Genetics

Since a number of people ask me what I do every day (zero is a number, look it up), I figured I'd give anyone interested a little summary. It's kind of funny to think about how much my field has changed since I started, since I just got my first real job in that field, but I guess that's science for you.

The goal of my field is to figure out what genes contribute to disease risk. After Gregor Mendel, tired of being teased about the lack of a "y" at the end of his first name, joined a man convent and channeled his sexual frustration into breeding pea plants, people figured out that genes change the way people and peas look, act, and get diseases. Years later Watson, Crick, and Rosalind Franklin (the undercredited woman who actually did the work upon which the boys based their theory) figured out what DNA looked like, and the hunt for actual disease genes was on. In the early goings, some egghead figured out that if you stain DNA with certain dyes it turns all stripey:

Then some different egghead figured out that people with certain disease have different stripey patterns than people without those diseases. Being eggheads, they correctly assumed that the genes that caused those diseases lie somewhere within the stripe that is different. The problem with this is that very few diseases are caused by a large enough genetic changes to show up in the stripey pattern. Furthermore, each stripe contains hundreds and hundreds of genes due to a miracle of packaging that allows "miles" of DNA to fit into the little structures seen above:

So if you want to nail down the culprit gene you need better resolution. Luckily, someone started noticing these "short tandem repeat" sequences spaced throughout the genome. Basically, once in a blue moon, the enzymes that copy DNA before cell division "skip" like a party house CD, causing a sequence that should have been T&A to be copied as T&A&T&A&T&A&T&A. Since this is exceedingly rare, we can assume you got yours from your parents. Side note: we share some of these repeats with chimps; why would a non-functional marker appear in exactly the same spot in humans and chimps if they didn't get it from a common ancestor? But that's another blog post. These repeats don't do anything and generally don't even lie within genes (if they happened in the middle of a gene, they would screw up that gene and that gene would not work) but they are a great way to figure out if you got a chunk of DNA from your father or your mother and whether you share that chunk of DNA with your siblings. If you share a chunk of DNA with your siblings and/or parents, and you also share a trait with that relative, we hypothesize that there is some gene within that chunk that may affect the trait. But again, the problem is resolution. We usually inherit a whole chromosome from a parent, one from mom and one from dad, so you might think the best we could do is say "the disease gene is on the dad chromosome." But luckily for us, there's a genetic phenomenon known as crossover. Basically, when a mommy chromosome and a daddy chromosome love each other very much, they lay down next to each other in the nucleus during prophase 1 of meiotic cell division and trade parts (usually, they get back the stretch of chromosome corresponding to the one they donated, but occasionally there's a mix up and big problems can result). Crossovers happen, on average, 34 times per baby. So when you get a sample of a whole bunch of families and look at the sections of DNA shared by people with similar traits in aggregate, you can narrow down the region that contains the gene that is causing the trait similarity considerably. This is called "linkage analysis," and we've found a fair number of disease genes this way.

But it hasn't worked out nearly as well as we hoped for several reasons. The primary reason is that most diseases aren't caused by a single gene. The ones we're most concerned with (hypertension, diabetes, cancer) are affected by many, many genes acting in concert to affect your overall risk of disease. No single gene has a large enough effect to easily detect. Another problem, again, is resolution. Although crossovers happen fairly frequently when you get a big enough sample of families, the best we can do is narrow down a region on a chromosome containing twenty to several hundred genes. Knowing that one of a set of a hundred genes probably contributes to disease isn't all that helpful.

Instead of sequencing relatively few markers that give us information about genetic similarity over a relatively wide region of a chromosome, people started realizing that there were single base changes (these are called single nucleotide polymorphisms, or SNPs, and happen when, like, a T becomes an A) basically everywhere, and if we sequenced a boatload of these, we could narrow down disease regions better. The problem was that this was expensive to do, on the order of 2-3 dollars per SNP back in the day. Multiply that by the half million or so SNPs you need in a several hundred people and pretty soon you're talking about real money. But much like iphones going from 500 to 200 dollars, we can now get 1.2 million SNPs typed on a person for about 400 bucks. There are now many studies with several thousand participants with a million SNPs each, which should be plenty to find the major genetic contributors to a given disease.

But guess what, again it hasn't worked out that way. We've found some disease genes to be sure, but not nearly the number we know must exist. One explanation is that common diseases are caused by tons of different rare mutations that all have the same end result. People are working on sequencing people's entire genomes to see if that's the case. Recall how the human genome project was supposed to take 20 or so years and cost billions to sequence a whole genome? Well, now we can do it in a few days at a cost of 300 grand. Pretty nuts. An alternate explanation for our lack of success in finding the reasons that both you and your mom are fat is that genetics is way more complicated than we thought. It may be that DNA sequence differences are not the primary cause of differential disease risk. But that's a whole nother issue. So now you know all you need to know about genetics. No stealing my job.

Boring Update of Zero Consequence

The past few weeks in Boston have been pretty uneventful. The weather has been too cold for urban outdoor activities, but I do feel our winter cred has been restored after our St. Louis hiatus. We discovered that the Imax movies at the Boston science museum are free on Fridays, so we saw Roving Mars and The Greatest Places the past two weekends. Spoiler alert: Mars had water and surprisingly Enid, Oklahoma is the world's greatest place. I saw Genesis in Imax as a very young lad and have been a fan ever since. I remember a time lapse sequence showing a landscape changing on a geological timescale and having my mind blown.

We needed to escape the confines of the house after being snowed in for the third time so we drove out to Cape Cod on MLK day. It was the best and only cape I've ever visited. We didn't go all the way out to the tip where the open spaces are, but the landward 2/3 do not warrant a special trip to Mass. Seeing the building that housed the "Sandwich Police" was good for a chuckle, however. Actually, a surprising number of unfunny building and business names are rendered mildly humorous when you stick the word sandwich in front of them. You know what else is surprisingly funny? A guy with very strong Boston accent who also has a very strong gay "accent." That's what.

In other news, Liz got a job tutoring kids who have to take extended leaves of absence from school. She's hoping for more "courageously battling cancer" kids than "a danger to his teachers and classmates" types. Also, I am unbeatable in Scrabble, which makes me feel...umm, good.

The Police Protect You

To celebrate the completion of my first very important scientific grant proposal, Liz met me after work last night for some half-priced happy hour tapas at a place we'd read was good. Turns out it was closed for a special event so we settled on grilled cheese at a place that has interesting and hard to find beers. It's called Bukowski's Tavern, and like it's namesake, has a reputation for being the tavern equivalent of a jerk. Their special of the day was "Beef Stew, Big Fucking Bowl Of." After a great IPA and an even better scotch ale, we headed home on the train. As we sat on the bus waiting for it to take us from our train stop to our neighborhood, a rotund, acne faced Hispanic gentleman, possibly intoxicated, got on and started talking to no one in particular:

"Can I get a fuck the po-lice?"
"No? Ok then, you guys must all LIKE the police."
"Because they protect you."

The bus pulled away and he proceeded to loudly eat a bag of Doritos, crunching and MMM-ing. I though it was pretty funny, he wasn't being particularly loud was more creative than your average obnoxious drunk. Things took a turn for the worse, however, when he asked the guy across from him what he was looking at and told him:

"I'm going to eat you for breakfast, and I'm not even going to finish my meal."

I don't really know what the not finishing the meal part meant, but the general message was clear, and the other guy wasn't pleased. To the probable drunk's "credit" he actually took the first swing at the minding-his-own-business guy, as opposed to being all talk like most other public nuisances. The other guy took the next 15-20 swings however, as the bystanders scrambled to avoid the scrum. The bus stopped, the beater got off and the beatee sat bleeding in his seat. Apparently familiar with this kind of situation, the other people told the beatee to get off since the bus couldn't leave until either he left or the police arrived. The police arrived after a few minutes and tried to persuade the bleeding man to exit the bus. Also to his credit, I guess, he refused to admit anything had happened and stated that he didn't have a problem with nobody. They finally got him to leave by promising him a free ride home, and we made it home with no further excitement. Maybe next time he'll ask if he can get a hug the police. Oh, and if you are sensitive to f-bombs in blogs, please stop reading two minutes ago.

A Heartbreaking Tale of Unfathomable Sorrow

Of the thousands of failed businesses sitting empty in cities across the country, what makes this humble Boston bakery any different? A tale of nearly unbearable sorrow spanning three decades and two states is what. Read on. But only if you’re not naturally predisposed to depression or bouts of soul crushing despair.

The story of this abandoned bakery begins in Harlem in the late seventies. As a wealthy industrialist pulls up to a basketball court, two young African American boys stop playing and climb into his waiting limousine. As they pull away to return to his Upper East Side penthouse, one boy stares after them, shivering in the thin, filthy jacket he'd found at a bus stop. A rather ugly boy, his apelike arms and heavy brow ridge gave him a brutish appearance fitting to the outbursts of violence to which he was prone. The first son of a poor mother and a father he never met, his life had been a series of hardships; one of the most crushing being abandonment by his mother after the strains of caring for him jeopardized her job with the above mentioned industrialist widower. The cruel ironies to befall Arthur Goocherson (named after his absent father so, as his mother put it, “She’d never forget the pain that man caused her”) were just beginning.

Although constantly wracked by guilt over the choice she’d made between her first born son and a return to abject poverty and unemployment, Arthur’s mother had eventually found love again—or so she thought. But certain women have tendencies to serially seek out unstable men, her new love eventually left her as well, leaving her with two new boys she was unable to properly care for. The strain was too much for Arthur’s mother, and although the doctors could find no medical explanation for her death, everyone knew it was the deep and horrible sadness that had killed her.

Realizing that the world moves to the beat of multiple drummers, the wealthy widower took pity on the two young sons of his deceased employee, taking them in and eventually adopting them; he raised them as his own along with his biological daughter whose mother had also died of a sadness based disease. Seeing his half brothers living lives of luxury while he bounced between foster homes was like battery acid on Arthur’s groin, and he lashed out at both brothers, constantly bullying the younger and savagely beating the elder when he attempted to intervene. The final straw was when his privileged half brothers were accepted to Digby, the elite prep school Arthur had always dreamed of attending. Completely oblivious to the great opportunity they’d been afforded by their adopted father’s standing with his alma mater, the ungrateful half brothers quit the school after their ridiculous request of having the school’s century old fight song replaced by a tacky, jived-up version of their own creation was denied. Their idiocy was like salted shards of glass in Arthur’s already chemically burned groin.

But before he could enact his final, murderous revenge on his younger siblings, a strange and wonderful thing happened to Arthur—he fell deeply and totally in love. Arthur’s metamorphosis was complete and profound, and love’s warmth melted away the hatred that had consumed him throughout his life like a poison fudgesicle. His repeated attempts to make amends with his half-brothers for his past bullying were met with scorn; they would never forgive him for his cruelty…much less for stealing the heart of their adopted sister.

After the death of their adopted father, the brothers used their inheritance to make life miserable for their step sister and her maligned lover. Having been disowned by her father over her relationship with Arthur (her father, despite being a man of peace on the surface and his own family being racially mixed, had an entirely different standard of tolerance where his only daughter was concerned, and the thought of Arthur’s rough, dark hands on her lily white skin ate at his mind like acid on groin skin), the youngsters, rich in love but strapped for cash, scraped together the last of their meager resources and ran off to Boston to escape their vengeful siblings.

The two bought a small storefront and some used baking equipment in the up-and-coming Boston neighborhood of Roslindale, so named for its resemblance to the hilly Glasgow suburb of Roslin. Their business, like their love, thrived initially, but the maniacal brothers would never allow them even a hint of happiness and used their fortune and influence to bribe suppliers and city officials to make running their bakery nearly impossible. Unable to afford flour and yeast at the inflated prices demanded by their unscrupulous suppliers, the bakery was on the verge of closing. One day, his love came home bearing a van load of baking supplies, saving their business from collapse. When asked where the money come from, she smiled bravely and stated that it must have been a Christmas miracle, hiding a tear and a shiny gold pendant shaped like a rabbit's head. But the profits made from those supplies couldn’t pay for the exorbitant license fees and taxes charged by corrupt city officials. But Arthur’s true love continued to bring home unexplained cash, and he was so happy to keep his business running that he hardly noticed the string of armed robberies plaguing the neighborhood.

The brothers were relentless in their quest to ruin the lives of the struggling bakers, eventually getting this story’s heroine hooked on the heroin they’d paid thugs to slip into her morning coffee. Arthur, although still alive from a medical perspective, died on the day that the only woman who’d ever loved him overdosed. As he rocked her pale, cooling body, he prayed to God to grant him just one stroke of luck and to take him away to rejoin his love. But God instead gave him a different stroke, hemorrhagic and debilitating. He spent the rest of his days in a semi-vegetative state, mumbling incoherently about "the evil midget," but his state appointed care givers didn't know what he was talkin’ `bout. The only mercy was his inability to remember the brief happiness he knew during him and Kimberly’s early days in Boston.

The elder brother, racked with guilt over what they’d done to their sister eventually turned to a life of drugs and crime as well. The younger brother, his fortune squandered on a pointless vendetta, filed for bankruptcy and was forced to work menial jobs and appear in demeaning cameo roles, eventually becoming a national symbol for lost opportunity. Pretty sad, all in all.