A Voyage of Viral Discovery

Richard Dawkins’ Selfish Gene came out 40 years ago, so it is only fitting that I get to write about the most selfish genes of all: viruses. Basically, viruses are pieces of genetic material–either DNA or RNA–surrounded by a protein shell and maybe some lipid membrane. Viruses are not living cells, and they do not fulfill most of the hallmarks of life that many of us learned in middle school: viruses do not catalyze their own chemical
reactions, they are not made up of cells, and they do not reproduce on their own. In order to do the chemical reactions necessary to reproduce and make more copies of themselves, viruses must find a way to put that genetic material that they carry into a living host cell and trick the host into using the code as it would use its own genome. This is how the virus manages to make the host into a veritable virus factory.

Since viruses rely on living cells for almost everything, it has not been easy to study them. In fact, we did not even know that viruses existed until the late 19th century. The first viruses were isolated when scientists studying a pathogen found that they could run infectious material through the smallest available filters without removing the infectious factor. At that point, they just called them “non-filterable agents” and reasoned that they must be extremely small, even smaller than bacteria. Experiments by others in the early and mid-20th century went on to discover that viruses were mostly protein and nucleic acid (RNA or DNA), making them radically different from previously known cellular life.

As biologists, we were pretty late to the virus party–shoot, we pretty much knew what cells were shortly after the first microscopes were built in the 1600s, but it somehow took until the 1800s to know that there was something smaller that could cause disease–so it is no surprise that there is still a lot for us to learn about the tiny “non-filterable agents.” Appropriately, a recent paper in Nature claimed to find over 1000 distinct viruses that are all new to science. To make this discovery, the scientists first had to pick a group of cellular hosts in which to look for viruses. They settled on invertebrates, a diverse group of animals that include everything from insects and squids to sea urchins and earthworms. They also had to decide what type of viruses they would look for, opting to search for RNA viruses, which invade a host using RNA instead of DNA as their genetic material. By collecting and sequencing RNA from over 200 different invertebrate species, they were able to piece together long strands of RNA using the sequencing data and a computer program. However, those long reconstructed strands of RNA did not necessarily come from a virus present within the host. Host cells make their own RNA all of the time using their own DNA as a template. In order to be sure that the piece of RNA they found originated in a virus, they needed a signature that could only be present in a viral RNA. They found that signature in the form of a RNA virus-specific gene called “RNA-dependent RNA polyermase” or RdRp. RNA viruses use RdRp to copy their RNA genome when they invade a host cell, but they have to bring their own as part of their RNA genome; animals just do not have an RdRp. (That is, unless you believe this group that claims to have found a possibly-functional RdRp gene in a bat genome. I hope you will agree with me when I say that living things tend to be amazing because all of the rules we have about them are inevitably broken in some other organism.)

With this handy tool to distinguish viral RNAs from the rest of the pool, the authors had a field day discovering new RNA viruses. In addition to classifying viruses based on the host they were discovered within, they also used a technique known as “phylogenetics” to compare the RNA sequence of all viruses in order to place them on a tree of life relative to each other. Since all life on earth can ultimately trace its root back to one common ancestor that is the evolutionary relative to all of us, from human to bacterium, we can compare the nucleic acid sequences of organisms or viruses in order to infer their evolutionary distance from each other. For example, two viruses with relatively similar RdRp genes would be inferred to be quite closely related compared to a third virus with less sequence in common in the RdRp gene.

These new viruses were not discovered as human pathogens, so it is unlikely that this finding will have any direct medical relevance. This result can instead be useful for ecologists and evolutionary biologists who want to understand the variety of viruses that infect the invertebrates studied. Moreover, since we know quite a lot about the evolutionary relationships between different invertebrates–owing to us having studied them quite intensely for decades or even centuries–we can now use the new phylogenetic information about viral genome relatedness to start to ask questions about how the viruses co-evolved with their hosts. For instance, a group of related beetles may tend to be infected with related RNA viruses. If this is the case, then it is possible that an early ancestor of those RNA viruses made a living infecting an early ancestor of those beetles. Basic studies like that might also help us to someday understand host-virus co-evolution in humans and our viruses. After all, humans are in no danger of hitting an evolutionary brick wall, and neither are our viral foes.

Sacrificing for Science

It is probably easy to forget it with all of the baseball and politics flying around this page, but I am a biologist and that is what currently pays most of my bills. As a biologist, I do try to keep up on the interesting goings-on in my field, which happens to be somewhere between genetics and genomics. To that end, I printed out a research article about a week ago to read on the train, so naturally I just got around to reading it. The title, “A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns,” caught my eye because DNA rearrangement is something of an interest of mine. Little did I know I would nearly cry while reading this paper.

Pancreatic cancer is interesting among cancers because it tends to go undiagnosed until a relatively late stage. By that time, it is often hard to stop metastasis of the primary tumor to other organs, leading to a pretty short five year survival rate. Due to the loss of life that pancreatic cancer causes, it represents an active field of research. Specifically, a group in Toronto looked at the genetic changes that have to happen in a precancerous lump of cells in the pancreas in order to allow those cells to break from the main tumor and metastasize to other organs, which is how cancer causes the most damage. A popular model to explain the progression of pancreatic cancer dictates that a specific series of gene mutations has to occur in order to allow a precancerous cell to get to the point where metastasis can occur. Interestingly, this group showed that precancerous cells often did not exhibit the step-by-step accumulation of mutations that we thought would lead to metastasis. Instead, many tumors show signatures of simultaneous mutations that could only occur in the event of whole chromosome rearrangements. Which takes us right back to the DNA rearrangement that I am interested in.

Now let me address how I ended that first paragraph. I do not usually get emotional while I am reading papers, but I do not usually read papers that study case-by-case examples of patients who died of pancreatic cancer. It is incredible to think that there could be something growing inside you right now that will kill you in mere months or years. Tragedies like this are enough to make me not want to get out of bed in the morning, because what’s the point? Anything can happen tomorrow: “Pcsi_0410” was a real person with real friends and a family and ideas and a personality, but now they are just Figure 2 in a Nature paper. But I want to thank Pcsi_0410 for teaching us a little more about a terrifying disease that we all want to learn to treat more effectively. Maybe this is the only way we can make the best of pancreatic cancer. People are going to be unlucky and die from it, but we humans have been trying to make sense of shit like this for millennia. We will continue to try to solve the pancreatic cancer mystery, but we need people like Pcsi_0410, who were dealt a shit hand but use it to help others. But as scientists, let’s never forget the important sacrifice that some people have to make in order for us to get some cool sequencing data.

If you like to read the primary literature, check out the paper I talked about at Nature.

Little Market, Big Possibilities

We have not seen the Cleveland ball club in the World Series since 1997 (although I saw them there on Netflix just a few months ago), but this most recent
AL pennant is important for another reason aside from the relative rarity. The simple storyline that we can attach to the Cleveland side of the World
Series would be that Cleveland is now “Believeland”, a place where pro team franchises can succeed and reinvigorate a downtrodden blue-collar town. But I
would argue that it is a terrible injustice to the entire Cleveland baseball organization to suggest that what they are doing is impressive only in light
of what the Cavaliers have already done in the NBA. Specifically, the front office is continuing to prove to the baseball community that small market,
small budget MLB teams can build from within and go all the way.

One of the most familiar symptoms of a small market team is a reliance on homegrown talent. Fortunately for Cleveland, they have done this quite
successfully. Nine out of Cleveland’s top twelve players,¬†by Baseball Reference’s wins above replacement model, made their MLB debut with the team, compared
to six of the Cub’s top twelve. In Chicago, only three of those twelve were drafted or signed as an amateur free agent by the Cubs, compared to six of
Cleveland’s top twelve. Both teams have struggled in the last decade or so, and have thus been rewarded with top draft picks. Specifically, Cleveland has been awarded seven top 20 overall draft picks since 2009, while Chicago came in just behind them with six*. So while it appears that the teams have been similarly lucky with draft picks in the last few years, Cleveland has done a better job of developing those guys and directly benefiting from them at major league level.

As a fan of a small market team, I can sympathize with Chris Antonetti and the baseball operations gang in Cleveland. I know that they are not drafting top prospects and painstakingly developing them all the way through the minor league system because they enjoy it as a pastime. Cleveland’s 2016 payroll is roughly half that of Chicago’s. Developing from within is really the only way that Cleveland can be successful. Cleveland certainly is not the first franchise to exploit this strategy to make it to the World Series, but it is inspirational to see another small market team go all the way. It really says a lot about our favorite sport that it is not just the New Yorks, the Los Angeleses, and the Chicagoes that are succeeding in October. However this next best-of-seven goes, we are guaranteed to have another great narrative when we have a champion. It just might even be another small market club that manages to beat the big boys.


*For the record, Cleveland actually had two of those guys on their roster in 2016, compared to three for the Chicago. But, to be fair, the third guy in Chicago is Kyle Schwarber, so do with that what you will.

An Open Letter to Trump Supporters

Okay, everyone. It’s time for us to all to have a grown-up conversation. Your guy is not going to win. Nor should he. He has said and allegedly done things (over and over again) that would disqualify anyone from the presidency. But come January, we are still going to have to govern this nation, including all of the Trump Trainers, the “I’m with Her”-ers, the Bernie Bros, the people who threw their hands up in frustration and swore to not vote in this election, and all the rest. We just spent more than a year vilifying each other and it is going to have to come to an end if we are going to make any kind of progress.

Look, I get that some of you have legitimate concerns about the direction that our country is taking. The lack of availabilty of ways to make a blue collar living in areas that used to thrive on manufacturing is a point well taken (you might remember that that point resonated well with people on both sides of the ideological spectrum). It is clear that people in those areas are suffering, and policies will have to be made that deal with rural and Rust Belt poverty and lack of opportunity. But what we objected to the most was the way that some of you tend to wrap that and other issues up with race and ethnicity. “Make America Great Again” might be a laudable motto if it was not widely viewed as a dog-whistle that roughly translates to “Make America White Again.” The fact is that our country has a long, rich history of racism that we would do well to keep in mind as historical context when we are examining current events. But never before has someone so successfully weaponized this hate to further their own political goals–we have never had to deal with a demagogue or a fascist.

I feel like I am qualified to say all of this because I am from Trump Country. I have more than one family member that wears the infamous red cap with pride. And I know that their motivations are complex. Yes, there is a generous helping of racial anxiety in there, and that I cannot excuse. But there is also a pining for the “old days” (which may or may not have ever existed in reality), in which a man (or hopefully now a woman) could earn enough to raise his or her family without a college degree. The problem is that the rose glow in which some people recall those “old days” seems to filter out the racial strife, the lack of opportunties for women and minorities, and the lack of a social safety net that actually existed in those days. It would be foolish to forget that history, and to act like it has not profoundly affected the situation in minority and immigrant communities today.

Maybe there are ways that we can work toward progressive goals in this country while also revitalizing the type of blue collar jobs that used to sustain people like my forebears in certain parts of the country. Or maybe that goal is antithetical to the idea of the type of society that we progressives want to build. That latter idea scares me because I hate the idea that we would leave behind an entire group of people in the name of progress. I’m lucky because I got out, and I have been lucky enough to get a hell of an education off of my cis-hetero-white male privilege and a modicum of hard work. But I am not so encased in my ivory tower bubble that I cannot see that the movement that swept Donald Trump to within mere votes of the White House will never go away until will deal with the lack of opportunties in some parts of the country. So I’m with you all if you want to build a society that offers access to a good life for everyone, from Rust Belt to the poorest of inner cities, for people of all backgrounds. But you need to drop the fascist. He isn’t helping to get that message across, and he will just serve to further alienate you from the current power structure. Together, maybe we can “Finally Make America Great for Everyone.” Slap that on a snapback and I might actually wear it.


The Dog Ate Trump’s Homework

That debate last night was painful. And not just for the obvious reasons. We all know that Donald Trump is a horrible misogynist. We all know that he is a horrible racist. We all know that he has no relevant experience that qualifies him for the presidency. But last night I saw something else. In fact, I’m surprised that I never saw this before. It’s a little embarrassing, in fact. This guy cannot even hold a conversation his counterpart, the press, nor the voters. He was completely outmatched up there. He obviously has not even read a newspaper or a briefing book. Just take his insistence that the military should not telegraph its strategy before major operations. Martha Raddatz and Hillary Clinton were visibly frustrated. He has no appreciation for nuance; the world that Trump inhabits is black and white, and he has no desire to complicate his simplistic view of the world. These debates are there so that we can compare the candidates on their policy ideas. But Trump does not even have the aptitude (or is it attitude?) to engage in that conversation. These debates are a waste of time. Trump is like a schoolkid that didn’t do the homework before class, and all American citizens are the rest of the class suffering as he slows down today’s lesson.

Review of Fox’s “Pitch”

I’m a fan of the new Fox show “Pitch.” I support all things baseball. But I do have an interesting point to make. Either the story is trying to be very progressive and insightful, or Mike Lawson’s character seems to have developed entirely too fast. We started the first episode with Lawson being an irredeemable shit-heel: he slapped Ginny’s ass with entirely too much familiarity and with complete disregard for the power imbalance in that slap, and he shit-talked Ginny to the other guys on the team, while being overheard by Ginny in the locker-room.

Great, every story can benefit from an asshole that can be redeemed with some hard-won knowledge and appreciation for other people’s perspectives. But “Pitch” did not choose to take that route. Instead, Lawson turns around in the middle of the first episode, and decides that he is going to hitch his wagon to the Ginny caravan, the only hope that he has of securing his legacy. Instead of having one irredeemable shit-heel to redeem this series, we have the rest of the 25 man roster, who are still having trouble accepting Ginny as a major leaguer. It is just one woman against the world, and one man willing to vouch for her.

Obviously, women do not need vouching for: Ginny has no problem getting the other male baseball players out. In other words, she is able to get by on her own merits. So the argument that “Pitch” makes–that women can only integrate into a traditionally male-only space when a man helps to make a place for them within that space–is a little sad. However, I leave it to women who have had experience moving into male-dominated fields to say whether or not this depiction is realistic. As a cis-het-male in a STEM field, I can only imagine that “Pitch” is a realistic depiction of sex-discrimination that occurs everyday. Which is why I am sure that this show is important. Damn the corny dialogue and shot composition: “Pitch” is doing important work. If you like baseball and/or women and have a stake in the progress of either, I suggest that you watch “Pitch.”

Space, man.

In the summer of 2012, I was a precocious undergraduate spending the summer at a certain Ivy League institution as a research assistant in the laboratory of a certain Nobel Prize winner. I plugged away at the microscope all day, with Earl Sweatshirt’s early shit blasting in my ears, the steady minimalist beats fueling me through my grueling days. But then I would come home, and unwind in front of my computer like any good millennial. One day the Curiosity rover landed to much fanfare, and I stayed up on my computer late into the night to watch it. Something about space is so inspirational to anyone with any real interest in science. We have run out of things to explore; those greedy colonialist pigs circled the globe long before I ever got the chance (and made a real mess of things by doing so). And space itself isn’t something new: JFK inspired the US to reach for the stars decades ago, while the USSR was also looking upward. Since then, it seems like every country has a space program. Maybe space is just mundane now? Maybe resupplying the International Space Station is like the monthly trip to Costco? But I think there is still some mystique in it. Because the night that Curiosity landed on Mars, I watched with wonder–and I was not the only one. We keep having these moments as a society where the space programs of our planet manage to keep us interested long after people were supposed to have gotten bored with space. I started to wonder if NASA is just getting better at marketing. Did they hire some big PR firm to drum up public support–and maybe secure a half a percent more of the next federal budget. Maybe it makes more sense that this wonder was never really gone. Because now Elon Musk is promising to send people to Mars and I want to be first in line. The truth is that the rational part of me doesn’t believe that SpaceX will ever send a soul to Mars. Hell, they can’t even get a resupply rocket off of the ground. But the idea is just so human. There’s nothing left for us to explore. So why not pile into aluminum tubes and blast off (or up) for the heavens, why not see what we can find out there? This monkey is ready to blast off into space, man.