Superior Syntheses: Sustainable Routes to Life-Saving Drugs

While HIV treatment has come a long way over the past few decades, there is still a discrepancy between total number of HIV patients and those with access to life-saving antiretroviral therapies (ART). The inability to access medications is often directly linked to the cost of the medication, demonstrating the need for ways to make these medicines cheaper. In October 2018, Dr. B. Frank Gupton and Dr. Tyler McQuade of Virginia Commonwealth University were awarded a 2018 Green Chemistry Challenge Award for their innovative work on the affordable synthesis of nevirapine, an essential component of some HIV combination drug therapies.

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Neviripine, a component of some HIV therapies.

For the past 22 years, the American Chemical Society (ACS) in partnership with the U.S. Environmental Protection Agency (EPA), has awarded scientists who have contributed to the development of processes that protect public health and the environment. Awardees have made significant contributions in reducing hazards linked to designing, manufacturing, and using chemicals. As of 2018, the prize-winning technologies have eliminated 826 million pounds of dangerous chemicals and solvents, enough to fill a train 47 miles long. The nominated technologies are judged on the level of science and innovation, the benefits to human health and the environment, and the impact of the discovery.

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Green Chemistry protects public health and the environment.

Gupton and McQuade were awarded the Green Chemistry Challenge Award for the development of a sustainable and efficient synthesis of nevirapine. The chemists argue that oftentimes, the process to produce a drug remains consistent over time, and is not improved to reflect new innovations and technologies in the field of chemistry, which could make syntheses easier, cheaper, and more environmentally friendly. Synthesizing a drug molecule is not unlike building a Lego tower; the tower starts with a single Lego and bricks are added one-by-one until it resembles a building. Researchers start with a simple chemical and add “chemical blocks” one-by-one until it is the desired drug molecule.  Gupton and McQuade demonstrated that by employing state-of-the-art chemical methods, they can significantly decrease the cost to synthesize nevirapine.

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Producing pharmaceutical molecules is like building a Lego house.

Before this discovery, there were two known routes toward the synthesis of nevirapine. Researchers used projections to determine which steps were the costliest. With this knowledge, they were able to improve the expensive step of the synthesis by developing a new reaction that used cheap reagents (“chemical blocks”) and proceeded in high yield. A chemical yield is the amount of product obtained relative to the amount of material used. The higher the yield, the more efficient the reaction. Reactions may have a poor yield because of alternative reactions that result in impurities, or unexpected, undesired products (byproducts). Pharmaceutical companies often quantify chemical efficiency by using the Process Mass Intensity (PMI), which is the mass of all materials used to produce 1 kg of product. Solvent, the medium in which the reaction takes place, is a big contributor to PMI because it is a material that is necessary for the reaction, but not incorporated into the final product. Gupton and McQuade were able to decrease the amount of solvent used because they streamlined reactions that reduced impurities, allowing them to recycle and reuse solvent. These improvements reduced the PMI to 11 relative to the industry standard PMI of 46.

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Molecular structure of nevirapine 

In addition to their synthesis of nevirapine, Gupton and McQuade also developed a series of core principles to improve drug access and affordability for all medications. The general principles include implementation of novel and innovative chemical technologies, a decrease in the total number of synthetic steps and solvent changes, and use of cheap starting materials. Oftentimes, the pharmaceutical industry focuses on starting with very complex molecules in order to decrease the number of steps needed to reach the target molecule. Interestingly/unfortunately, starting with complex “chemical blocks” is often the most expensive part of  producing a medication. By starting with simpler chemicals, they believe production costs can be significantly decreased. Virginia Commonwealth University recently established the Medicines for All Institute in collaboration with the Bill & Melinda Gates foundation, and Gupton and McQuade hope that by employing the process development principles, they will be able to more efficiently and affordably synthesize many life-saving medications.

Peer edited by Dominika Trzilova and Connor Wander.

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Mr. Turtle

In 2012, I was working at the Cooperative Oxford Lab in Oxford, Maryland, when we were notified of and rescued a stranded sea turtle. Sadly, the turtle was so sick that it died. An intern performed the necropsy (an autopsy on animals) and found that the turtle’s stomach was full of plastic trash and even a belt buckle and a hair comb. I never got  the image of the dying turtle out of my head.

Meanwhile, besides mourning plastic-choked sea turtles, I was also feeling bewildered and upset by the constant talk from overseas outlaws, urging us Muslims living in the west to commit destructive acts. I decided I needed to do something to protest such talk, and it suddenly hit me that I could teach myself how to make animated videos declaring my love for the exquisitely lovely country of Sweden, where I used to live, and my darling home state of North Carolina. Little did I know that this commitment would eventually serve me in many more ways.

It took a few years, but a light bulb finally went off in my head, and I put two and two together: why not use my new animation skills to shed light on environmental concerns?  Even better, why not do this as a project with children? This is how the animation “Mr. Turtle Gets Sick” came to be.

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Teaching children how to animate!

A second grade teacher at Northside Elementary, right here in Chapel Hill, graciously allowed me into her classroom last October through December. Along with help from my little brother, two fellow geology students, and especially my brother’s roommate, we first taught the children sea turtle ecology, let them draw illustrations, and recorded each child’s voice for the narration.

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The crew of “Mr. Turtle Gets Sick.”

After this, we began animating. We first taught this to the whole class and then worked with each child individually. We provided the oversight and structure while letting the kids decide on the different actions and take the helm of doing the actual computer work. For example, if a child wanted to show Mr. Turtle swimming, then he or she specified Mr. Turtle’s position at both his start and end point, and the amount of time it took him to move that far. The fact that there was a “timeline” component meant that, in addition to the reading, artwork, and animation involved, the kids even practiced their math skills by learning how to space the actions out evenly. The illustrations the kids had drawn served as the background scenery.

 

At the unveiling, the children saw the finished product for the first time, and all the parents were invited for the viewing. The parents were thrilled! Afterwards, I contacted a local sea turtle expert, and he came to the classroom and did a follow-up presentation. He told the kids about sea turtle nests on North Carolina’s beaches, how sea turtles get caught in fishing nets, and how actually not all species of sea turtles eat jellyfish. The kids had so many questions that we kept going right until it was time to go to lunch.

Working with children was a beautiful experience, especially after being around academics all day. If anyone is interested and would like to be involved in future similar activities, please email me!

Animation: “Mr. Turtle Gets Sick”

Credits: Sharla Coleman’s second grade classroom at Northside Elementary, Mejs Hasan, Sean Catangui, Ali Hasan, Elsemarie deVries, Theo Jass

Software used: Blender, a free, open-source 3D modeling and animation program.

See ‘Mr. Turtle Gets Sick’ and other animations by Mejs here:

Mr. Turtle Gets Sick: http://youtu.be/ierH4oUaqO4

Dear Foreigner: http://youtu.be/jW99oPD3gK4

Freedom: http://youtu.be/H4inZuEF4ZM

Peer edited by Suzan Ok and Leanna Gentry.

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Arctic Tales of Icy Trails

Far out in eastern Russia, deep in the Siberian Plateau, lies one of the great waterways of the world. 

The Lena is the eleventh longest river on Earth. For thousands of treacherous kilometers, she makes her way through forests and across tundra, eventually delivering her waters into the icy cradle of the Arctic Ocean. The power of these frigid landscapes is such that for six months out of the year, the surface of the Lena is completely frozen.

The freeze starts with the deepening chill of October and extends through black December twilights and a solemn New Year.

Even when fresh springtime breezes arrive, melting the ice, the Lena pays a terrible price for her freedom. The sheets of ice do not yield peacefully, drop by drop, in a quiet surrender to the warmth. Instead, the process is rife with violence. As some parts of the ice destabilize, the flow of the river increases suddenly, and before the ice has a chance to melt, it sweeps downstream, displacing and spilling water over the banks and causing major flooding. This process is called “ice break-up.”

Very few people live along the vast plain where the Lena alternates between flow and ice. Near the Arctic Circle, a lonely station is the last shivering wisp of human life before the river dissolves into its northern grave.

Sarah Cooley in the lovely Scandinavian dream of Iceland, just one of the countries where she has pursued her polar studies as a UNC student.

Sarah Cooley in the lovely Scandinavian dream of Iceland, just one of the countries where she has pursued her polar studies as a UNC student.

Records made at this station over several decades indicate the precise date in spring when the Lena breaks free of her icy grip – the precise date when the ice crumbles and the entire river flows again. Over the past years, this date on which the ice breaks has crept earlier and earlier.

Thousands of miles away, in an office at UNC, sits Sarah Cooley. She has never been to Russia, nor seen the Lena with her own eyes, so she cannot tell you about its beauty, or ferocity, or chill. However, she has seen the Lena plenty through images. These are not images captured by a camera, but rather images captured by satellites, whose falcon-like eyes see much from their distant orbits. Can careful mastery and manipulation of these images tell us something about ice break-up on the Lena, something beyond the comprehension of a single station outpost?

It was August 2014, and Sarah was preparing to start her senior thesis. She wanted to focus on glaciers and satellites, so she went to find Dr. Tamlin Pavelsky, a professor in the geology department, whose earlier research focused on ice break-up in Arctic Rivers. However, Dr. Pavelsky completed his project in 2004, during the infancy of the newly-launched Terra and Aqua satellites. These satellites carry onboard quite a remarkable instrument called MODIS.

Although its name makes every aspiration at modesty, MODIS has much of which to be proud. Since 2000, the MODIS sensor has snapped images of the entire planet, every day. That means hundreds of thousands, if not millions, of images dedicated just to Arctic rivers like the Lena are available, free of charge, on a NASA website.

Now that MODIS is fifteen years old, her idea was to recreate Dr. Pavelsky’s project, incorporating the many extra years of data into the study. The first step required Sarah’s full familiarity with the NASA LAADS website, from which she had to download over 16,000 satellite images.

“It might be the most images anyone’s ever ordered before,” Sarah explains. The four Arctic Rivers she studied stretch out over 18 MODIS scenes. For each of those 18 scenes, Sarah downloaded 60 days’ worth of images over the fifteen years of MODIS’ existence. The sixty days were centered on March, April, and May, since that is the window in which the ice break-up occurs. Eighteen scenes on sixty days for fifteen years added up quickly!

It took Sarah three months to acquire her full library of images. The ordering process is not too difficult, “but then you have to wait for it, and when you get it, it’s not always what you expected, it might have errors, or wrong dates and be the wrong place.”

These images from MODIS show the progression of ice break-up on the Lena River of Russia. Where the river shows white, it is frozen ice. The white slowly overtaken by black water indicates that the ice is disappearing.

Nevertheless, after a Christmas break spent watching Sherlock and trying the utter patience of the NASA LAADS website, Sarah eventually was ready to proceed with her analysis of those thousands of images.

The thing to know about satellite images is that they are not precisely like the pictures we might snap, with ambitions of posting to Facebook and getting 100 likes.

A satellite image is a record of how much light is being reflected off the surface of the Earth – and not just the ordinary, commonplace lights like blue light, red light, and green light. Satellites also venture into the realms of light humans can’t see, such as near-infrared light, and short-wave infrared light, and all sorts. The falcon eyes of MODIS captures these wavelengths of light, then translates its findings into simple numbers that computers and brains can interpret and analyze.

Sarah was sitting on a trove of 16,000 MODIS images of near-infrared light. But can near-infrared light actually tell us anything about ice in Arctic rivers? This is where Sarah had to experiment.

She found that when the Lena was frozen, it reflected almost all near-infrared light that reached it. On the other hand, when the river was an unshackled tumult of free-flowing water, its reflectance was very low. And when the river was a mix of ice and water, its reflectance value was somewhere in between.

Sitting in her warm office thousands of miles away, Sarah started watching the progression of ice break-up on the Lena by using near-infrared light as the key to unlock her satellite images.

With her reflectance data in hand, Sarah sliced her northern rivers into ten kilometer slabs. Then, like a child playing with its food, each slab was cut into impossibly tiny 250 meter pixels. For all her MODIS images, Sarah counted up which of her tiny pixels crossed the threshold that equaled ice; which lay in the range of water; and which belonged to the brew that denotes a mixture of ice and water.

On the day that 75% of the tiny pixels in a given slab passed the threshold that implies water, that slab was declared to have undergone its spring melting. This method finds the exact date that each slab of river melted, allowing detailed analysis of melting time on a year to year basis. It means that instead of a single date of ice break-up provided by a lonely station near the Arctic Circle, Sarah can now produce an estimate of when ice break-up is happening along the entire river.

It’s a very straightforward approach, and that’s one of the things Sarah likes about MODIS. “I really enjoy the simplicity, and it being daily is great. You can really do a lot with it.”

Of course, Sarah did not count all of the pixels and separate them into categories by hand. Instead, she wrote a series of computer scripts that did the work. The first part of her script classified the MODIS images into land, water, ice, and ice and water mixture. Then, all clouds were removed. Finally, computers calculated the amount of ice melt in each 10-kilometer slab. These scripts took three hours to run per river, much preferable to the hundreds of tedious hours it would take to do by hand. Now the scripts can be passed on and used by others, absorbing the newer images that MODIS keeps adding to its archives.

It is quite an achievement, especially compared to how Sarah felt when she first arrived at UNC as a freshman and saw older classmates doing sophisticated projects.

She remembers vividly thinking: “Oh my gosh, I can never do that. Now I realize I can do so many more things than I ever thought I could. And I realize that learning all those things isn’t something that happens overnight, it’s something you learn by taking classes, doing research, working in the lab. And now I’m never intimidated by coding. I love coding and seeing the things I can do with it.”

We are now in the waning days of April, and Sarah will soon graduate from UNC Chapel Hill. She and Dr. Pavelsky are finalizing a paper on their results.

After UNC, Sarah is moving to England to complete a Masters of Philosophy degree in Polar Studies at Cambridge University as a Gates Cambridge Scholar. Showing a persistent interest in Arctic ice, she plans to focus on glacier flow in Greenland.

Sarah fell in love with Greenland and wanted to pursue polar science ever since she studied abroad in Denmark and visited the Greenland ice sheet. “It’s really cool being out there, and there’s people, wildlife. Some people like to study polar science in Antarctica, but to me, it seems so empty. I like how in the Arctic everything feels connected to the people and the land.”

Meanwhile, the Lena still succumbs to the bleak icy thrall that envelops her every October, from which she cannot relax until the spring ice break-up, which every year creeps earlier in the calendar. Signs of climate change are everywhere.

Will the river change its melting patterns? Will its ice break-up involve more flooding in the future, or will it occur in irregular patches that do not progress linearly down its Siberian route? All of these are questions that satellites, ground station data, and scientists like Sarah can help to answer.

Peer edited by Chris Givens and Chelsea Boyd. 

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