Could we rewrite the instructions for life?

Every living thing on earth is made from a genetic sequence that contains four different nitrogenous bases – adenine (A), guanine (G), cytosine (C) and thymine (T). You can think of these bases like letters in a language – different words arise depending on the way they are arranged. However, unlike the 26 letters we have in the English language, nature only has four. But marvelously, these four letters are used to write genetic codes for over a million different types of living species. It stands to reason then that these four letters are special; they’re selected, optimized, and entrusted by nature to hold the instructions for life.

But what if we could rewrite those instructions? A group of scientists were recently able to make a DNA sequence with four new, completely synthetic, nucleobases. This eight-letter genetic code combined the standard A, G, C, and T, with new letters Z, P, S, and B. Normal DNA sequences fold into the shape of a long, spirally structure called a double helix. This shape is crucial for the long-term storage of genetic information and is therefore necessary for preserving the fidelity of life. These scientists showed that different 8-letter DNA sequences were all able to maintain a double helical structure and also exhibit chemical and physical properties similar to normal DNA. To further demonstrate the legitimacy of these new letters, they also showed that their synthetic sequence could be used to make RNA, the functional genetic instructions that are “read” by cellular machinery to make living things.  

The successful advent of 8-letter DNA expands our ability to store information – with 8 letters, we could write the same instructions in significantly less space, improving the potential for DNA to be used as a hard drive of sorts. Additionally, synthetic DNA could have medical and biotechnological implications. Short sequences of DNA are sometimes used to locate specific molecules, such as those that are uniquely expressed in cancer cells. More base options allow for more specificity, improving the targeting properties of these DNA sequences.

Most profoundly however, synthetic DNA also suggests that our DNA isn’t particularly special. There isn’t something uniquely perfect about the four bases nature chose for life on earth – in fact, life on other planets could exist with completely different types of genetic information, and a DNA scan may be insufficient to survey for life. Even if we don’t find extraterrestrial life forms, research in this field could be en route to engineering its own synthetic organisms – which would maybe be too close to all those famous sci-fi dystopian movies for comfort.

Peer edited by Nicole Fleming.

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March Madness Mayhem: Analyzing Performance Under Pressure

March Madness has arrived, which means my alter ego – the one that worships Coach Roy Williams, mumbles curses against Zion, and says words like “offensive rebound percentage” – has officially been unleashed.  As I fervently check my NCAA bracket and get misty eyed at the mention of graduating senior Luke Maye, I am keenly aware that the success of my bracket and any team’s ability to ascend to the Championship comes down to how well players perform under pressure. This leads me to ask an important question for the sake of science (let’s face it, it’s really for the success of my bracket and perhaps yours): What is it that allows humans to execute a series of learned behaviors at peak performance under stress?

Fascinatingly, sports and athletic endeavors of excellence allow us to ask this question and make observations in a relatively controlled environment. Let me take you back to a crushing but incredible memory for many Tar Heels.  It was a dark night on April 4th, 2016 and my boys (during the month of March I refer to the Tar Heels as “my boys,” bear with me) were playing Villanova in the Championship game. With seconds to the finish, my main man Marcus Paige shot a three-pointer and the CROWD WENT WILD. Three seconds later, Villanova responded and dreams were crushed, babies were no longer to be named Marcus Paige, and bonfires were doused. HOWEVER, THAT IS NOT THE POINT. Within the last ten seconds of this harrowing game, two teams had the ability to hit three pointers within mere seconds of each other in the Championship game. Was it nerves of steel? Was it sheer grit and determination? Was it just basketball destiny that we were to fall so that we may rise again in 2017? As I thought back to Marcus, I reflected on what many psychologists and behavioral scientists consider a critical facet in performance: balancing eustress and stress.

Frankenhouser first introduced the term “eustress” in 1980 and denoted it as a positive type of stress, the kind of motivation that enables you to use that nervous feeling or mild anxiety and channel it into positive outcomes. Eustress differs from the negative form of stress (also referred to as distress) in that it is a low underlying level of stimulus rather than acute and sudden stress. How does this act of balancing eustress with distress actually work? So as it turns out, that low to moderate levels of controlled stress (e.g. consistent exposure to high stakes games but at regularly paced intervals) can really help mediate this balance. In addition, eustress is most present when there’s considerable joy experienced by the expended effort (e.g. you really love the game). Let’s think back to our scenario, both UNC and Villanova are big-name teams. These so-called “blue-bloods,” are the schools that consistently make it to the top 32, top 16 or even the Elite Eight year after year. This means that there’s substantial exposure to this environment over the course of a player’s career, and more importantly, senior players pass down these experiences to the incoming recruits. Both teams also have notorious rivals that push and magnify even regular season games to be of tournament calibre. So, in part this explains how both of these teams were able to place outstanding shots with 10 seconds left in the game. However, you may say, is that the only factor here? Did Marcus Paige truly abandon all distress in the face of Villanova to bring us back on the scoreboard? I believe in addition to moderate levels of consistent NCAA exposure, there was an important secondary factor in play for Marcus.

If we really break down how I think peak performance is achieved, we have to consider how fear and anxiety are accepted and internalized. We just discussed eustress and practice theory, in which you overcome stress and channel it into eustress with consistent hard work and exposure. But what if you can’t do that? What if the acute distress is truly overwhelming? I would like to bring in a non-basketball example for a brief moment to really drive this point home (yes, I will use basketball puns all day err’day in this article). Recently, National Geographic released a documentary on Alex Honnold free climbing El Capitan (the death tower of granite in Yosemite Valley) without any ropes or gear. Most people would cringe at the mere thought of this venture and some, myself included, may just pass out from the dizzying idea of plummeting 3000 feet. However, Alex did his climb successfully and with an immeasurable amount of calmness. When interviewed, he stated that it wasn’t the lack of fear of dying that allowed him to perform these feats. Rather, it was an acceptance and compartmentalization of that fear and the acceptance of the outcomes of failure. I think what makes peak performance under stress truly possible is a combination of training along with internalization of fear. What’s most important in a stressful situation is acceptance of distress, taking control of it, visualizing the possible outcomes, and being okay with moving forward. That said, it’s very well possible that in those final moments of that game against Villanova, Marcus Paige saw the final seconds of his college basketball career and accepted that situation, found joy in it, and made a career-defining move.

The Tar Heels and March Madness have taught me a lot of things, but above all, they have taught me a lot about how stress and anxiety can be channeled into productive outlets and how to rise above the pressure to try to do your best when you can. As Coach Roy Williams would say, “That’s a pretty daggum good basketball team.” Yes, I did watch a 1-minute sports clip of all of Roy’s choice game interviews to come up with that for this article, but he’s right because they are able to play well under pressure. I can’t wait to see how March Madness will conclude this year and look forward to see who will rise to become champions.

Peer edited by Keean Braceros.

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Dietary Supplements: The Uncomfortable Truth

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Dietary supplements by zone.

Unfortunately, the link between dietary supplement use and negative health impacts is not new. This is likely because the selling of these supplements is not controlled by the U.S. Food and Drug Administration (FDA). The FDA is the U.S. government agency that ensures the safety of the food, drugs, and even the cosmetics sold in this country. They ensure that there is scientifically sound evidence to support safe human and animal usage of these products. However, the FDA is not legally permitted to conduct research and lead safety investigations on dietary supplements before they have hit our markets (find out why here). Only after certain evidence is collected – such as records of hospitalizations – can the FDA then begin an investigation into assessing the safety of the supplements and confirming the identity of all the ingredients.

Shifting to a healthier lifestyle can be a monumental challenge, but often a rewarding one. It can also be a slow process. In and out of the gym environment, we’re constantly bombarded by ads, commercials, and fellow gym members all ranting about their quick solutions to dropping pounds, gaining muscle, or getting “bigger, faster”. It’s likely that some of these quick solutions involve the use of easily obtainable dietary supplements. In 2016 it was estimated that 70% of Americans use some form of dietary supplement. The uncomfortable truth is that while many of these dietary supplements claim to improve health and fitness, their use is often connected with emergency room visits, hospitalizations, and in extreme cases, death.

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Assessing the safety of supplements for human health is a multi-step process. A major stage of this process is assessing whether the supplement or a particular ingredient induces liver damage. The human liver is one of the largest organs in the human body, and plays a key role in removing chemicals and breaking down drugs in our body. For example, our livers break down the alcohol that is transferred from our stomach to our bloodstream after drinking. Excessive alcohol drinking can exhaust our liver, preventing it from completing its many other essential tasks like storing sugar for when our bodies need the extra energy. Like excessive drinking, supplements can also damage our liver. Specifically, supplements with high steroid levels hamper the liver’s ability to dispose of waste products.

Ultimately the usage of dietary supplements is a potentially dangerous game and the decision to take supplements should not be taken lightly. In fact, many of the key components of these supplements can simply be acquired from our diets. Thus, avoiding dietary supplements or consulting with a doctor beforehand is a much safer way to accomplish a healthier life transition.

Peer edited by: Kasey Skinner

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Climate change and environmental justice: a case study in ethics and science

A key part of the fight against climate change is to reduce greenhouse gases (GHGs). So, when a massive corporation reduces their emissions by an amount equivalent to taking 900,000 cars off the road, we should celebrate their efforts in “breaking sustainability barriers” – right? Shouldn’t we nudge other companies to follow their lead? In an era where our government is denying climate change, why wouldn’t we embrace our climate allies in the business world?

A report was recently released about how Smithfield Foods is meeting its pledge to reduce GHGs. Since 2013, Smithfield has worked in partnership with the Environmental Defense Fund (EDF), a nonprofit at the forefront of environmental sustainability. As the EDF attests, it is true that Smithfield is leading other food industries in cutting GHGs. Yet it is also true that Smithfield continues to extort marginalized communities here in North Carolina.

In this article, I use the case of Smithfield Foods to ask broader questions about ethics and advocacy. I challenge my fellow scientists to consider how power is distributed between industry, academia and communities compared to how it should be distributed. Before we follow the EDF and hold Smithfield up as a role model, we must ask ourselves: if we’re only focused on reducing GHGs, on whose backs are we fighting climate change?

Smithfield Foods

The bacon on your BLT, the pork in your sausage and the carnitas in your taco likely all come from the same source: Smithfield. The scope of their business is massive, and in 2013 they were acquired by a Chinese company, WH Group. Smithfield is both the world’s largest hog producer and pork processor, which means that they raise and slaughter pigs and package meat for distribution. In 2017 alone, global sales exceeded $15 billion. In North Carolina, Smithfield owns 225 hog farms and contracts 1,200 of the state’s 2,200 hog farms (altogether this accounts for 90 percent of North Carolina’s hog production).

Smithfield hog farms are Consolidated Animal Feeding Operations (CAFOs), where hogs are raised in large barns where they eat, sleep and defecate. The shift from pastures to CAFOs has been a seismic shift in North Carolina’s hog industry. In 1974, there were 22,975 hog farms and 1.4 million hogs in North Carolina. Today, there are 2,200 hog farms and over 9 million hogs. All of those hogs need to eat a tremendous amount of grain, which they then digest to produce a tremendous amount of waste. To put “tremendous” in perspective, consider that there are 10.3 million people in North Carolina. Imagine that each person weighed between 300 to 700 pounds, and that these giant North Carolinians lived almost exclusively in three counties. Now imagine that the volume of waste produced by these animals was stored in uncovered, football field-sized pits.

Hogs and Environmental Justice in North Carolina

If you didn’t know your pork chops came from Smithfield, you may have heard about them in the news. Smithfield has been heavily criticized for its waste management practices, which were brought to national attention last year due to a series of nuisance lawsuit settlements and contamination caused by hurricane-related flooding. Stick with me in this section – the injustices perpetrated by Smithfield run deep, but this understanding is necessary to engage with the ethics questions at the end.

The waste management practices in question involve the contamination of lagoons and sprayfields, which have been the focus of most environmental justice organizing against Smithfield. In an industrial hog operation, barns are constructed so that waste falls through holes in the floor and then is periodically flushed out into outdoor waste lagoons. As of January 2018, North Carolina’s Department of Environmental Quality (DEQ) had issued hog farms permits for the operation of over 3,700 waste lagoons. When the lagoons become full, liquid waste is sprayed on to nearby fields. As you can imagine, this leads to a number of problems: the build up of nutrients and metals in the lagoon water contaminates nearby groundwater and surface water through lagoon leakage or spraying; methane, hydrogen sulfide and nitrous oxides are released as the organics in the lagoon water decomposes; the risk of lagoon flooding during storms increases; and spraying  aerosolizes fecal water. The odor and pollution impact people’s health and quality of life. Although DEQ waste permits specify when, where, and how much lagoon waste can be sprayed, the process is self-regulated and frequently violated by hog farms. Besides waste management, neighboring communities are also affected by the use of antibiotics in animal feed, pollution from the storage of dead pig carcasses, and heavy truck traffic.

What makes this environmental pollution an issue of environmental justice? According to the US Department of Energy, environmental justice ensures that “no population bears a disproportionate share of negative environmental consequences” and that historically marginalized populations have a seat at the table when environmental decisions are to be made. Hog operations, however, disproportionately affect low-income communities of color. In North Carolina, African Americans, Latinos, and Native Americans are 1.4, 1.26, and 2.39 times as likely, respectively, to live within three miles of at least one hog operation. In total, an estimated 1 million North Carolinians live within three miles of hog operation, and over half of them live within three miles of two or more. In fact, about 16,000 residents live within only half a mile of 2 – 5 industrial hog operations [reference: public comment submitted by UNC faculty and students regarding the renewal of NC’s animal operations general permit]. A recent study found that residents living near industrial hog operations had a higher risk of infant mortality and low birth weights as well as higher risk of adult mortality from anemia, kidney disease, tuberculosis, and blood bacterial infections as compared to communities of similar demographics.

Civil rights groups have taken two legal strategies to advocate for these communities. First, in 2013, 600 residents filed 26 lawsuits against Murphy-Brown LLC, the subsidiary of Smithfield that produces the majority of Smithfield’s pork in North Carolina. This started a series of retaliatory steps by Smithfield and its allies in the North Carolina legislature. Immediately after the lawsuits were filed, the General Assembly made it more difficult to file nuisance lawsuits against agriculture (Right to Farm Act). In 2017, the General Assembly passed HB 467, limiting the total compensatory damages that can be awarded in nuisance lawsuits. HB 467 was sponsored by Representative Jimmy Dixon from Duplin County, which is home to over 500 industrial hog operations. In 2018, after the first trial ended and a jury awarded the plaintiffs $51 million, the General Assembly passed SB 711 by Senator Brent Jackson and Rep. Dixon, both of whom receive contributions directly from Smithfield or from political organizations funded by Smithfield. SB 711 further limits when a nuisance lawsuit can be filed as well as when punitive damages can be awarded. Both HB 467 and SB 711 were passed over Governor Roy Cooper’s veto. In the three cases settled in 2018, plaintiffs were awarded $51 million, $25 million, and a historic $473.5 million in damages, but these were reduced to $630,000, $3.2 million and $118 million, respectively, due to HB 467 and SB 711. An additional two cases have been settled, both finding Smithfield Foods at fault. Although plaintiffs were suing Murphy-Brown and not individual farmers, Smithfield chose to remove hogs from the specific farms involved in each of the three settled lawsuits, putting the hog farmers out of business. Smithfield has successfully framed nuisance lawsuits not as a right of property owners, but as an attack on farming families. Since hog farmers tend to be white and the plaintiffs are mostly people of color, this has flared tensions along racial lines.

Civil rights groups have used another legal tool: appealing to the Environmental Protection Agency (EPA) to fight the North Carolina Department of Environmental Quality (DEQ). In 2014, the Waterkeeper Alliance, North Carolina Environmental Justice Network (NCEJN) and Rural Empowerment Association for Community Help (REACH) filed a complaint with the EPA that the DEQ was violating Title VI of the Civil Rights Act of 1964, which prohibits entities receiving federal funding from acting in ways that disproportionately harm communities of color. As mentioned previously, the DEQ grants permits to hog operations so they can have waste lagoons that, in turn, harm neighboring communities of color. Former North Carolina Governor Patrick McCroy had disregarded public requests to account for the racial and ethnic impacts of the hog industry when issuing waste permits. Under his tenure, civil rights groups attempted to negotiate with DEQ over the Title VI violation, but civil rights organizations were subject to intimidation by the hog industry. However, under Governor Roy Cooper, the DEQ has cooperated with the EPA and formed an Environmental Justice and Equity Advisory Board. As part of the settlement, DEQ will be more transparent about how it investigates animal waste complaints.

Finally, it is worth noting that Smithfield’s business practices do not only negatively impact neighboring communities, but the farmers themselves. Contract farming is responsible for 81% of hog production for Smithfield. In these contracts, farmers supply labor and equipment and are responsible for waste disposal (the part of the business that costs money), but Smithfield owns the feed and the pigs (the part of the business that makes money). This arrangement puts contract farmers in a financially difficult situation. The debt they face after constructing facilities keeps them vulnerable to their terms of contract and they are not left with sufficient resources to upgrade their facilities beyond what Smithfield requires. Furthermore, Smithfield controls almost every part of the supply chain in eastern North Carolina, from the distribution of grain-based feed supply to pork processing plants, a process called vertical integration. This means that even if a farmer wanted to break a contract and convert their land to a smaller hog farm, they would be operating in a place without easy access to feed or processing plants to support their business.

Didn’t the EDF say there was good news? Smithfield’s Sustainability Goals

In 2010, Walmart approached 15 of their major suppliers to lower their GHG emissions (an initiative which they renewed with their 2017 Gigaton Challenge to reduce emissions among suppliers). As a result, in 2013, Smithfield partnered with the Environmental Defense Fund to reduce emissions, largely by reducing fertilizer loss from grain production. The details of their progress were published in the case study mentioned earlier. Indeed, Smithfield has met their target for reducing GHG emissions from grain farms and feed milling, and has supported the majority of farmers from which they source  to adopt more sustainable fertilizer practices.

However, the case study points out that while 19% of Smithfield’s GHG emissions came from grain farms in 2018, 43% came from manure management. This refers to the methane and nitrous oxides given off by open waste lagoons. Smithfield is now turning towards biogas technology to address this issue, which captures methane and other gases and refines them into natural gas that can be used for energy. Biogas is a promising technology for curbing emissions, creating jobs, and providing renewable energy for North Carolina. However, Smithfield’s current plans do not involve community advocates nor do they ensure that their waste management practices will comply with environmental standards set by the North Carolina General Assembly in 2007 for new hog operations. Waste will still be pumped into lagoons that may pollute groundwater or be prone to overflow in storms, and effluent will still be sprayed on to neighboring fields. Smithfield has yet to include host community benefit agreements as part of their plan.      

The EDF and Smithfield have a clear strategy for environmental issues: make progress by putting aside differences and focus on common ground. This led to the successful reduction of GHGs through supporting grain farmers. This strategy seems pragmatic. However, after six years of partnership, at what point is pragmatism a euphemism for complicity?

Advocacy and hard questions

This case study illustrates how systems and sociopolitical context influence the way the scientific challenges of our day, like climate change and environmental justice, are tackled. Smithfield is an example of a powerful corporation both making meaningful contributions to fighting climate change through reductions in GHGs, while at the same time polluting the environment and investing heavily in the perpetuation of environmental injustice.

Yet if Smithfield can pay for lawyers to fight nuisance cases, buy the influence of North Carolina representatives, and support monarch butterfly preservation, they certainly can afford to compensate communities suffering from their hog operations and remediate the damage they have caused. And if the Environmental Defense Fund is truly committed to their mission of protecting our climate and human health and truly values ethical action, they should be transparent about the injustices Smithfield still has to right.

There are three main calls-to-action I would like to put forth.

1: Learn from communities. If you conduct research in a field related to identifying and treating hazards, recognize the expertise of communities affected by these hazards and learn how to support community organizing. Community-based participatory research (CBPR) is a method that involves the community in every step of the research process, using their lived experience to drive research questions, collect data and interpret results. In this way, CBPR transforms “research from a top-down, expert-driven process into one of co-learning and co-production.” For example, when UNC’s Dr. Steve Wing investigated the health effects of living near hog operations in North Carolina, the project was a result of working with community members rather than simply in communities. Through their lived experience, community members best understood the kinds of healths effects of living near CAFOs, the relationships between different community members, and the relationship between Smithfield and contract farmers. When results were published, community partners were included as coauthors. Even if findings are not published, communities can use them as evidence when pushing for change, such as submitting public comments to local government or in court.

If your research is relevant to community health, how do you engage communities? Do you value their expertise? Are they involved in research design? Do you invest time into building trust and relationships? Do you compensate community members for their time? Do you present or disseminate results in a way that’s accessible, relevant and empowering for communities?

As an aside, if you follow no other link in this article, I urge you to read more about the late Dr. Wing here or here.

2: Be an engaged scientist. CBPR is most common in the health and environmental sciences, and not all STEM fields lend themselves to community engagement. For example, understanding the chemical bonds in tertiary protein structure or figuring out how to travel to Alpha Centauri  are scientific endeavors that expand our knowledge of how the world works. We do them because, as Mae Jemison has said, “pursuing an extraordinary tomorrow builds a better today.”

However, there are still ways to be an advocate in science, regardless of your field. Be aware that every stage of the scientific process is influenced by the politics of scientists, funders and institutions: the questions to be answered, the datasets to be used, the solutions that are offered and the way solutions are evaluated. This reality reflects the importance for diverse perspectives, both by increasing representation from marginalized communities within the scientific community as well as developing equal partnerships with communities themselves.

In addition, be vigilant against the influence of special interests in science. Advocate for a democratic scientific process in the institutions you work in. Unfortunately, the publication and dissemination of scientific findings are vulnerable to industry and political pressures. Recently we have seen this at the EPA with climate change. At UNC, Dr. Steve Wing’s documents were seized by North Carolina’s Pork Council, a special interest group funded by Smithfield.

How can science advance the public good when research is increasingly privately funded? Is any of your institution’s funding tied to special interest groups, and does this give science a lack of power? How can an academic best partner with community organizers to advocate for change, when institutions may have mixed support for more progressive and political causes? Is there an equal sharing of power between your research institution and communities?

3: Be an engaged citizen.  Show up to fight for a more equitable and sustainable future.

There are some individual actions you can take. Voting is one. In North Carolina, Governor Cooper unsuccessfully tried to veto HB 467 and SB 711, two pieces of legislation mentioned earlier that have dismantled community power, making it harder to file nuisance lawsuits and reducing the compensation plaintiffs can receive. Governor Cooper will be up for reelection in 2020, and many of his potential opponents receive contributions from Smithfield and  plan to use his support for HB 467 and SB 711 against him. You can also buy pork products from small, sustainable farms, such as Cane Creek Farms in Saxapahaw.

Unfortunately, in a gerrymandered state, your vote is not enough. In a consolidated food system, with large corporations like Smithfield, buying local is not enough. We must advocate for systems changes. Fighting climate change or environmental injustice both require a combination of public education, political legislation and engaged corporations.

As Dr. Wing advocated, “we need to insist that industrial producers pay for their damages to human health and the environment.” The most important direct action you can take is to aid organizations that uplift the voices of affected community members, through donations or volunteering. We must support their efforts to raise awareness of their issue, to lobby political leaders for increased regulation and enforcement and to negotiate with corporations. In the case of Smithfield, you can support NCEJN or REACH. If you are financially able, you can donate. You can also volunteer your time.

How else can you advocate for communities and support their right to self-determination? How can we work to make systems changes while up against corporations with large lobbies? And in pursuing a career in science where objectivity is valued, in a world where future employers in academia or industry will google who you are, are you willing to speak truth to power as a citizen to demand systems change?

I don’t pose these as rhetorical questions. I would love to hear what you think. Please leave comments! Or email me, at amlacko@ad.unc.edu

I would like to thank Justine Grabiec for her help with editing. I would also like to give a special thanks to Danielle Gartner, Adrien Wilkie, Mike Dolan Fliss and Libby McClure for their thoughtful comments on how to improve my framing of this article, for their links to additional resources, for their continued partnership with organizations like NCEJN and REACH, and for all they do to keep Dr. Steve Wing’s legacy alive through the Epidemiology and Justice group. You all are rockstars.

Peer edited by Justine Grabiec and Rita Meganck..

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Chemistry of Antihistamines, Nothing to Sneeze At

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Springtime in Chapel Hill

March in North Carolina brings out one of the country’s greatest rivalries. No, I’m not talking about UNC vs Duke basketball. I’m talking about when the flowers start to bloom in the Tar Heel state, and pandemonium ensues. North Carolinians run to their local pharmacy to pick up their preferred allergy medication: according to US News and World Report, cetirizine (Zyrtec) and loratadine (Claritin) are neck-in-neck for the top pharmacist-recommended over-the-counter allergy medication. As an organic chemist and sufferer of seasonal allergies myself, I was curious: how do antihistamines work, and is one better than the other?

To understand the differences between these two medications, we need to go back to 1910, when histamine (aptly named for containing an amine, or NH2, in the structure) was first studied. Histamine is a small molecule that is formed from the amino acid histadine through enzymatic removal of carbon dioxide. Histamine is released when allergens enter the body. It can then bind to a four G protein-coupled receptor which causes the allergy symptoms we are familiar with, including itchy eyes, stuffy nose, and sneezing.

Histamine vs Diphenhydramine

Antihistamine medicines are antagonists that compete with histamine for receptor binding. The first generation of antihistamine drugs, most notably diphenhydramine, (aka Benadryl), sought to mimic histamine.  Histamine and diphenhydramine are small molecules with many structural similarities; scientists determined that the functional groups necessary for histamine binding are an amine, or nitrogen (red), a linker containing 2-3 atoms (green), and an aromatic ring (blue). Antihistamines are more lipophilic than histamine because they have two aromatic groups (blue) and have carbons attached to the nitrogen (instead of hydrogens). Though molecules like diphenhydramine work very well at competitively binding histamine and reducing allergy symptoms, first generation antihistamines are small and structurally simple. Because of this, they have potential to bind to many other receptors in the body and can easily cross the blood brain barrier, creating many side effects including drowsiness.

Second Generation Antihistamines

The second generation antihistamines sought to have higher H1 receptor selectivity and lower brain penetrability. You will notice the second generation antihistamines like cetirizine (Zyrtec) and loratadine (Claritin) have the same important binding features as diphenhydramine, including a nitrogen connected to an aromatic ring via a small linker. This is structurally similar to the linear amine found in Benadryl and binds similarly. However, the major structure change between the first and second generation antihistamines is the addition of a carboxyl (or CO2) group (pink). Though loratadine does not have a carboxyl group as drawn, it is a prodrug: it undergoes a change in the body to make it into the active pharmaceutical molecule. The prodrug reacts with water in the body to form a carboxyl group. Under physiological pH, amines are protonated to form a positive charge, and the -OH of the carboxyl is deprotonated to form a negative charge. When a positive and a negative charge exist in a single molecule, it is called a zwitterion. Because zwitterions do not readily cross the blood brain barrier, many of the adverse side effects (like drowsiness) from the first generation antihistamines are not present in diphenhydramine and cetirizine.

https://www.flickr.com/photos/jeepersmedia/17352284302
Zyrtec is an over-the-counter antihistamine.

In general, it is accepted that Claritin and Zyrtec work similarly to one another. Because they bind the same receptor and have similar functional groups, they are seen as equally as effective. Some people react differently to the different active ingredients. Zyrtec starts working faster, sometimes within one hour, but Claritin tends to last longest in the body, which results in longer-lasting side-effects. Additionally, they interact differently with other medications. Loratadine may not be broken down as easily in the presence of erythromycin, cimetidine, and ketoconazole, which can result in increased side effects,but typically does not present a problem. Similarly, theophylline has a similar effect on cetirizine, and can increase drowsiness. Doctors recommend trying both and sticking with the one that seems most effective for you. This spring, I hope that a new understanding of antihistamines helps suppress your symptoms, no matter which allergy medicine you “ah-choose.”

Peer edited by Clare Gyorke.

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Your Guide to the CRISPR Babies

Imagine a future in which we can edit genes like a sentence in Microsoft Word. We could highlight, delete, and correct a section of a gene known to cause disease, virtually eliminating the devastating genetic illnesses that cost the world billions of dollars and countless hours of heartache every year. This is a future envisioned by many scientists working on the CRISPR-Cas9 system of gene editing. These researchers have used the technology to cure everything from liver disease to cataracts in mice. Ethical concerns have limited these experiments to model organisms and until recently, on-demand gene editing in humans seemed like more of a science fiction fantasy than a potential reality. All of that appears to have changed, however, with a Chinese scientist named He Jiankui claiming to have successfully used CRISPR to delete an HIV-related gene in two human babies late last year. This claim has stirred up quite a bit of controversy, to put it lightly, in the scientific community, but why is it such a big deal? Let’s take a closer look at the experiment and the hopes and concerns it brings to light.

A CRISPR introduction

CRISPR, short for CRISPR-Cas9, stands for “clusters of regularly interspaced palindromic repeats.” The major player in the CRISPR system is Cas9, which is a protein that acts like molecular scissors to chop up DNA. This system first evolved as a bacterial defense mechanism that targeted Cas9 to common sequences found in viruses, allowing the bacteria to chew up viral DNA and prevent infection. However, scientists then discovered that Cas9 could be targeted to just about any sequence of DNA they wanted. The secret lies in how Cas9 targets specific DNA sequences: the protein works together with a piece of RNA called guide RNA that matches up to the target DNA sequence. Modify this RNA and you can cause Cas9 to cut up whatever DNA you choose. Thanks to DNA repair, scientists can even provide a template sequence, say to correct a bad version of the gene, that can be incorporated into the DNA cut by Cas9 to fix a genetic mutation. These manipulations can be done in cells in a dish or even by injecting the CRISPR components into animals.

An overview of using CRISPR to delete a segment of DNA. Made using biorender.io.

The first CRISPR humans?

Until last November, using CRISPR to induce inheritable changes in live organisms was restricted to animals like fruit flies and mice. However, on November 26, 2018, the Associated Press reported that Chinese scientist He Jiankui claimed to have successfully used CRISPR to delete a gene associated with HIV infection in two human embryos. The edited embryos were created using in vitro fertilization (IVF), checked for successful editing after CRISPR treatment, and implanted back into the women who donated them. Allegedly, the edited embryos resulted in the birth of healthy twin girls. The gene Jiankui claims to have deleted encodes the protein CCR5, a human cell surface receptor that the HIV virus requires to infect immune cells. Essentially, deletion of CCR5 results in no HIV infection. This manipulation, Jiankui says, could protect the children from acquiring HIV and has broad implications for the management of HIV from a public health perspective. From a basic science perspective, the birth of children from CRISPR-edited embryos is an incredible achievement. However, as with almost every method of genome editing, the ethical controversy of Jiankui’s work has become just as important as the scientific implications.

Ethical and scientific concerns

One of the largest outstanding questions surrounding the alleged CRISPR babies is the fact that they are just that: alleged. Jiankui has not published the results of his manipulations in a peer-reviewed scientific journal and the identities of the children’s parents have been kept private to protect them from media scrutiny and potential backlash. However, let’s say that Jiankui actually did successfully delete the CCR5 gene in embryos that went on to become healthy human babies. What’s the problem with that? First, although some people have naturally occurring mutations that inactivate CCR5, the changes that Jiankui made in the embryos do not appear to mimic those natural mutations, leading to concerns about potential unintended consequences. Additionally, a well-known issue with CRISPR is its potential for off-target effects, or making changes in genes other than the targeted one. Finally, even if CCR5 was correctly inactivated with no off-target effects, the naturally occurring inactivating CCR5 mutations have been shown to have negative health effects, such as increasing the risk for infection and complications of West Nile virus. The scientific consensus is that using CRISPR to make such drastic, inheritable changes is unsafe simply because we don’t know enough about it yet. Ethically, a large concern with gene editing in humans is the old slippery slope argument: if we can delete disease-causing genes, what’s to stop people from editing embryos to select for traits like eye color or intelligence? Along the same lines, proponents of CRISPR gene editing in humans speak of “curing” conditions with a probable genetic basis like autism. However, advocacy organizations like Autism Speaks say this is a fundamental misunderstanding of this complex condition and that many people with autism view it as an inextricable part of themselves, not a disease to be cured. For these reasons and more, the larger scientific community has condemned Jiankui’s alleged experiments as risky and unethical. More extensive experiments in model organisms and strict ethical guidelines are needed before scientists can even think about bringing CRISPR into the mainstream.  Although this technology seems like it could be a magic bullet for genetic editing, it’s clear that the way forward is uncertain and each new advance creates more questions than it does answers. For now, at least, a world of CRISPR on-demand is still a distant future.

Peer edited by Rachel Battaglia and Breanna Turman.

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Data Storage: Easy as ATCG

In the digital age, our world revolves around data. Archives of data provide proof of our own existence, such as birth records and proof of the mundanity of everyday life, like that grocery list you wrote in your Notes app. Tech companies in particular create a demand for efficient and secure data storage that is beginning to outstrip our current ability to store and retrieve this information. Today, we produce an almost inconceivable 16 zettabytes of data per year (1 zettabyte = 1 billion terabytes). Some estimates suggest that by 2040, worldwide data storage needs will outpace the expected supply of microchip-grade silicon, a material commonly used to store computer memory. As our data storage needs quickly near the limits of existing technology, data storage innovators have begun to look within themselves for solutions. Specifically, researchers have started to look within their own cells to the quintessential storage platform: the DNA molecule.

Server farms, or data centers, like the one shown here, consume massive amounts of energy and generate a significant carbon footprint. These data centers house information for major technology companies and cloud computing.
Image credit: By BalticServers.com – Self-photographed CC BY-SA 3.0
commons.wikimedia.org/w/index.php?curid=26575836

DNA, nature’s bespoke server farm, can store a data density of about 214 petabytes per gram (1 zettabyte = 1 million petabytes). That means that the 16 zettabytes of data that we currently produce per year could be stored in about 75,000 grams of DNA, or about 75 kg, the mass of about four large German Shepherds. Although biological molecules aren’t always associated with durability, DNA can withstand the test of time. When stored in a dry, cool place, DNA lasts for thousands of years, as evidenced by DNA sequenced from long-dead organisms including a 700,000 year old horse. Another advantage of DNA storage is that the tools required to copy data exist in each and every one of our cells: DNA polymerase, an enzyme which can read and copy DNA ad infinitum.

So far, plans for storing and retrieving data from DNA involve a specific workflow pioneered by Yaniv Erlich and Dina Zielinski. First, the files to be stored are encoded as binary strings of 1s and 0s, the ubiquitous language of computers. These binary strings of information are then assigned to short stretches of DNA using an algorithm the researchers call the “DNA Fountain.” From here, DNA can be synthesized in short tracts by biotech companies. By sequencing the DNA, the information contained within can be reassembled in the proper order to reconstitute the original files. Remarkably, the researchers reported complete fidelity in data retrieval – each of the files was entirely intact after being encoded in DNA.

Scientists have encoded files like books, movies and even entire computer operating systems within the DNA molecule.
Image credit: TheDigitalArtist on Pixabay

Storage of information in DNA is not without its drawbacks. For example, the DNA polymerase molecules that replicate DNA are not error-proof. In fact, errors introduced by unfaithful replication are the grist of genetic variation and the basis of natural selection. However, scientists are hard at work designing algorithms that make DNA storage systems more refractory to these natural coding errors.

Furthermore, the capacity for efficient and compact data storage using the DNA molecule is still being expanded. Groundbreaking scientists have recently synthesized DNA made up of eight base pairs rather than four. Including our classic favorites, A, C, T and G, Hachimoji (“eight letters”) DNA also features four new base pairs: P, Z, B and S. The doubling of the DNA code has the capacity to dramatically increase the density at which information can be stored in the molecule.

The need for data storage will only accelerate in the years to come. In the meantime, scientists are taking inspiration from the DNA molecule: the solution nature has already been tweaking for four billion years.

Peer edited by Joanna Warren.

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My Scientific Training Brought Me to My New Favorite Book Genre

‘Tis the season of failed New Year’s resolutions

It was about this time last year that I found myself falling flat on the admirable New Year’s resolutions I had set. My daily yoga routine had evolved into a 30 second toe-touch in the morning and my new eco-friendly products were still in a shopping list on Amazon. As a 4th year graduate student all too familiar with failed experiments, I couldn’t stomach an unsuccessful project at home as well. Luckily, pursuing a PhD comes with strong problem solving skill sets. What is Step 1 of The Scientist’s Plan of Attack when faced with a problem? Turn to the literature to see if a solution has already been found. This is how I found myself in the societally constructed land where sad, desperate singles with three too many cats hang out: the self-help aisle at the bookstore.

Rather than using SciFinder to tease out quality sources, I turned to Goodreads to sort through books that could help troubleshoot my failed resolutions. My first self-help purchase was “The Willpower Instinct” written by Kelly McGonigal, a health psychologist. Professor McGonigal (Harry Potter fans rejoice) wrote the book based on a course she taught at Stanford about the science of willpower. After a few years of teaching and feedback from her students, she wrote this book outlining the currently accepted research associated with willpower, peppered in with some anecdotes from her students and how they applied the conclusions from these published studies to their own habits. Between the author’s credentials, solid reviews, and over 20 pages of references in the back of the book, this seemed like a good place to start.

It’s a year later, and I am now one of those people that goes around flinging self-help book recommendations to anyone who mentions a personal problem they’re having and constantly saying things like “this book changed my life”. But… this book changed my life.

“Self-Help” has taken on such a negative connotation that many bookstores re-brand these aisles with names such as “Personal Growth”

McGonigal walks us through a series of published rat and human studies that identifies two separate parts of the brain that either experience anticipation of a reward or the pleasure from the reward itself. In other words, while the anticipation of binging Netflix sure feels more rewarding than anticipating 20 minutes of yoga, this book taught me to pay attention to how much pleasure each activity actually brought me. I immediately found that I felt happier and less anxious during and after yoga, while watching TV left me feeling less refreshed. After learning to be mindful of what I was anticipating versus actually enjoying, I had a better shot at ignoring the distracting anticipation of a television reward.

I also learned that I was using what psychologists call “moral licensing” to give myself permission to not adapt green habits because of the little things I did, like making a saved shopping list on Amazon or sharing articles on social media. She cites many studies demonstrating the ways consumers use small green actions to assuage their guilt for participating in more harmful behaviors. After realizing what I was doing, I took concrete steps to switch to reusable grocery bags and decline plastic straws at restaurants. However, I wouldn’t let that give me permission to make more wasteful decisions later in the day.

My new identity as a self-help book reader is a year old and I am still learning new cheat codes to navigating adult life with each addition to my library. However, the stigma of the genre makes my recommendations for others often fall on the ears of unwilling readers. My 2019 New Year’s resolution? Convince you, the reader, that this genre deserves a re-brand and a chance. As scientists we are trained to find reputable sources of information, and as graduate students we have a remarkably high chance of suffering from mental illnesses. Let’s use our skill set to find quality self-help books to add to our artillery of problem solving tactics that can be applied to ease some of these stresses that make it home with us after a long day in the lab. I hope to one day walk into the self-help aisle and see lonely, desperate singles with three too many cats and any other person who wants to be a proactive researcher and peruse the literature to find personal solutions to any minor problems they find themselves needing better resources to solve.

Peer edited by Rashmi Kumar.

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Watch what you drink! Or, can you?

GenX protest in downtown Wilmington (StarNews)

Do you remember when Wilmington, NC made national news in 2017 for having serious chemical contamination in their drinking water? An investigation by the EPA had identified that a chemical-manufacturing plant Chemours (a spin-off of DuPont, one of the largest chemical-manufacturing companies in the world) had been dumping the chemical known as GenX into the Cape Fear River, which is a drinking water source for residents of Wilmington. The issue was that, at that time, there was only limited information on GenX, a relatively new man-made chemical. Despite the limited information, the State ordered Chemours to stop their dumping. Perhaps a previous lawsuit against DuPont regarding C8 helped facilitate the State’s decision? Even so, there is still an ongoing effort to investigate and prevent GenX contamination in the area. The good news is that on February 14, 2019, the EPA announced a nationwide action plan for PFAS (per- and polyfluoroalkyl substances), in which GenX is included.

PFAS are a group of man-made chemicals, manufactured and used widely since the 1940s. They are often used in food packaging to make things grease and stain resistant (Teflon is also a type of PFAS!) but are also found in firefighting foams and have industrial applications. The drinking water contamination reported in Wilmington is an example of high-level exposures to such PFAS, and similarly, there could be other communities that are exposed to drinking water contamination from industrial facilities or places that use firefighting foams. Elevated PFAS exposure is concerning since these substances accumulate in our bodies, and an increasing number of studies link high-level exposures to adverse health outcomes.

Chemical structure of PFAS: commonly used (PFOA & PFOS) and emerging (GenX)
Source: EPA PFAS infographics

Amongst PFAS, the two of the most commonly used chemicals were PFOA (perfluorooctanoic acid) and PFOS (perfluorooctanesulfonic acid).
An increasing number of studies observed PFOA and PFOS accumulate in the human body and linked them to adverse health outcomes related to infant birth weights, immune system, cancer, and thyroid function. Due to the increasing health concerns, US manufacturers voluntarily phased out the two PFAS chemicals between 2000 and 2002, replacing them with new PFAS such as GenX. However, there is limited information about the potential adverse health effects in humans for the emerging PFAS, and we can still be exposed to PFOA and PFOS on multiple occasions. You could be unknowingly exposed to high levels of emerging PFAS, as in the case of drinking water contamination in Wilmington. Maybe you still use some consumer products that were manufactured before the phase-out of PFOA and PFOS. Even if you managed to get rid of all those products at home, PFOA and PFOS may be present in our surrounding environment since they do not break down easily. Or, consumer products manufactured internationally may contain PFOA and PFOS, if these substances are not regulated as in the US. So you can see here how difficult it would be for an individual to avoid high levels of exposures to chemicals that are known to be harmful to human health, and a combined effort at a population level is needed, like the PFAS action plan released by the EPA.

Current guidelines on PFAS by State
(Bloomberg Environment)

The PFAS action plan consists of regulatory actions to restrict on the known “bad actor” compounds, along with short- and long-term plans to better understand the exposure levels and potential health outcomes associated with PFAS, including the emerging compounds. Since PFOS and PFOA are the most commonly used types of PFAS with evidence of harmful human health effects, they are a high priority in administering regulations. Currently, PFAS are not regulated and there is only a non-enforceable and non-regulatory advisory level called “health advisory level”. The health advisory level, established in 2016 for PFAS, state that if both PFOA and PFOS are found in drinking water, the combined concentrations of PFOA and PFOS at 70 parts per trillion is the margin of protection for all Americans throughout their life. To enforce mandatory and nationwide regulations, the EPA is planning to include PFOA and PFOS in multiple laws and regulations.

There is no doubt that the comprehensive action plan for PFAS laid out by the EPA will help communities that are already affected by PFAS contamination, and advance the current state of knowledge. However, there is one more issue that requires careful attention – a concept called “regrettable substitution”. Under the current system, implementing regulations on a substance with known adverse human health effect could unintentionally bring about the same problem again with a substituting substance: manufacturers often replace a substance under regulation with a substituting substance that has similar chemical properties as the substance under regulation but has not been identified as a “bad actor”. Commonly, there is just not enough evidence on the substituting substance for it to be labeled as a “bad actor”: the chemical could be completely new to the market or just been used rarely that it was not sufficient to trigger noticeable adverse health outcome in humans. The absence of evidence is not evidence of absence! A classic example is the phase-out of bisphenol A (BPA) and replacement with bisphenol S (BPS). Mounting evidence in potential health outcomes associated with BPA led to voluntary phase-out of BPA by manufacturers and replacement with various substitutes including BPS. However, the toxicity and potential human health effects of these substituting chemicals were unknown at the time of substitution. Shortly after BPS became widely used as the substituting chemical for BPA, studies observed that the substituting chemical BPS was as harmful as the substituted chemical BPA. The replacement of BPA with BPS is not the only example of such regrettable substitution; man-made chemicals such as diacetyl, organophosphate pesticides, and polybrominated flame retardants are also well-known examples. The case of PFOA substitution with GenX could also be viewed in this perspective. There is increasing animal studies that identified potential harmful effects of GenX, but limited studies on human health. Upon future studies, GenX could also end up being a regrettable substitution! Given the repeated history of regrettable substitution in the man-made chemicals, it is now a time to take a step back and revisit the effectiveness of the current framework and develop a more stable platform to aid the selection of safe alternatives.

Want to learn more about how different countries are trying to tackle regrettable substitution? Visit the EPA website and the European Chemicals Agency website

Want to learn more about PFAS and EPA’s action plan? Visit EPA website that includes information on the PFAS action plan, data, and state-specific resources!

Want to learn more about drinking water contamination by PFAS in the US? Visit a website with an interactive map, developed by SSEHRI, Northeastern University.

Peer edited by Brittany Shephard and Candice Crilly.

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How Your Gut Bacteria May Be Talking To Your Brain

Bacteria are a big part of who we are as humans. They live all over us, forming distinct communities, or microbiomes, on our skin, in our hair, in our mouths, and in our guts. We host these microbes, and increasingly we’re learning that in turn they have a profound effect on our health. This is particularly true when it comes to the gut microbiome, which has been linked to conditions like Crohn’s disease and Irritable Bowel Disease.

The idea that the bacteria making a home in our guts have a role in our intestinal health doesn’t seem that far-fetched, but for several years there have been intriguing suggestions that our gut bacteria may also have an influence on our mental health.   

This has lead to a lot of hype around the idea that our gut bacteria may be controlling our moods or appetites to further their own ends. Experiments in mice and small-scale human studies have shown correlations between mood disorders like anxiety and depression, and alterations in gut microbiome composition.

source: www.mattniederhuber.com/PublicImages/gutbrainaxis.jpg
The gut-brain axis is like a high-speed connection between your central nervous and digestive systems.

It’s long been known that there is an intimate connection between the gut and the brain. Often termed the gut-brain-axis, this connection is like an eight lane highway facilitating a constant exchange of chemical information between the central nervous system and your belly. Ever since it was discovered in the 1980’s that bacteria produce compounds that have significant similarity to human hormones like insulin, scientists have wondered if gut bacteria may influence our mental state by producing their own sets of chemical signals.  

But the field hasn’t quite gotten far enough to definitively say how exactly that process might be taking place. This problem is particularly challenging because of how hard it is to make observations in the human gut. How can we work out what gut bacteria are doing if we can’t directly see them?  

Now, recent work from a group in Belgium has made one of the first efforts to address this question and functionally characterize how bacteria might influence mental state.  

By comparing the gut microbial compositions  and quality of life scores among a cohort of 1,054 Belgians, the group was able to test if particular bacteria were correlated with different mental health markers. While this type of association study isn’t new,  what is most exciting about their work is that they have developed a method for characterizing the neuroactive potential of certain gut bacteria.

The group built what they call “gut-brain modules,” which are essentially groups of genes associated with the synthesis of compounds with potential to interact with the human nervous system. They constructed 56 such modules, all centered around a different neuroactive molecule, such as dopamine or serotonin.  

By applying this gut-brain module framework to the gut microbial makeups of patients diagnosed with depression, they were able to identify and verify a single gut-brain module correlated with higher scores for social functioning. This module is associated with metabolism of Dopamine, a neurotransmitter that has been linked to pleasure and depressive disorders.

While this study doesn’t go so far as to argue a causative role for gut microbes in mental health, it does demonstrate a feasible approach to studying the black box of the human gut and that we may be one step closer to  understanding the role microbiomes play in our health.

Peer edited by Gabrielle Dardis.

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