Nature’s perpetual role in the evolution of medicine

It was March 2019, I was at the end of my fourth year of graduate school, and finally taking a ‘real’ vacation. This meant I tried my best to unplug from the stresses of school by leaving my computer and scientific papers at home. I was going to be road-tripping through southern Germany and I wanted to experience the culture and take in the surroundings without the distractions of work. And although I tried to leave science at home, I still naturally gravitated towards science-related attractions.

In Frankfurt, we visited the Naturmuseum Senckenberg, a natural history museum with an extensive collection of dinosaur fossils and a near-complete cast of Lucy’s skeleton, a 3.2 million year old ancestor to Homo sapiens. In Munich, we went to the Deutsches Museum, the world’s largest science and technology museum, which had exhibits in all areas of interest, including physics,mathematics,pharmaceutics, cosmology, and aviation. One of my favorite science-themed visits, however, was to the German Pharmacy Museum at Heidelberg Castle as it sparked a personal reflection on the development of modern medicine and the role of nature, particularly plants, in that process.

The German Pharmacy Museum (Deutsches Apotheken Museum)

Entering this museum is like taking a step back in time.I walked through re-creations of 17th-19th century apothecaries (pharmacies)with beautifully labeled cabinets in fancy script containing delicate vials and bottles for many remedies. Just past the apothecaries was a room where you can more closely inspect these vials and the contents within. Some of the most recognizable medicines displayed, and still used today, were morphine and aspirin, both of which were isolated from nature by German scientists.

Although morphine and aspirin are now synthesized by chemists in pharmaceutical laboratories, it was nature that inspired the initial use of these chemicals as remedies for ailments. Morphine was first isolated from the opium poppy plant by German scientist Friedrich Sertürner in 1803. Opium, or ‘poppy tears’, however, has been used by humans for millennia to treat pain with evidence of its use pointing back as far  as the Neolithic age (~5000 BC). Aspirin, whose chemical name is acetylsalicyclic acid, was isolated in its pure and stable form in 1897 by German chemist Felix Hoffmann, although the attribution of aspirin’s discovery is a bit controversial. The creation of aspirin was made possible by the extraction of salicin from willow bark. Throughout history, willow bark has been used as a natural remedy for pain and fevers by many cultures including ancient Sumerians and Egyptians nearly 4000 years ago.

https://commons.wikimedia.org/wiki/File:Papaver_somniferum_%27Opium_poppy%27_(Papaveraceae)_seed_pod.JPGhttps://commons.wikimedia.org/wiki/File:2014_Bald_Eagle_State_Park_weeping_willow.jpg
Left: Opium poppy from which opium can be extracted. Right: Weeping willow tree whose bark contains silacin.

Although these are only two examples, nature has been a continuous inspiration for remedies for human ailments since the beginning of human existence. All cultures across the world and throughout history have been touched by the medicinal properties of chemicals derived from natural sources like plants and micro-organsims. Modern chemistry has enabled the isolation, creation, and study of these active natural compounds and the realization of those promising compounds into modern medicines. With the extreme diversity in plants and animals on Earth, nature provides the ideal inspiration and source for numerous new medicines.

Peer edited by Jacob Pawlik.

Follow us on social media and never miss an article:

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.

https://www.flickr.com/photos/blyth/1074446532

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.

https://www.flickr.com/photos/37873897@N06/8277000022

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.

https://www.flickr.com/photos/billward/5818794375

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.

https://commons.wikimedia.org/wiki/File:Nevirapine.svg

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.

Follow us on social media and never miss an article:

 

 

Pharmacies of the Future: Chemical Lego Towers

Chemists and engineers are in the process of making on-demand production of pharmaceuticals less of an idea from a movie, and potentially a viable option for situations where medicines may not be easily accessible.

Imagine taking a vacation to an isolated rainforest resort.  You explored your adventurous side, hiking through the lush vegetation with a knowledgeable tour. Less than 10 minutes after arriving back at the hotel, an uncontrollable itch began on your forearms. It traveled up your arms, across your chest, and began rising up your neck. Was it from a bug or a plant you encountered during the hike? At this point, you are unconcerned about the cause, and just want a solution. The closest drug store is hours away; when booking the trip, it seemed like a great idea to pick the most isolated resort for your dream vacation. Even if the drug store was closer, it was not a guarantee that they would even have anything to help you. In the US, there were over 200 instances of drugs shortages from the years 2011-2014. There was no telling how difficult it would be to get medicine to this remote location.

You head to the front desk of the hotel, hoping they have something to give you for relief. They lead you down the hall and into a small room. There are a few chairs and an appliance that is similar in size and shape to a refrigerator. The employee enters a few commands into a keyboard and the machine starts working. In fifteen minutes, the employee hands you two tablets- diphenhydramine hydrochloride, more commonly known as Benadryl®.  

https://www.flickr.com/photos/mindonfire/3249070405

Diphenhydramine, better known by the brand name Benadryl, is one of the four medications that can be synthesized by the original compact, reconfigurable pharmaceutical production system.

While this scenario is not plausible in the current day, it will be in the near future. In a 2016 Science article, researchers from around the world introduced a refrigerator-sized machine that could make four common medicines. More recently, a 2nd generation prototype was released; the new model is 25% smaller and contains enhanced features necessary for the synthesis of four additional drugs that meet US Pharmacopeia standards. This is possible by technology known as flow chemistry. Flow chemistry is a development where chemicals are pumped through tiny tubes. When two tubes merge, a reaction between the two chemicals occurs, resulting in a new molecule. Compared to traditional chemical reactions (stirring two chemicals together in a flask), flow reactions are generally safer and happen faster.

In this new machine, there are different “synthesis modules,” or small boxes that contain the equipment to do a single chemical reaction. Much like an assembly line to build a car, pharmaceutical molecules are made by starting with something very simple, and pieces are added on and manipulated until it is something useful. In the case of pharmaceuticals, the assembly line consists of molecules and reactions. The modules, or boxes, can be rearranged to do the chemical reactions in the order needed to make the desired medicine. To make a different medicine, the modules must simply be rearranged. Researchers can use the original prototype to make Benadryl, Lidocaine (local anesthetic), Valium (anti-anxiety), and Prozac (anti-depressant), using different combinations of the exact same modules. As of July 2018, the FDA reported that both diazepam (Valium) and lidocaine were currently in a shortage, due to manufacturing delays.

http://www.columbus.af.mil/News/Photos/igphoto/2000125986/

On demand pharmaceutical production would allow access to medicines in rural locations and war zones.

The future of this technology would allow anyone to use it. A user could simply input the medicine they want, and computers would rearrange the modules and use the correct starting chemicals, and in about 15 minutes, you could receive the desired medicine. This technology has vast applications. It could help alleviate the aforementioned drug shortages. Additionally, it could allow access to medicine in locations where it may be difficult to ship to, including rural locations or war zones, often places that need medicines most. In these places, delivery may be difficult, and some medicines go bad quickly. With this technology, it would not be necessary to store medicines that could go bad; it could simply be made as soon as it is needed. This could also prevent waste from medicines that are not used before they go out of date. These developments could revolutionize the pharmaceutical industry and I look forward to seeing the good that these technology advances can lead to. 

Peer edited by Nicholas Martinez

Follow us on social media and never miss an article: