How to Succeed in Grad School by James Wade

I'm nearing the end of grad school--or so I hope! After a few years, I'm starting to get the hang of it. I know how to design a good experiment. I manage to stay reasonably up-to-date on my notebook. And, I'm ready to get the hell out!

I constantly feel like there is so much I can learn, so much to improve. Every now and again I think back to my first years in grad school and wish that I could have known then what I know now. In honor of that low-lying regret, I offer my advice to those who come next.

So you've arrived on campus and finished your orientation. Class is starting soon, and your graduate career is about to begin. You made it through college, and you're ready for what comes next. You know how to take classes. You probably have a decent idea of how to work in a lab and even to TA a class. How do you make sure that your graduate experience is the best it could be? Here's my advice.

Listen. (You're new. Don't forget that.)

Your biggest advantage as an incoming graduate student is your enthusiasm. You are ready to learn. Part of learning is listening. Always remember that everyone around you has been in your shoes. They already took these classes, taught those undergrads, and did that experiment. Use their experience to your advantage. Advice will probably be free flowing. Not all advice is good, but a lot of it will be. The older students know the good classes, the professors to avoid, and the best tactics for dealing with the undergrads that won't stop pestering you about a regrade. They perfected that complicated assay, and they already went down that rabbit hole or know of the that postdoc who did.

I have noticed through the years that the quiet first years are the ones people tend to like. Even if you are the graduate student of the century, you are still a first year. Your advice is not wanted and probably not warranted. If you have questions, ask them. If you have suggestions, deliver them respectfully and carefully. Or at the very least, frame it in the form of a question. For instance: "I noticed you used this reagent in that protocol. What do you think would happen if you used this one instead?" Or: "I was reading about a project similar to yours in a paper. I had an idea I was hoping you could help me flesh out. Do you have any free time this week to discuss it? Coffees on me!"

Grad school is full of drama and gossip. Avoid it at all costs. There is not need to create enemies or to take sides. Stay positive and friendly. This sounds simple, but the stress of grad school often channels into animosity, usually directed at other graduate students or your adviser. Do your best to avoid this negativity.

Manage your time.

Sometimes, I will hear the occasional student talk about how little there is to do, saying things like: "I didn't know grad school was this easy!" No one likes that kid. If you're finding that you have a lot of free time in your first semester, there is probably something you should be doing that you're not. This graduate school honeymoon period doesn't usually last very long. Between teaching, classes, and research, there are plenty of ways to fill up the hours of your week. Your best bet is to establish a system before you feel overwhelmed. I use the GTD (Getting Things Done) method along with Evernote and Todoist to keep track of notes and tasks. The method you choose is mostly irrelevant. Pick a system that works for you, then stick to it.

You got into graduate school because of your academic success. Some of you may have glided through undergrad without the all-nighters or Saturday night study sessions. Great! Grad school is not about classes or grades. You will be running two or three experiments at once while trying not to miss lab meeting or office hours. Do not try to keep all of this in your head! The earlier you learn this the better. As a bonus, the more efficient you are with your time, the more time you will have to have fun and explore your new community!

I struggled to adjust to the lack of deadlines. Grad school is a race to a hidden finish line. Sometimes you will feel like you are running that race in the wrong direction. Sometimes you will stop running all together. Having a reliable time management system will help you make steady progress.

Work in Lab, Have Fun at Home

Remember, every day you waste in grad school is another day you stay in grad school. Every week you spend without a PhD is $1000 out of your pocket. You'll be amazed at how easy it is to spend a day playing around with data workup, skimming through the literature, chatting over coffee with some friends - the list goes on.

To avoid wasting your day, have a routine. Some people read a paper first thing in the morning. Some spend some quiet time planning their day. It does not really matter what you do, just have something to get you going in the morning.

You do not have to be all serious and focused all the time. Give yourself time to relax, to make new friends, to get to know your future colleagues. When people invite you to go grab a drink, to go to a fooball game, or to watch the Bachelor, say yes. You might feel an urge to always work. That feeling can be productive when you're in lab, but don't let it keep you from having a life outside of lab. You will work better if you find some time to get your mind off of work.

Finally, do not forget to take care of your body. Carolyn Bertozzi published an editorial recently on the importance of exercise. I do not think this can be overstated. Find a way to exercise, the more fun it is the better.

Okay, that's enough advice for now. Please leave your advice in the comments!

Picking the Stories Worth Telling in Science - Emoji Take the Stage on Science Friday by James Wade

Orchids, Zika virus, tigers, brain-computer interfaces, and emojis - what do all of these have in common? Probably not much except that Ira Plato covered each of them on the April 15th episode of Science Friday. Although I'm usually a big fan of the show, I was doing some major eye rolling during one of their segments this week.

In a new study from the Grouplens research group at the University of Minnesota, the researchers find that emoji interpretation depends in part on a user's platform. Android users see a different emoji than iPhone users. In fact, one of the advertised features of the upcoming Android N is the new and improved emoji. After quantifying the discordance in emoji interpretation, the researchers state that there is a "significant potential for miscommunication, both for individual emoji renderings and for different emoji renderings across platforms."

Here's what bothers me about the story: their findings are obvious and their methods are boring. Who's surprised that people have different interpretations of emoji? What listener is surprised that the researched pulled off an online survey about emoji?

All of that said, let me state explicitly that I'm not trying to attack the researchers. Sometimes our results are boring as are the methods we used to get there. That does not mean the study should not be done. Gaps in the literature often need to be filled, and seemingly dull investigations have often yielded fascinating discoveries. Where I'd draw the line is with the production team for Science Friday. I can't understand why they chose to cover this given the vast availability of fascinating studies. Maybe I'm being unfair. Sometimes there are fluff pieces used to fill the airtime. Not every segment can be radio gold. For those times where reaching two hours is a stretch, I'd much prefer reaching into the archives for us listeners to relive the great segments from all the years of the show.

I have yet to fully grasp what makes a story worthy of news coverage (other than anything I publish, of course!), nor do I fully understand what makes a discovery important. But in the immortal words of Justice Stewart "I shall not today attempt further to define the kinds of material I understand to be embraced within that shorthand description..., and perhaps I could never succeed in intelligibly doing so. But I know it when I see it."

Designer Humans: A Response to the First Report of Human Germ Cell Line Editing with CRISPR-Cas9 by James Wade

The word is out. Scientists have successfully rewritten the genes of a human embryo. Gattaca, here we come! Or do we?

Last month, researchers out of Sun Yat-sen University in Guangzhou, China, published the first report on editing the genes of a human zygote. They used the gene editing technology that is exploding in popularity called CRISPR-Cas9. The paper, published in the low-impact journal Protein & Cell (impact factor 2.851), came right on the heels of a comment in Nature calling for an outright ban on editing human germ line cells. 

Before we call on the angry mobs to storm the lab performing the germ line alteration studies, we should first look at what the researchers actually did. Quoting directly from the controversial study:

“In this report, we used tripronuclear (3PN) zygotes to further investigate CRISPR/Cas9-mediated gene editing in human cells. We found that CRISPR/Cas9 could effectively cleave the endogenous β-globin gene (HBB)."

The researchers used tripronuclear (3PN) zygotes. These cells are a byproduct of in vitro fertilization (IVF), and they contain DNA from an egg along with the DNA from two sperm cells. Prior to fertilization, germ line cells (egg and sperm cells) are haploid, which means that they only contain a single copy of each chromosome. A normal fertilized egg has two copies of each chromosome, termed diploid. The 3PN zygotes have an additional copy of each chromosome (from the extra sperm), making it a triploid cell. These embryos are known to produce poor quality embryos and are viewed as a waster product of the IVF process. Since they are typically discarded, the researchers sought to use these cells to study the effects of the CRISPR-Cas9 system on germ line cells. As a proof-of-concept study, they attempted to remove the β-globin gene (HBB), a gene encoding a sub-unit of adult hemoglobin protein.

Quoting, again, from the abstract of the paper:

“We found that CRISPR/Cas9 could effectively cleave the endogenous β-globin gene (HBB). However, the efficiency of homologous recombination directed repair (HDR) of HBB was low and the edited embryos were mosaic. Off-target cleavage was also apparent in these 3PN zygotes as revealed by the T7E1 assay and whole-exome sequencing."

The CRISPR-Cas9 system has been shown to edit many different cell types across a number of genes. Feng Zhang and Jennifer Doudna, pioneers of this technology, have published extensively on the development of the CRISPR-Cas9 gene editing method. Unsurprisingly, when the researchers in this study attempted to target the HBB gene, they successfully removed it from the genome. The CRISPR-Cas9 gene editing method works by forming a double strand break (DSB) in the DNA. This can be repaired in two ways: non-homologous end joining (NHEJ) and homologous recombination directed repair (HDR). When the researchers attempted to repair the DSB created by removing the HBB gene, they were unable to perform the repair with perfect control. This imperfect repair creates what are called mosaic embryos, making predicting the outcomes of gene editing impossible.  Here are some videos to help explain the process:

Not only were the researchers unable to control the repair process after removal of the HBB gene, they also observed cleavage of DNA at off-target locations in the genome. In other words, the method to remove the HBB gene removed additional pieces of the genetic code.  From these results, the researchers claim (correctly in my opinion) that the CRISPR-Cas9 gene editing system is not ready for clinical application. Clearly, much work needs to be done to improve the accuracy of gene removal and the reliability of putting proper genes back in place.

So, what are we left with? Scientists used cells that were never intended to develop fully into humans to demonstrate that gene editing technologies are dangerous and much more research should take place before we consider using these methods to improve the next generation. This study initiated a lot of discussion, some of it quite vitriolic,  but it seems that it was the small spark that triggered a burst of excitement and concern.

In a perspective article (paywall, sorryin Science in early April of this year, top scientists expressed their recommendations for the future of human genetic engineering. Though they do not cite the 3PN zygote study directly, they were most certainly aware of its imminent publication, motivating their release of the perspective piece. In it, they list four recommendations:

1) Strongly discourage, even in those countries with lax jurisdictions where it might be permitted, any attempts at germline genome modification for clinical application in humans, while societal, environmental, and ethical implications of such activity are discussed among scientific and governmental organizations. (In countries with a highly developed bioscience capacity, germline genome modification in humans is currently illegal or tightly regulated.) This will enable pathways to responsible uses of this technology, if any, to be identified.
2) Create forums in which experts from the scientific and bioethics communities can provide information and education about this new era of human biology, the issues accompanying the risks and rewards of using such powerful technology for a wide variety of applications including the potential to treat or cure human genetic disease, and the attendant ethical, social, and legal implications of genome modification.
3) Encourage and support transparent research to evaluate the efficacy and specificity of CRISPR-Cas9 genome engineering technology in human and nonhuman model systems relevant to its potential applications for germline gene therapy. Such research is essential to inform deliberations about what clinical applications, if any, might in the future be deemed permissible.
4) Convene a globally representative group of developers and users of genome engineering technology and experts in genetics, law, and bioethics, as well as members of the scientific community, the public, and relevant government agencies and interest groups, to further consider these important issues, and where appropriate, recommend policies.

Each of their recommendations are well founded and sensible. I'm really not seeing what all of the fuss was about. Are people in some hidden lab attempting to genetically engineer embryos to be brought to term? It is a strong possibility. But, we at the societal level cannot effectively block these sorts of efforts. Genetic engineering is coming, and I believe the approach that the Chinese scientists took for the most recent study is a good example for others to follow.  Let's all hope others are as responsible in the future.

Interstellar gets Some Science Wrong ... Who Cares? by James Wade

Source: Nasa

Source: Nasa

There has been a lot of criticism across the web (e.g., Robert Trotta over at The Guardian) about the scientific accuracy of Interstellar, Christopher Nolan's newest sci-fi thriller. There was a lot of hype surrounding this movie, in part due to physicist Kip Thorne's involvement and the simulations used to create the spectacular black hole visual. Thorne and Nolan have even published a book about the science behind Interstellar. I think that's the right approach. If you want to read accurate science, go read about it in a book or a journal. The movies are entertainment, not activism or outreach. Sure, Thorne admits his annoyance at the impossibility of ice clouds, but it is such a minor moment in the film and provides a surprising, albeit inaccurate visual.

Interstellar is not unique in receiving much criticism about scientific inaccuracies. Earlier this year, Lucy was widely mocked for spewing the common misconception that we only use 10% of our brains. What made this claim worse was that Morgan Freeman's voice repeating the fallacy in every preview of the widely marketed film. Sure, the statement is a tired one that has long since been debunked nearly as many times as it has been said. This can be frustrating to science communicators, but I think we overreact to the inaccuracy. I do not mean to place Lucy and Interstellar on the same level of accuracy in their depiction of scientific plausibilities. Rather, they represent the gambit of recent mainstream sci-fi productions.

This brings me to a larger point about science fiction more generally. The fantastical and implausible scenarios that run through science fiction literature are designed to make us ponder impossibilities. It is supposed to make us think, and these impossibilities inspire child-like imaginations. "What if we could use all of our brain power?" the middle schooler says to himself while watching Lucy tear apart bad guys on an elevator. "Could I really travel to the future by flying close to a black hole in a spaceship?" says the young girl while watching Matthew McConaughey make a face simultaneously reminiscent of loneliness and constipation on a spaceship soaring into another galaxy.

The role of sci-fi, of course, extends beyond the science. By framing a situation in an unfamiliar or unrealistic world, we are more willing to engage with controversial topics or push social boundaries as an audience. From Captain Kirk and Lt. Uhura's famous kiss to portraying the tragic consequences of climate change in Interstellar, sci-fi challenges the consumer to question, predict, and wonder.

Egregious scientific errors can be distracting to scientists and engineers, but we are not really the intended audience. There are occasional examples of the miraculous achievement: a scientifically accurate work. Andy Weir's The Martian springs to mind as a recent example. Literature and film, however, deserve some suspensions of our disbelief.  We do not watch Star Wars to learn scientific facts, we watch to get lost in the fantasy world in a galaxy far, far away.

At this point, I realize I'm whining about whiners, though I do find that criticizing the critics is necessary. We want to encourage scientific literacy, and that starts by making science approachable. Across social media, you can commonly find smug comments discrediting any mainstream depiction of science. It feels like no one can be excited about any of it without being dismissed as naive and shallow. We should be more welcoming as a community. Sure, identify the inaccuracies, but don't let them ruin the experience.

Anonymity is the Cure? Nature Nanotech's Double Blind Peer Review by James Wade

The journal Nature Nanotechnology is adding double-blind peer review as an option for new submissions. The intent is to increase objectivity, but they are ignoring a much better solution: transparency.

Damn review number three! That's the refrain commonly uttered by scientists, reflecting frustrations with the peer review process. Authors often lament that the anonymous reviewer must have a vendetta against them, and he or she is hellbent on ruining competitors' careers. This is largely hyperbole, but the perception of unfairness is common. To fix the issue, the editors at Nature Nanotechnology recently announced a change to the peer review process: make it double blind. The editorial announcing the policy change cites evidence of bias against women and against less prominent labs. I agree with the sentiment. The scientific community should seek to eliminate these biases. After all, the goal is to effectively communicate scientific discoveries regardless of their origin. But, is this the best way to move forward?

There is no formal training in reviewing papers in most graduate programs, creating enormous variety in quality and composition of the reviews. Graduate students are often called to review papers by their advisors, which helps PIs reduce their work load and provides an opportunity for students to experience the peer review process. It is vital, however, that advisors guide students through this process in the beginning. A recent editorial in Analytical Chemistry went into detail about crafting manuscript reviews, specifically citing the lack of consistency and training resulting in common dissatisfaction with peer reviews. 

One issue is that some among us equate writing a review as a directive to find and list all of the mistakes in the paper. Perhaps this is to be expected after years of getting comments back from instructors pointing out our mistakes and omissions. While it is important to note any problems, it is just as important to describe what is significant and novel in a manuscript. Not surprisingly, I have found that individuals who submit reviews without a single positive comment are often the ones that complain when they receive a similarly negative review.

In other words, it is no wonder that we are unhappy with reviews because most of us are writing reviews we would hate to receive.  The goal, contrary to the approach of many, is not to discover reasons to not publish the paper. The goal is to assess the worth of the research and to identify where (and if) the researchers should expand the paper to create a more compelling scientific narrative. Papers do not have to transform a field to be worthy of publication, and reviewers must remember that.

The best method to improve the peer review process - more so than training - is to increase openness and transparency. Why not allow the public to view the peer review process with identities attached to all involved? Hiding the reviews makes no sense in this digital age. If peer reviews are publicly available, then it becomes much easier to identify prejudice and unfair practice. We are called as members of the scientific community to participate in its cultivation on a scale much larger than our individual labs, and we should not be ashamed or hesitant to reveal our praise and criticism of papers. The transparency will also discourage reviewers from being unnecessarily harsh or demeaning or from tacitly approving unworthy science of our friends. In general, we tend to be better actors when we know someone is watching.

Scientists should not fear the peer review process, and we must not hide it. Attaching our identities to reviews should not hinder our willingness to comment genuinely, positive or negative. Peer review is the bedrock of scientific integrity. If we want reliable science, then we must position ourselves to ensure honesty and fairness in the ways our results are disseminated. Transparency is the way to do that, and transparency is the way forward.

Politics, Funding, and Bans: Don't Ask the Question by James Wade

Benjamin Franklin Drawing Electricity from the Sky by Benjamin West

Benjamin Franklin Drawing Electricity from the Sky by Benjamin West

Last week, congress voted mostly along party lines to amend the Defense Departments's budget, prohibiting the Pentagon from further investigating the effects of climate change or enacting any initiatives in response to the climate disturbances based on the reports from the Intergovernmental Panel on Climate Change or the National Climate Assessment. Healthy skepticism is an integral component to successful research, but in this instance, congress has overreached for political gains. The only chance for Republicans to ever "win" the climate debate is to allow further climate research to better understand the precise direction and underlying causes of any changes. The science will not change because of a politics. Of course, there are biases researchers inject into their investigations, but the goal of the scientific community is to sail beyond such individual predispositions and to arrive at the truth.

Congress carries unique powers in directing the focus of research efforts across the United States. Most recently, the Committee on Science, Space, and Technology threatens to cut major research efforts in the social sciences and humanities. The committee chairman - Rep. Lamar Smith (R-TX) - has spearheaded a new appropriations bill that slashes spending on research the committee deems inappropriate for taxpayer dollars. In addition to the spending reductions (note: spending on so-called hard sciences will increase slightly), Smith's bill also proposes new criteria for the the National Science Foundation (NSF) to use when allocating research funds. Currently, NSF focuses on two criteria: intellectual merit and broader impacts. The new metrics (see Sec. 106(B) for details) would urge the agency to focus on aspects such as economic competitiveness, development of a STEM workforce, and national security. These are certainly lofty goals, but many scientists worry that such guidelines would leave out much of the basic research that innovation in the sciences has relied upon (see NSF's Discoveries page for examples). 

The movement to change funding distributions for research at the federal level caught wind when Rep. Andy Harris (R-MD) voiced major opposition over a paper by Stanton Glantz, which traced the close involvement of Big Tobacco in the origins of the Tea Party. Harris, joined by Smith and Rep. Tom Coburn (R-OK) - himself a habitual critic of "wasteful" federal research spending - decided to take on these funding agencies to prevent what they view as wasteful research spending. In essence, Tea Party politicians went after research about the Tea Party they didn't like. Of course, NSF along with the National Institutes of Health (NIH) must be good stewards of their resources, but I find it frustrating that these and other congressmen choose to focus on a relatively small amount of US spending (combined NSF and NIH spending comprise less than 7% of US military spending) for ostensibly political motivations. What's more, the opposition primarily points to projects the representatives disagree with, rather than identifying fraud and abuse that plagues so much of our other government spending (especially defense spending). Again, the justification for going after research funding agencies appears to emerge more from an attempt to gain political brownie points than to best serve the American people.

In my current capacity as a researcher in training, my own funding and career path will be heavily influenced by the resources available for federal funding agencies. I certainly have some meat in the game, and I admit my bias is strong. To be clear, I don't mean for this to be an attack on the Tea Party or on the political right. My objection is to allowing political partisanship to dictate the research questions scientists and engineers can pursue. Science must be the guiding light. Legislators are within their right to enact laws and regulations to ensure that research remains within the moral imperatives of our country. Such imperatives must extend beyond party lines, and I judge that in these instances, the congressmen have gone too far.

Science as a pursuit of knowledge is apolitical and amoral in its purest form. Data acquisition and rigorous testing of hypotheses drive research from one locale to the next. The researcher ensures the work remains within ethical and fiduciary bounds, but progress more commonly emerges out of diligent record keeping than an individual's ingenious guidance. Arbitrary limitations on the direction research may turn serve to delay what is likely inevitable. Knowledge cannot be suppressed in an age of unprecedented global prosperity and connectivity.

We must remember: refusing to ask the question does not change the answer. The ones hurt by the results of scientific inquiry are the ignorant and the selfish.

Patents, Structures, and Licensing by James Wade

Kim Janda from Scripps recently discovered that the structure small molecule drug currently undergoing stage I/II clinical trials is incorrect.  The drug, known as ONC201, selectively triggers apoptosis in tumor cells. Researchers from Penn State originally reported on the therapeutic potential ONC201 (called TIC10 in the paper), and they licensed the drug to Oncoceutics to begin human trials. The key to the molecule's selectivity is the TRAIL protein (Tumor necrosis factor [TNF]-related apoptosis-inducing ligand). TRAIL is present at high levels in cancerous tissues but not in healthy ones. ONC201 binds to TRAIL and triggers apoptosis.

While the biochemistry is certainly fascinating, and Janda's discovery of the structural oversight is sure to create some bickering across academy, the newsworthy part of the story stems from what Janda does after discovering the structural error. Since any intellectual property related to the ONC201 is ostensibly covering the wrong structure, Janda decides to take advantage of the 'unpatented' active drug, and he licenses the drug to another company to begin independent clinical trials.

Beyond the fact that Janda's licensing deal is not exactly gentlemanly, the move could have major implications for pharmaceutical patents moving forward. For a small molecule, the issue is relatively straightforward (though the lawyers from each side will surely have a fit over Janda's move and the fate of ONC201). The confusion arises with the progression to more advanced pharmaceuticals, such as antibody therapeutics, antibody-drug conjugates, and nanomedicines.

Further, as sophisticated delivery mechanisms (e.g., spherical nucleic acids, MOFs, nanoparticles, etc.) continue to enter the clinic, it seems that the levels of intellectual property involved in a single treatment regimen is becoming overwhelmingly jumbled. With the advent of paired therapies in which a diagnostic procedure is coupled to a personalized therapeutic, the situation is only going to get even messier. While patent lawyers salivate at the jumbling, it is important to remember that the patient must be the ultimate concern. The complexity will almost certainly increase cost, but, hopefully, the end result will be adequate financial rewards for novel solutions to healthcare challenges.

Derek Lowe from In the Pipeline has a great overview of the story where his many years of industry experience provide a better context for the situation.