ultimately underlies AD.

Long story short, there's a decent chance that we have dumped billions of dollars into treatment strategies for AD that are just plain wrong and - by virtue of being off-target - have no chance whatsoever of success*. It's impressive then that, knowing none of this at the time, Mark Smith looked at this complex issue and saw something different. Moreover, he stuck to his guns and pushed the idea until his death. This is not easy to do in academia, where a herdlike mentality exists and challenging existing dogmas is, at best, an uphill fight and, at worst, career suicide.

Circumstances as they are, there's little chance I'll ever work on AD again. Passing on the unique perspective of guys like Mark is the best way I can think of to promote the independent thought necessary to make the big leaps forward that define the practice of bench research. 

*Don't read this footnote if you have a relative with AD and/or believe that ignorance is bliss. There is one AD-specific compound on the market as I write this. It's called Aricept, and it doesn't work for shit. Everyone in the industry knows it, yet it's still prescribed, probably to make the patient (and maybe the doctors) feel like they're doing something.   

Remember the Ice Bucket Challenge? The one where attention whores made videos of themselves inexplicably dumping cold water on themselves for ALS? These efforts raised about 100 million dollars. I was meh on the whole thing. It was sweet that people wanted to cure a disease, but the effort was far too small to be effective (the amount of money raised was really not very much in the research world). In the end, I predicted nothing would come of it and moved on. 

 As I predicted, nothing happened... until a week or so ago, when there was an article on ESPN about some breakthrough research that supposedly stemmed from the Ice Bucket Challenge (the thing where you dump cold water over your head and - maybe - donate a few bucks to ALS research). 

Could Noah have been wrong? Short answer: No way. The report was quickly contradicted by people who know what they're fucking talking about. It won't ruin the feel-good message for most people, who viewed the report as a happy addendum to a wonderful, heartwarming story. 

If you're at all interested in understanding how shitty, superficial reporting has mucked up the story, take a look at the original ESPN article, which reports the identification of a "new gene" linked to ALS. 

Sigh. 

First of all, we've mapped every conventional gene in the human genome. There aren't any "new" genes out there, at least not in the sense that the average person on the street would understand. This includes NEK1, the gene purportedly identified in the ESPN article. In fact, it was discovered (and published) in 1992 by these guys: 

Interestingly, NEK1 was linked to ALS earlier this year, in May. So the newest "ice bucket" report isn't even the first one to reach that conclusion. Ignoring that, there's a bigger issue here: the findings in the new paper don't even remotely put us onto a cure for ALS, as the ESPN article suggests. Why? Because the authors conducted a genetic linkage study and found that alterations in NEK1 occur in only 3% of ALS cases. In other words, any failure in the NEK1 gene product probably doesn't cause ALS alone. 

So what's with this "new gene discovered" reporting approach? Honestly, I think that reporters are reluctant to believe that the average man on the street can understand potential genetic contributions to complex diseases of unknown etiology with a heritable component. 

That's bullshit though, and I'm going to prove it by explaining complex genetic contribution to diseases in a couple of paragraphs using an easy metaphor I made up less than a minute ago.

Step One: Forget the peas

When we learn about genetics in school, we're given the old story of Mendel and his pea plants, where he figures out dominant and recessive. Punnett squares and all that. 

The problem is, this has virtually no applicability in the real world. For one thing, there are tens of thousands of genes, which work together in dizzyingly complex ways. For another, big 'R' and little 'r' don't really exist; they represent transcript variants of a gene. Think of them more like flavors than simply dominant and recessive.

In many diseases (often the tough diseases that remain largely untreatable), there seems to be a genetic component. For example, a father with the disease is more likely to pass it on. But it's not 100%, and people who don't have the disease (or even a family history of the disease) can have offspring who are affected. Clearly, there's some genetic component, but it's not remotely clear what it is or where it comes from. 

Step Two: Start Thinking About Planes. 

Here's where a metaphor might be useful. I was at an airshow last weekend. On the drive home, I was pondering how marvelously complex planes can be, and also how incredibly safe they are - the odds of a mechanical failure causing commercial airliner to crash are astronomically small (most crashes are caused by human error). 

In the story, I saw strong parallels to genetics and disease. Planes, like people, are marvelously redundant (by design or evolution, depending on how much magic you believe in). Think of your mother and father as two commercial airliners. Each plane is made up of millions of individual parts. Naturally, most of the parts work but, as I've said, airplanes are complex and there's always something broken. Most of the time, this matters not a whit, because there's a backup system (and occasionally a backup to the backup). So even though bits and pieces don't work, mommy and daddy planes have flown safely (i.e., healthily) their whole lives. 

Now, to make a baby plane, pieces from the mother plane and father plane are copied and reassembled to form a new aircraft. This new plane will, naturally, look like its parents, but will be slightly different, as its components are a mixture of its predecessors. However, new planes are occasionally created who possess a flaw in both the primary and backup system. This occurs when (for example) plane one has a faulty first-line system and a functioning backup, while plane two has a properly functioning main system but a malfunctioning backup. In this cruel twist of fate, the new plane receives one faulty system from each parent plane.

Applying this to biology, it is now possible to see how two fully functioning individuals can be combined to create a person that is functionally screwed. Now replace 'airplane component' with 'gene' and you now have an understanding of biology that surpasses that of most reporters.

Apply this to the current study and the relevance becomes clear. Whatever function NEK1 participates in is, in some way, related to changes in the body that frequently contribute to the development of ALS pathology. IIn the majority of people, the backup system kicks in and we see no disease phenotype (i.e., healthy patient). However, in a small (3%) fraction of people with the NEK1 mutation, the systems that would ordinarily compensate for are broken, resulting in the emergence of ALS. Thus, this finding is important for a number of reasons. For example, determining what NEK1 does (and how it relates to ALS) is tremendously helpful in determining what biological changes trigger the disease. This can get nuanced (and boring) very quickly (ex: there can be 10+ 'backup systems' for some things), but the important takeaways are these: New genes are rarely discovered and people are even more complex than planes.