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.

It is critical that we scientists not be afraid to share our political 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.

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.