Is the CRISPR Craze a Rerun?

Some years ago there was a basic science discovery that took the biomedical field by storm. Scientists working in a model organism had found a way to selectively target nucleic acids in the cell, shutting down gene expression. There was a ton of hype over the next several years, with everyone imagining the therapies that would start to help patients in no time.

You might think that I am talking about CRISPR; everyone else is, after all. But I am talking about RNAi, which was once touted as the discovery that would revolutionize medicine forever. I was talking to a colleague who is a bigwig in the CRISPR field who was speculating about the future of his field when he said something that shocked me at first. He suggested that CRISPR will not be the revolutionary clinical discovery that some people think it will turn out to be. When I pressed him, he compared it the hype behind RNAi a decade ago. Given this perspective, a couple of questions started to float around in my head. How similar was the hype behind RNAi to that of CRISPR/Cas9 today? Could CRISPR lead to the same letdown?

I did not know much about the RNAi craze–I know RNAi as a handy lab technique, but I never thought of it as a viable clinical treatment–so I went back and did some Googles. RNAi, which stands for “RNA interference,” is a set of cellular systems that cut up RNA and use the pieces to target and attack matching RNA transcripts in the cell. This turns down the expression of certain genes, which can be an effective way of doing genetic experiments in the lab.

It did not take much imagination to dream of how RNAi could be useful in treating human disease. Since plenty of diseases are due to the expression of disease-causing genes, doctors could treat the disease by giving the patient a drug to mobilize the RNAi system against the disease gene.

But in practice, RNAi ended up being difficult to use in patients. Hopes for RNAi therapy peaked during the mid 2000s, and started to ebb during the next few years after human trials showed no real benefit to patients or led to unintended immune responses.

Some people were afraid that RNAi would never live up to its promise. Biotechnology companies shuttered their RNAi research divisions. Human trials slowed down. Luckily, things did bounce back. There are still companies today working on RNAi therapies. It would seem that RNAi was over-hyped, it nearly crashed, then it became what it was always going to be: a therapy with some promise, but no miracle.

Today, CRISPR is just as hyped as RNAi was back then…if not more. CRISPR genome editing is popular science. In many ways, the lay public believes that this will be the century of biology: we will crack the mysteries of aging, we will edit human embryos to eliminate genetic disorders, we will cure all of the diseases. CRISPR genome editing is at the center of these hopes. But there are lessons to learn from the original breakthrough to end all breakthroughs. RNAi was not a complete failure, but we were certainly naive about its potential.

Part of what we got wrong was how unrealistic we were about the limitations of RNAi technology. Living cells have strong negative reactions to double-stranded RNA, which is a necessary step in the RNAi pathway. Delivery systems would be hard to engineer, just like the problems that still plague gene therapy. Finally, there is something that RNAi and CRISPR have in common: off-target effects.

Both RNAi and CRISPR depend on nucleic acids lining up and binding to each other in a pairwise manner before they can have their effect. Since the RNA sequences that bind to targets in RNAi and CRISPR are short and there is quite a bit of nucleic acid sequence in the cell, there is a possibility that you will get your molecule pairing up with an unintended target. It is like taking a short sentence fragment at random from a book and then searching the book for that fragment. You can find the target that you are looking for, but you might also find other perfect or near perfect matches elsewhere in the book, especially when you are searching through a large, complex book.

When these off-target effects happen with RNAi, you could shut down the expression of another gene. If that other gene is important, you might risk harming the cell. The same thing can happen with CRISPR. In fact, CRISPR has the potential to have more dire off-target effects:  CRISPR involves changing the DNA archive, rather than the RNA copy, which can lead to irrevocable changes to the cell.

Luckily, it does seem like CRISPR researchers have taken this to heart. Research into CRISPR’s off-target potential is an active field. I even blogged about a system that might be able to fine-tune the activity of CRISPR/Cas9 with the goal of reducing off-target effects in CRISPR therapy.

To be fair, CRISPR is at least a decade away from the clinic. But there are reasons to be concerned. Scientists have edited human embryos, and ethicists are scrambling to come up with rules to inform how we use this technology. If we learned anything from the RNAi experience, we should carry it over to CRISPR/Cas9. These systems seem to break out onto the scene with a ton of potential and bold claims. Eventually, we might be disappointed. There might be CRISPR trials somewhere down the road that will have to stop, with patients who thought they might be helped instead left wondering what all the hype was about. But if we have learned anything, it is that these systems will change our world. We will end up better off because of CRISPR. We just have to be willing to take the time to figure it out first.

Science Writing You Should Read

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I tweeted that a little while ago, and I really do try to live those words. Don’t tell my advisor, but I have been reading more popular science writing than actual research papers. But it can be pretty hard to know what to read. Where can a savvy consumer go for quality science writing? I’m here for you. Take these tips to heart.

New York Times

“The Gray Lady” has been a bastion of quality journalism for more than a century and a half. Fortunately, this includes the science coverage. The Times employs some great writers, including Carl Zimmer. You should start reading his work now if you have not already. In a world of science writers who just over-hype stories and don’t try to find holes, he is extremely skilled at getting all of the angles. If you want to read great, complex science stories, he is a great place to start.

Washington Post

Like the Times, this paper does great science writing in a newsy style. Their work tends to be a quicker read than the Times, and they print some quality stories. Check out Sarah Kaplan‘s work; she always has some interesting bylines.

The Guardian

Along with the Post and Times, the Guardian is also a newsy publication. The science coverage is always interesting, but I have detected a little sensationalism at times. It is nothing if not entertaining.

The Atlantic

Ed Yong might just be the best science writer doing it right now. Not only is his stuff great to read, but he also very accessible on social media (he favorited my tweet once). He is also extremely prolific, so check out his stuff on the Atlantic’s site.

Vox

Vox is a really cool online publication, where the writers always seem to be thinking just ahead of the curve. My new favorite science writer Brian Reznick writes for Vox, and I would encourage you to check out his work. He writes about anything, but he does seem to have a real interest in psychology and neuroscience. The rest of the science writers publish a ton of stories that will keep you reading throughout your workday.

FiveThirtyEight

I am a huge FiveThirtyEight fanboy. My heart stops every time I think I see Nate Silver on the street. Unfortunately, I have been a little disappointed with their science coverage. They just don’t publish that often…but what they do publish is pure gold. The main science writers, Maggie Koerth-Baker and Christie Aschwanden, are incredible. They also co-host a monthly science podcast in the FiveThirtyEightWhat’s the Point?” feed, if podcasts are more your thing.

Science

Science is usually regarded as a top research journal, but they have some great news writers. They will write up anything from their journal–or a competitor–as long as it is an interesting story. They do so accessibly enough for non-scientists to enjoy, but rigorously enough that scientists do not get bored. They also do some great writing on the intersection between science and politics, which is becoming a more and more interesting field in our current political moment.

Blogs
There are plenty of great blogs out there (just like this one). If you want to find some quality writing by people who just love to write about science, you should check out SciBlogHub or one of the other communities that compile and promote amateur science writing. Don’t forget to tell the writers what you think of their stuff. I know I love feedback, and I only wish I could get more of it.

RealClearScience

RealClearScience is just a page to point you toward the best science writing of the day. If you are just looking for someone to tell you what to read–and I’m busy or otherwise not responding on Twitter–just ask RealClearScience.

In the age of digital media, it is really not that hard to find science writing. Quality writing that is also accessible can be a stretch, though. But it is out there, and I will always be here seeking it out wherever I can–and trying to produce it, when I can. Let me know if you have any suggestions on publications that I missed. Happy readings.

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.

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.