Forget March Madness…Watch the WBC

You probably didn’t hear about it, but the World Baseball Classic just started. Don’t feel like you are out of the loop; no one seems to know or care much about the WBC. And although you have March Madness, spring training, or maybe your own fulfilling career to distract you from creeping existential angst, I want to make the argument that you should focus on the WBC.

(I would be remiss if I did not mention that Michael Baumann over at the Ringer made his own list of reasons to watch the WBC. It’s a quick, fun read, so click over there if you need more convincing. He also touches on at least two of the points I will bring up.)

1. Prospects, prospects, prospects. One of the main problems with the WBC–at least the United States team–is that it has trouble enticing the real stars of the game to take time out of their preseason workouts and exhibition games to play internationally. Seen another way, though, this can also be one of the biggest opportunities of the tournament: the hole left by veteran ballplayers is readily filled by the young up-and-comers of the game. The WBC can be one of the best ways to get a look at the players who will be leading the MLB in a few short years.

2. They have a bracket, so you won’t have to miss the communal part of March Madness. Just get some friends together and see who can guess which country will go all the way. Does the Dominican Republic have what it takes to repeat 2013? Or will the perennially solid Japanese team rise to the occasion? With any luck, all of our brackets will be shot by the end of March, finally clearing the path for the United States to collect a WBC title.

3. It’s an alternative to spring training. If you are a consummate baseball fan like me, you want to enjoy the game as soon as possible. You were on Twitter all winter, reading Jon Heyman and Ken Rosenthal’s feeds, trying to find any informational morsel to nourish you until spring. Then when spring training arrives, you’re forced to keep up the facade that exhibition games are what you have been waiting for all year. But alas, spring training just isn’t meaningful enough. The WBC can be that bridge to competitive baseball. Instead of watching teams field half-strength lineups in glorified scrimmages, why not watch a real tournament for international glory? Then, just when the WBC is over and we are all done processing, the first pitches will be thrown on opening day.

4. It shows you the scale and influence of the sport. As an American, I think it is easy to take baseball for granted. One of the most beautiful things about the game is that it happens everyday from April until October, giving us a way to mark the progress of the middle of the year. But this omnipresence can lend itself to complacency. If my team plays every evening at 7, why bother listening in or reading the box score? The entire season is so long that every individual game loses any sense of urgency or importance when you are face-to-face with the sheer scale of the entire endeavor.

But the WBC allows us to take a step back and get a global perspective. We can see how the game that is uniquely ours (or our own bastardization of a game played in England centuries ago, depending on how you look at it) has been taken up by other countries, molded by their own cultures and perspectives, with the same basic rules holding sway, but with entirely different styles and characters emerging to fill the gaps in those rules. In the end, we are left to grapple with the question: Is baseball really is America’s game? Does America even want it anymore? Sure the MLB is making money hand over fist, but the American fan base is aging and today’s youngsters just aren’t into baseball like their grandparents were.

On the other hand, maybe baseball isn’t for America anymore, but it has ascended to some higher plane. Maybe it is a citizen of the world. Like those other uniquely American innovations of jazz and the Constitution, maybe baseball is just some vague framework that anyone can paint their own ideals and prejudices onto. If so, watching the WBC lets us experience other cultures through the lens of baseball. It’s just a simple bat and ball sport, but for much of the twentieth century the world could have learned a lot about Americans by understanding the game: what they valued, who their heroes were like, even how they felt about labor versus capital. Maybe now in the twenty-first century, baseball is what Americans need to understand the world.

Did Viruses Teach Us Sex?

Sex is a weird thing. At its core, the process involves a cell from one organism meeting up with another cell from another organism. These two cells have to become one when they collide, and they do this by fusing. New evidence suggests that the molecules responsible for this fusion might have come from viruses.

A new paper in the journal Current Biology noticed that proteins called fusogens in a single-celled organism are remarkably similar to another group of proteins produced by several types of viruses. Both types of fusogens are responsible for cell fusion in their respective organism/virus. In the single-celled organism, called Tetrahymena, fusogens dot the outside of the cell and allow the cells to undergo fusion and a primitive version of sex. Viruses, on the other hand, use fusogens to invade their cellular hosts.

mating_tetrahymena
Sex in Tetrahymena — Image: Jmf368w (CC BY-SA 4.0 via Wikimedia Commons)

The researchers involved in the present study were surprised when they saw just how similar Tetrahymena and viral fusogens look. Since proteins are just long strings of amino acids that are folded into complex shapes, we can represent a protein as a string of letters similar to what is done with DNA sequences. Then we can use a computer program to align the protein strings together by similarity. If two protein sequences align with a great deal of similarity–such that there is relatively little difference between the amino acid sequences of the two–it is often inferred that the proteins share a recent ancestor in evolutionary time. This is because evolutionary change is due to change at the DNA level, and the DNA change ultimately determines the protein change. When the viral and Tetrahymena fusogens were aligned, they appeared to be closely related based on similarity.

Not only did viral and Tetrahymena fusogens look strikingly similar, but the researchers were also able to show that they behaved quite similarly in a test tube. Specifically, they were similar in how they interacted with the chemicals that make up the exteriors of cells. The researchers concluded from this that both the structure and function of fusogens are conserved between viruses and Tetrahymena. When we see conservation of structure and function in biology, it is usually suggests that structures share an evolutionary origin.

So could viruses have passed sex on to us by leaving behind fusogens in our ancestor’s cells? Maybe, but the team that wrote this paper is not sure, and even admit that it might have happened the other way around. The bottom line is that we will need more evidence to know for sure, but this is certainly good circumstantial evidence that sexually reproducing organisms might owe a debt of gratitude to our infectious viral frenemies.

Sequencing the World

It looks like the beginnings of a consortium are taking shape, with the goal of sequencing all life on earth. As something of a genomicist, I am psyched by the goal, unattainable as it may be. I also want to say why lofty goals are helpful, and this one will be too.

The Human Genome Project took years to finish, and ended up costing about a dollar per base-pair, which are the chemical “letters” that make up the genetic code. Since then, sequencing has become orders of magnitude cheaper. The current genome sequencing leader, Illumina, famously announced that sequencing a genome could be done for a thousand dollars. If we compare that to the investment required for the human sequence, we certainly have made strides. This is due  to the technology we use to sequence genomes. The most popular way to do it today is to take a sample of DNA from an organism, which is typically present in long stretches of DNA called chromosomes, and break it into short fragments. Since we have a lot of DNA in the sample, we end up having more than one copy of each letter of the genome. Using the powerful genome sequences that we have developed , we can sequence a little bit of each of these fragments before using a computer program to take the short reads and assemble them into a contiguous sequence. If you can imagine taking a few hundred copies of “Moby Dick” and randomly cutting out stretches of letters before trying to reassemble the book from the fragments by looking for overlap between random fragments, then you understand the basic strategy that genome sequencing uses today.

In spite of the cutting edge technology, it still takes a ton of work to go from a draft genome assembly–which is what you could immediately get after putting a thousand dollars into an Illumina machine and plugging the resulting reads into the computer to assemble–to the kind of gold-standard genome assemblies that we have in well-studied organisms like mice and humans. Typically, more work has to be put in to fill in gaps in the assembly that result from highly repetitive DNA, which confounds assemblers. Scientists sometimes have to do follow-up experiments to prove that their genome assembly is real and is not just a computer error. Finally, the genome sequence is useless until you start to figure out where the genes and other features lie. This means more follow-up experiments and comparing the genome to those of other related organisms.

All of this take a significant investment of time and treasure, and there is no way that we could do that for all life on earth. You would never be able to have a gold-standard genome assembly for every organism on earth. Much like the oft-told anecdote about restaurants in New York City–where it is said that you could never eat at every restaurant in the city because new ones are opening for business and going out of business faster than you could visit them all–new organisms are evolving and going extinct all of the time. The idea of putting in enough work to get something as polished as the fruit fly genome, let alone the mouse or human genome, is laughable if you start to think about it. But it would allow researchers to gain an appreciation for the diversity of life that exists on earth, specifically at the DNA level. Just having fractions of the genomes of most of the species on earth would allow us to better understand the evolutionary relationships between all life on earth.

As for this goal being a little too big to handle, big goals are important to push us to new heights. Getting to the moon seemed ridiculous at the time, and sequencing the human genome was impossible when we first started to plan how to do it. These goals ended up being attainable, but just imagine if they had not been. Even if we had never made it to the moon, we would have still developed the kind of technology that allowed us to put satellites into orbit that now power our ubiquitous mobile devices. Even if the human genome proved intractable, we would have still ended up with improved sequencing technology. This is because setting these lofty goals has the effect of pushing us to achieve things that we would have never thought to accomplish without a lofty goal. If we set out sequence all life on earth, just imagine what we might find we can do along the way.

*I found a post by professor/blogger Jeff Ollerton who also had his own take on the proposal. While he and I do not agree, he has an interesting take that I enjoyed reading. It should also be said that he has more expertise than me in this area.

March for Science, but that’s Just the First Step

*Emily Willingham at Forbes expressed some of these same ideas and then some over here. Please give that a read and let her know how great she is.

Anyone reading this blog knows that I am a scientist and that I am into politics. Currently, there is a debate happening in the scientific community about whether the March for Science that is planned for April 22 should be “political.” I think that the question is stupid. The March for Science is necessarily political. I think detractors question whether the march needs to be partisan, which is a separate question. Incidentally, I think the March for Science is necessarily partisan too. I want to point out why the march is necessarily political and partisan, and explain why I think the march–and what it represents–is important.

The March is being organized in response to a specific series of events. We did not call a march when Bush stopped stem cell research. This time it feels different though. We have a president who has openly doubted the value of vaccinations. He expressed skepticism toward the science of climate change. He showed disdain for the EPA and nominated a director who wants to dismantle the agency. The Trump administration’s habit of consistently disregarding the knowledge of experts seems to signal that he will try to govern without using empirical data to inform policy decision-making. Since this is a question of how our nation is governed, it is necessarily a political issue. The GOP has also made it clear that this widely-held belief among their adherents, making it partisan. As proponents of evidence-based policy, we are obliged to stand up to these decisions and the people making them.

None of this is entirely new or unexpected. We could have assumed that a Republican administration would lead to the same deregulation and climate science denial that was the hallmark of the Bush administration. The Republican Party has been denying the science behind climate change for years. But this is clearly a larger problem. Now we are litigating the value of vaccines, the EPA, and whether research will continue to be funded. Trump is the inevitable conclusion to years of conservative anti-science policy. Not content to just disagreeing on how to translate widely accepted scientific facts into policy, conservatives deny the validity of those facts and the experts who work to uncover those facts. The attitude of denying facts and questioning the motives of scientific experts reached its logical conclusion in the election of the authoritarian Trump, who eschews expert advice, norms of conduct, and the validity of facts. It is up to us–scientists and empirically-minded non-scientists, alike–to take our place in policy discussions. We should have been there all along, making sure that our worldviews were represented in the realm of public policy. After all, we are highly skilled professionals with a unique way of seeing the world. We have a lot of value to add to policy discussions. But many of us have neglected our roles as citizens. Now is the time for us to show that we have something to say about governing based on solid facts instead of a partisan agenda. Marching for science is a solid start.

Don’t Stick to Science

I have not experienced it firsthand, but I have heard a lot about “stick to X” phenomenon. Specifically, we all have our area of expertise. Some of us are doctors, some are bricklayers, some are chefs. That is how we pay the rent. Some of us either choose or are compelled to interact with the wider public about this specialty. Writers necessarily put themselves out there and broadcast their expertise to the world. Some scientists with writing habits do that too. Those of us with blogs or enough recognition to get published in periodicals put our views on the progress of science out there for wider consumption.

But we all have ancillary interests too. I am a scientist with a real interest in baseball and politics (real original, I know). If I were a little more well-known, I would probably have eggs in my Twitter mentions telling me to “stick to science” whenever I share a political opinion. In fact, plenty of scientists and other writers I follow have shared stories about people tell them to stick to their respective area of expertise. The whole idea of sticking to X is ridiculous. I have never known a bricklayer or other blue-collar worker shy about sharing their political beliefs, so why should I?

I have been thinking about this a lot more lately because I have been thinking a lot more about politics. As an American–and a progressive one, at that–I have been shocked by the new presidential administration. I feel compelled to share my opinions with my followers. Luckily, it does not seem like I am the only one. Plenty of scientists that I follow have started to speak up. Some are concerned about the way the new administration will employ–or not employ–evidence-based policy-making. Others have broader concerns about the effect Trumpism might have on the culture of diversity and inclusion that we progressives idealize. I believe that it is critical that we not be afraid to share these opinions. Too many scientists that I know have tunnel-vision, unable to see beyond the next grant to be written, the next committee to chair, or the next experiment to run. I swear, I thought some of these folks did not even know that 2016 was a presidential election year until November 7. But we have a lot to share with the world. We scientists are intelligent, rational people, and our expertise should not be pigeonholed. If you think that scientific training only matters in the field of science, then you might as well set up your lab on a deserted island and never leave. You are not doing science any favors by pretending that we are separate from the rest of the world. So I implore those of you who have been silent: start a blog, tweet up a storm, write a letter to the editor. Stay as up on local politics as you do on the latest issues of Nature and Cell (news articles are, by design, much easier to read than papers). Hell, run for office if you have the chance. You can have it all, and in doing so we will make sure that the scientists of the next generation feel comfortable being citizens as well as scientists. Remember, we cannot do science in a vacuum (unless you are a particle physicist, I mean), and the continued success of the scientific endeavor is not preordained. We have to advocate for our science, our way of solving problems, and our vision of the world. The world will be better for it.

Pirates Go Super-Nova

The weather outside is frightful, but the hot stove fire is so delightful. I am delighting even more after my Pirates re-signed free agent starter Ivan Nova to a three year, $26 million dollar contract. Putting aside the fact that $26 million is more than I will ever earn in my lifetime (and probably you too, dear reader), $26 million over three years is steal for a pitcher of Nova’s caliber. Simply put, Nova should have made much more on the open market than he got from the Pirates in his freshly-inked three year deal.

To understand how valuable Nova is, you have to understand how players are valued. Typically, a ballplayer’s value is expressed in terms of wins. There are different formulae that attempt to model the value of a player in terms of wins, but several of them fall under the heading of “wins above replacement (WAR),” meaning the number of wins–above that of a replacement level player–that a given player brings to his team over the course of a season. The different formulae to calculate WAR mean that there are different flavors of WAR depending on who you talk to, but I will be focusing on Fangraphs data and the Fangraphs WAR calculation (fWAR). If you look at Fangraph’s Free Agent Tracker, you can see that most of the 2016 free agents with the highest 2016 fWAR values are projected to regress toward the mean/come back to earth/not do as well in 2017. But if you look for Ivan Nova on that list, you will notice that he is among the select group of free agents projected to have a better 2017 than 2016 by fWAR. The caveat here is that we are talking about a projection, and baseball projections have been shown season after season to not hold up in retrospect. But this should make for a fun exercise nonetheless. If we restrict our analysis to 2017 free agents with a positive fWAR, Nova ends up in the top 25% of free agents by projected increase in 2017 fWAR. But the real kicker for me? Nova is the only 2016 free agent with a 2016 fWAR greater than 2 (denoting a “solid starter“) who is projected to have a better 2017 fWAR. In short, among the best players who would become free agents in 2016, he is expected to be the one to continue to get better in 2017.

Another key point I want to make is that the Pirates may have turned the free agent market on its head with this signing. The free agent market tends to be all about big paydays for past achievements. A lot of players do not live up to the numbers they put up before their first free agent paycheck, but that is how the business side of the sport works. By signing Nova, and from my investigation into his previous and projected fWAR marks, I propose that the Pirates might actually be paying him for future value. If Nova lives up to his 2.5 win Fangraphs projection before giving another couple of years as a one to two win player, the Pirates come out on top. Based on analysis by Neil Paine at FiveThirtyEight, those 5.5 or so wins over the three years of Nova’s contract would cost about $42 million on the open market. This sounds more like the Pirates club that we all know and love, with a front office that seeks value above all other things.

I cannot help but wonder what made Nova offer the deep discount to Pittsburgh. Plenty of ink has been spilled on the topic of the contracts that starters are commanding this off-season, but Nova seems to have given the Pirates a hometown discount. Not being the type to look a gift horse in the mouth, I am just excited to see him pitch at PNC Park in 2017. Maybe I can even catch him at a doubleheader with Jose Quintana.

*Note added after publication: a blog post by Travis Sawchik at the Pittsburgh Tribune-Review hit on some of the same points.

Anti-CRISPRs Could Fine-Tune Genome Editing

Everything needs an off switch. I would have been bankrupt a long, long time ago if I could not turn off the lights in my apartment and C-3PO would have quickly worn out his welcome if he could not shut himself down like he did in Ben Kenobi’s hut. The important thing to remember here is that these things are useful most of the time: light helps me to see but it would not do me any good in the daytime, and C-3PO is like a sassy Google Translate…sometimes too sassy though. And it turns out that even the genome editor CRISPR-Cas9 has an off switch.

Maybe this is the first biology piece you have read in the last three years. If so, you may not know about CRISPR-Cas9 and the genome editing revolution. Commonly referred to as simply “CRISPR” in the popular press, CRISPR-Cas9 is a laboratory method for editing the DNA sequence in a living organism. Throughout the last several years, CRISPR-Cas9 has shown itself time and time again to be a simple and effective way of changing the genome of many different organisms. One group even pursued a controversial study that edited non-viable human embryos, showing that the method can likely be used to edit viable human embryos–as well as setting off a firestorm in the popular press and a lot of ethical hand-wringing within the biomedical community.

The CRISPR-Cas9 system was originally discovered in bacteria, and it functions a kind of anti-viral immune system in bacteria. As I have written before, viruses do their job by injecting a genetic material–DNA in some cases–into a host cell. Some viruses specifically target bacteria. Much like our bodies have evolved defenses against pathogens, bacteria have evolved defenses against viral invaders. This is where CRISPR-Cas9 comes in. Scientists–at a yogurt company of all places–discovered pieces of viral DNA in the genome of a bacterial species that is normally used in yogurt-making. Interestingly, bacteria with these viral signatures were also immune to the corresponding virus. Later work showed that these stretches of viral DNA were actually added to the bacteria’s genome after a viral infection. After that initial infection, the new viral DNA pieces in the bacterium could be made into RNA and loaded onto the protein Cas9. The RNA-Cas9 complex is then free to go bind to DNA that is specified by the RNA, which would be viral DNA in this example. After seeking out complementary DNA from an invading virus, Cas9 performs its molecular function: cutting that DNA into pieces that cannot take over the host cell.

Research on CRISPR-Cas9 has been moving forward at a rapid pace, so I could write exclusively about it and never run out of things to talk about. But a recent published result showed that some bacterial viruses have evolved special proteins to inactivate Cas9, effectively shutting down the CRISPR-Cas9 immune system. It has been known since the middle of the 20th century that protein activity can be controlled by the binding of another molecule. The phenomenon is broadly known as protein regulation, and it is useful because a cell often needs to fine-tune the activity of certain proteins in order to survive. For example, Escherichia coli bacteria prefer to use glucose sugar for energy, but they also can also produce an enzyme to utilize another sugar, lactose, for energy. Interestingly, a lactose molecule can bind to the protein that prevents the production of the lactose-digesting enzyme and allow for the utilization of lactose. Similarly to how lactose can control the protein that shuts down lactose metabolism, scientists recently discovered that a group of viral proteins can shut down Cas9. Importantly, they showed that the “anti-CRISPRs,” as they dubbed the molecules, can bind to the RNA-Cas9 complex and strongly inhibit the DNA-cutting activity of Cas9 in a test tube.

However, the real appeal of CRISPR-Cas9 is not that we can mix it with DNA in a test tube and see DNA cleavage. Instead, we can do all of this in a living cell and cause DNA mutations that can be useful for research or maybe even therapy. If we are going to continue using CRISPR-Cas9 in living cells–perhaps someday therapeutically–we are going to want to fine-tune its activity. Luckily, these same researchers showed that anti-CRISPRs can block CRISPR-Cas9 genome editing in human cells. This result could someday help to avoid “off-target effects” that CRISPR-Cas9 sometimes causes, which are basically just unintended editing effects that could cause more harm than good.