Transforming Blood Transfusions

Blood is essential. It carries the oxygen you breathe throughout your body and to your lungs, keeping you alive and invigorated. However, our body can only produce so much blood in a day, and when we undergo serious blood loss through car accidents, genetic disorders, or surgeries, we need to replenish our body’s blood supply. People around the world donate their blood to those who are in desperate need and each year, 4.5 million lives are saved thanks to blood donations.

The transfer of one person’s blood to another person’s body is called transfusion, and in the United States alone, someone needs a transfusion every two seconds1. Currently, blood transfusions are limited by the type of blood one has – and therefore needs. Blood has four major types: ‘A’, ‘B’, ‘AB’, and ‘O’, and each of these major types has two subtypes, positive or negative. This means there are a total of eight blood types: A+, A-, B+, B-, AB+, AB-, O+, O-. These types are determined by different molecules called antigens (you can think of them as tags or signs) on the outside of the blood cell (see image below, different blood types have different molecular patterns or “tags”). 

The four major blood types are defined by the antigens, or “tags”, on their surfaces. The “H” antigen of blood type “O” is the most common, and can be converted by enzymes to “A” or “B” antigens. If you don’t have “A” or “B” blood types, it is because you don’t have the enzymes that can convert antigen “H” to the other antigen types.

Blood transfusions are limited by these specific antigens (tags) because the antigens are recognized by a person’s immune system or, the body’s defense system. If you have blood type “B”, and now have blood type “A” in your body, due to a transfusion, your immune system will recognize that “A” is not part of your body, and will trigger an immune response which attacks and destroys the blood that has been transfused.

A group from the University of British Columbia in Canada identified a bacterium in the human stomach that can convert blood type ‘A’ to the universal donor type, ‘O’2. By screening thousands of microbes in our stomachs, the scientists identified a particular obligate anaerobe (can only survive when oxygen is not present), Flavonifractor plautii. Inside F. plautii, two enzymes were found to work together to change the molecules on the surface of red blood cells of blood type ‘A’ to molecules of blood type ‘O’.

But how can blood types be changed from one blood type to another? 

Below is a diagram of blood type ‘A’ and blood type ‘O’. They have some “tags” in common (the blue squares, orange circles, and grey diamonds), and some that differ (green pentagon). The enzymes in F. plautii are able to cut off the extra molecular tag of blood type ‘A’, which then leaves blood type ‘O’! First, the enzyme FpGalNAcDeAc changes the ‘A’ blood type molecules to a slightly different molecule, which can then be recognized and cut by the second enzyme, FpGalNase, leaving blood type ‘O’. Not only can these enzymes change blood type ‘A’ to ‘O’, but they can do it fairly efficiently, which could greatly increase the blood supply for transfusions. 

Blood Type “A” to Blood Type “O” Conversion Pathway. FpGalNAcDeAc enzyme recognizes the “A” antigen, and changes it to a different molecule. This new molecule is recognized and removed by FpGalNase, leaving only the “H” antigen which characterizes blood type “O”.

The group from British Columbia are not the first to try changing blood type3. A previous study converted blood type ‘B’ to blood type ‘O’, albeit very inefficiently. So inefficiently, in fact, that the conversion would never have practical use4

Since the enzymes from F. plautii are bacterial, and only small amounts of the enzymes are needed for conversion of blood type ‘A’ to blood type ‘O’, it could be possible to mass produce the enzymes to be able to transform large quantities of blood for transfusions, increasing blood supply for medical procedures and saving more lives.

Sources:

  1. https://www.redcrossblood.org/donate-blood/blood-types.html
  2. Rahfeld, P., Sim, L., Moon, H., Constantinescu, I., Morgan-Lang, C., Hallam, S. J., Kizhakkedathu, J. N., and Withers, S. G. (2019) An enzymatic pathway in the human gut microbiome that converts A to universal O type blood. Nat. Microbiol. 10.1038/s41564-019-0469-7
  3. Goldstein, J., Siviglia, G., Hurst, R., Lenny, L. & Reich, L. Group-B erythrocytes enzymatically converted to Group-O survive normally in A, B, and O individuals. Science 215, 168–170 (1982).
  4. Kruskall, M. S. et al. Transfusion to blood group A and O patients of group B RBCs that have been enzymatically converted to group O. Transfusion 40, 1290–1298 (2000).

Peer edited by Abigail Agoglia

High-Throughput Urinary Testing: More Data, More Problems?

If a urinary tract infection (UTI) has ever ruined your day, you’re not alone. This uncomfortable condition is one of the most common infectious illnesses in the United States, responsible for more than ten million office visits and nearly $4 billion in costs each year. UTIs are usually diagnosed based on the results of three different types of test:

1.     Dipstick test: a prepared test strip provides basic information about the urine, including things like pH and the presence of blood cells or nitrites (a byproduct of some bacterial infections). The dipstick is fast and inexpensive but not very sensitive, leading to both false negative and false positive results.

2.     Microscopy: examining urine under a microscope to check for the presence of red and white blood cells or bacteria directly. This is a relatively quick and inexpensive test but is also prone to false negatives and false positives.

3.     Urine culture: currently the gold standard of UTI diagnosis. For this test, a sample of urine is plated on materials that will allow bacteria to thrive and then it is observed for 48 hours to see if any bacterial colonies will grow. Culturing urine samples allows the lab to identify the species of bacteria responsible for an infection and test antibiotics to determine the best treatment. Growing cells in culture can be difficult, however, particularly if bacteria live together cooperatively in a growth called a biofilm which is common in the urinary tract. This makes false negative results a problem for urine culture.

Staphylococcus aureus bacteria bound by a biofilm. These growths make bacteria more difficult to detect with urine culture. Photo credit Rodney M. Donlan, Ph.D and Janice Carr, 2005.

Recently, new technology has been introduced into UTI diagnosis that may eventually change the way in which infections are identified. Polymerase chain reaction (PCR) allows the lab to test urine samples for several bacterial genes to identify infections without the need to grow bacteria directly in culture. PCR is more sensitive than urinary culture and may be able to provide evidence of bacteria that are more difficult to identify by culture, like biofilm infections. More sensitive still is next-generation sequencing (NGS).In this technique, rather than testing for a few specific bacterial genes that may be present in the urine sample, the lab can identify every single bit of genetic material in the urine. This allows the lab to identify every organism that is living in the urinary tract, and test for the presence of genes that confer antibiotic resistance to suggest a more targeted antibiotic therapy. These methods are poised to make UTI diagnosis and treatment more precise and less prone to false negatives.

How next generation sequencing works. Photo credit to Jenny Cham, based on a lecture by Alan Pittman, Ph.D.

However, these more sensitive tests do have limitations. By identifying many more species of bacteria than urine culture, NGS may detect species that are present in urine but not responsible for urinary symptoms. In a comparison of NGS and urine culture, although NGS and culture identified the same bacteria in UTI patients 96% of the time, NGS also identified many species of bacteria in healthy control participants. Why were these healthy patients testing positive for bacteria? Although historically the urinary tract has been described as a sterile environment, modern evidence suggests that the urinary tract has its own microbiome, where multiple species of microbes live without causing human illness. This research is still in its infancy, and until the microbiome of the bladder has been thoroughly described it will be difficult for doctors to determine whether a species identified via NGS is an infectious organism or a normal part of the patient’s urinary tract. Another disadvantage is cost: these new tests are also much more expensive and not often covered by insurance, and not all doctors are willing to use the results to make treatment decisions. 

So, are these new tests worth it? That’s a question only the patient and their doctor can answer. For now, these more sophisticated techniques are best used as a companion to traditional urinary culture, not a replacement, until clinical standards are established. It might be helpful to think of NGS as similar to “23andMe for your bladder”- the information is interesting, and some of it might be useful for your medical provider, but for now it’s mostly medical trivia. Here’s a summary of the test options:

TEST SPEED COST DRUG
TESTING
FALSE
NEGATIVES
FALSE
POSITIVES
Dipstick Instant $
Microscopy Instant $
Culture 2 days $$ Uncommon
PCR 1 day $$$ Uncommon Uncommon
NGS 4 days $$$$ Uncommon

Peer-edited by Kathryn Weatherford and Chiung-Wei Huang.



Chemistry of Antihistamines, Nothing to Sneeze At

https://commons.wikimedia.org/wiki/File:The_%22Old_Well%22,_center_of_campus,_University_of_North_Carolina,_Chapel_Hill.jpg
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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Golden Medicine: Use of Plasmons for Cancer Therapy

Cancer is an immensely complex disease to treat. The number of mutations and combinations of mutations that can lead to its development make each “cure” more of a patch to a few specific cases. Couple that with the increasing rate of mutation within cancer cells, and it becomes difficult to even diagnose the issue. Plasmon therapy offers the potential for a broadly applicable treatment, and because it couples well with the bodies immune response, offers a therapy that could decrease the chance for metastatic tumor development.

Before we discuss this topic with greater specificity, a few terms should be defined. Plasmons, from the word plasma, are a material that has electrons that flow back and forth in a wave when light shines on them. Plasmas are just gaseous ions, like lightning or neon signs, and in the case of a plasmon, this plasma is confined to the surface of a nanoparticle. You can read more about plasmon theory here.

Nanoparticles abound in modern technologies and are defined by one dimension, the so called “critical dimension”, which is around two hundred nanometers. For reference, that’s roughly one hundred thousand times smaller than a human hair. This size can afford a variety of unique properties to a molecule: distinct colors, uncharacteristic electronic activities, and even the ability to move through a cellular membrane. All these attributes will come into play in how these molecules interact with cancer cells, so they’re important to keep in mind.  Plasmons are nanoparticles that are so small, that the plasma on the surface can be manipulated by light. This rapid movement of plasma gives rise to heat as it collides with surface particles just as your hands generate heat rubbing together. The type of light that does this can be visible or even radio waves, meaning that very low-energy and harmless beams can be used to generate this rapid heat.

The second bit of background knowledge necessary for this discussion is: how is cancer treated in the first place? Many current cancer therapies come from small molecules roughly the size of glucose. Whether they use metals or strictly carbon, small molecule cancer therapies usually rely on interrupting one or a few cellular pathways, like DNA replication or a checkpoint before mitosis (cell splitting). One of the first nanoparticles approved for cancer therapy have been gold nanorods, which are thousands of times larger than a small molecule and have used physical rather than chemical mechanisms for therapy. To clarify, instead of changing some pathway in a cell, these nanorods can selectively heat cancer cells until the cell dies. If you were to think about this in terms of pest control, nanoparticle therapy is like burning a nest of cockroaches. In that same case, using small molecules like cisplatin would be like spraying the cockroaches with the latest bugkiller.

Extending this analogy, it’s fairly obvious that setting a fire inside someone’s body is not a good medicinal practice, so it would be fair to question how plasmon therapy might be helpful. There are two strategies for plasmon cancer therapy: precision lasers and radio waves which can pass through a body. The earliest use of plasmon cancer therapy used a fiber optic that was inserted under the skin to a location near the tumor. Then, beams of light would hit only the tumor. This has the advantage of targeted dosing, but can still be considered fairly invasive. Others have begun using plasmons that generate that intense heat with radio waves so that no procedure is necessary: simply an injection or ingestion of nanoparticles and then stepping into a radio transmitter This can be impractical if the tumor is not in a confined space. Common gold plasmonic nanoparticles would go inside all cells so healthy cells would be damaged just as easily as cancerous ones. Recent work shows that the surface of the nanoparticle can be changed so that the majority of uptake occurs by cancer cells. Cancer cell metabolism makes the charge of cancer cell membranes different from the charge of normal cell membranes, so these nanoparticles can exploit that difference to target only cancer cells.

With this targeted dosing, plasmons show promise as a noninvasive form of therapy that do not harm the patient and would be applicable to most forms of cancer. Even though the safest and most effective nanoparticles will use gold, treatment costs are currently around  $1000, thereby promising a treatment that will not be prohibitively expensive for the future.

Peer edited by Kasey Skinner.

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Why Pharmaceutical Companies Care About Your Saliva

Earwax stickiness. Neanderthal ancestry. Caffeine metabolism. Tasting soap when you eat cilantro. Direct-to-consumer genotyping companies like 23andme boast this kind of information in exchange for a tube of your finest spit and a chunk of change about equivalent to a week’s worth of groceries. In the process of unlocking the whimsy of the human genome, however, companies that deal in providing genetic information to consumers have amassed an enormous collection of data.

Unique genetic variants are responsible for many of our traits — including disease.

Nearly 80% of 23andme’s consumers consent to have their information used for research purposes. One of the most valuable applications for information about millions of genomes and their owners is to uncover genes that can be targeted for therapies to treat diseases. A new multi-million-dollar collaboration between pharmaceutical company GlaxoSmithKline and 23andme promises to make identification of pharmaceutical targets quicker and aid in the design of therapies that are more likely to succeed in clinical trials on an unprecedentedly large scale.

But what does this have to do with whether you like the taste of cilantro? To find out, we first need to dive in to what kind of data direct-to-consumer genotyping companies have and how they get it.

In order to keep costs lower for the company and the consumer, most direct-to-consumer genetic testing companies use a simple method called a DNA microarray to test for specific snippets of the genome that are correlated with certain characteristics.

DNA microarray chip. Spots glow when a perfect match is made between query DNA and probe DNA that is linked to the chip.
Source: NASA

To generate the DNA microarray, microscopic “spots” of DNA are linked to the surface of a tiny chip. These “probe” DNA sequences pair with specific sequences in the human genome that signify certain traits. Often, these specific sequences are portions  of the genome where one individual may differ from another by a single nucleotide. The substitution of one base pair for another at a specific site in the genome is called a single nucleotide polymorphism, or a SNP. Many SNPs are commonly associated with specific traits, and are therefore a mainstay for direct-to-consumer genotyping companies. Only a fraction of existing SNPs are known to correlate with certain traits or diseases, limiting the number of probe sequences needed to test a single individual.

The company typically requests a saliva sample, which would contain both white blood cells and skin cells from within the mouth that are suitable for purifying large quantities of DNA. Once the saliva sample is received, DNA is extracted and subjected to an amplification process which generates more copies of the DNA from the sample. The DNA is then heated so that it no longer binds to its original pairing strand. Proteins that can cut DNA are then used to chop the genome into smaller pieces. From here, the DNA fragments are tagged with a unique fluorescent molecule that can track the position of the query DNA on the microchip. The processed sample is then applied to the chip, where query DNA will pair with probe DNA if it is complementary in sequence. To obtain test results, the microchip is analyzed for bright spots, which represent a positive test result for the genetic variant at that position on the microarray. Direct-to-consumer genetic testing companies typically include a catalog of probe DNA sequences that are strongly associated with specific traits, common ancestral backgrounds, and predisposition to a small subset of diseases.

So how can this information be useful to pharmaceutical companies? The answer is in the numbers. Associating features of the genome with traits or disease requires a large sample size to give the us more confidence that the association is real, and doesn’t simply occur because of random chance. Take the example of a SNP in the genome. Each human genome has about 10 million SNPs, or about 1 SNP per 300 base pairs. Some of these SNPs are insignificant and will be averaged out in the context of 2 million genomes. However, if a SNP is significantly associated with a disease, it will be found proportionally more often in genomes of people who have or are predisposed to having a disease compared to normal individuals. Pharmaceutical companies increasingly rely on finding new drug targets to develop new therapies, and are looking deeper into the genome to find new gene targets for therapies. Where to start? Genes with variations that correlate with certain traits or diseases –the exact information you can purchase from a direct-to-consumer genotyping service.

An approach to parsing these millions of genomes is referred to as PheWAS (phenome-wide association study). This study begins by looking at a genetic variant such as a SNP, and seeks to determine whether this variant is associated with a particular trait or set of traits in the individuals who have the variant. The data collected by direct-to-consumer genotyping companies are well-suited to be analyzed by PheWAS, as the companies often collect self-reported survey information on their customers. Myriad symptoms can be linked back to a single genetic variant with the power of huge genomic datasets to jumpstart the therapies of the future.

Old approaches allowed scientists to start with a trait and find common genetic variants in individuals with this trait. Here, scientists trace facial features back to common genetic variants. Approaches like PheWAS, however, start with the genetic variant and analyze the range of traits associated with the variant in many individuals.
Source: Kaustubh Adhikari, T. F., et al. Nature Communications. (2016) (Wikimedia Commons)

Access to large databases of genotyping information may also give pharmaceutical companies further insight into more complex traits that are determined by a wide array of genes. An example of a complex trait is human height. There are a massive number of SNPs that contribute to the height of an individual. If you divide the genome up into ~30,000 equivalent-sized sections, nearly every one of these sections contributes to a person’s height. Many of the genetic variants that affect someone’s height are seemingly random and can only be identified by using large amounts of data. Similar to height, human disease is also connected to a combination of many genetic variants. It’s likely that pharmaceutical companies will begin looking not only at the genes that we think contribute to disease, but also throughout the rest of the genome for previously unknown variants that might be to blame. This information can be used to find new genes to target and help to avoid clinical pitfalls of previous drug strategies which were largely inefficient.

Despite the promises of big data in big pharma, it is unclear as yet whether or not partnerships between direct-to-consumer genotyping companies and pharmaceutical companies will be fruitful. Undoubtedly, developing drugs to treat diseases that have ineffective or nonexistent therapies is an attractive possibility. Furthermore, projects like these could promote a personalized medicine approach, where treatments are tailored to one’s specific therapeutic needs, as signified by their genome. An in-house effort within 23andme uses customer data to peg new drug targets. They claim to have uncovered 10 new targets for drug development. However, this collaboration raises the issue of consumers paying for the privilege of having their genomes used to garner profits for both their genotyping service and a pharmaceutical giant. A caveat to using such datasets is that the sample genomes mostly represent middle-to-upper-class individuals who live in Western countries, limiting the scope of the potential therapies developed as a result of the collaboration. Nevertheless, the marriage of genotype big-data and drug development holds exciting promise for the future of targeted therapies.

Peer edited by Jacob Pawlik and Giehae Choi.

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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

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Getting to the Heart of the Matter: “Fish are friends, not food”

https://www.flickr.com/photos/shany_410/1125438164

Repeat after me: “Fish are friends, not food”

When most people think about “Finding Nemo,” they likely think about Nemo, the adventurous young clownfish who got caught up in a fishy situation (no pun intended) and ended up in a dentist’s fish tank. Or, they might remember Marlin, the overprotective father. However, what about Dory? Though some might characterize Dory as loopy, she was the real hero who saved Marlin and Nemo’s lives and reunited father and son. Who would have thought that the loopy blue tang fish would be the unsung hero?

https://commons.wikimedia.org/wiki/File:Zebrafish_(26436913602).jpg

Zebrafish (Danio rerio), possibly the key to treat/cure heart disease

Just like Nemo, humans have their own fish hero too: the zebrafish. The zebrafish is a tropical freshwater fish that is currently used in many research labs as a powerful model organism for studying various diseases such as heart disease, cancer, diabetes, and gastrointestinal disease. You might be thinking that there is no way a 3-5 cm fish, with fins and no lungs, can model human disease; humans are extremely different from zebrafish. However, zebrafish are much more similar to people than one might initially think. In fact, according to a paper published in Nature, 84% of genes known to be associated with human disease have a zebrafish counterpart. You might also be wondering why not use mice? After all, they’re at least mammals. Good question!

Zebrafish models actually have many advantages over mouse or rat models:

  1. Zebrafish reproduce more frequently (every week) than mice and rats.
  2. Zebrafish can easily be genetically manipulated to study a disease; it takes less time to generate a zebrafish mutant line than a mouse mutant line.

    https://www.flickr.com/photos/nihgov/29229249924

    Picture above shows zebrafish blood vessels labelled in red and lymphatic vessels labelled in green

  3. In zebrafish, important pathways can be easily blocked and examined by simply adding the drug to the water. This allows for more cost effective and faster identification of new drugs and new uses for current drugs.
  4. The zebrafish is see-through; fluorescence markers can be used to “highlight” various cells in tissues and organs. Imagine being able to see individual cells migrate from one location to the next and form an entire heart that begins to beat 24 hours later- in real time. THAT’S AMAZING!

Other advantages of the zebrafish are disease specific. For example, zebrafish are an advantageous model for studying congenital heart disease because they can survive severe cardiac defects that are typically lethal in mice. Therefore, the zebrafish model allows scientists to follow a disease longer than they would be able to in a mouse model. Zebrafish models of heart failure have been found to exhibit similar defects to those found in patients with heart disease. In addition, zebrafish heart models have provided genetic evidence that certain signaling pathways protect humans against heart problems.

https://www.flickr.com/photos/uwiscseagrant/7250836704

Zebrafish organs or tissues can be easily visualized because they are see-through

One of the major reasons why people succumb to heart attacks is because heart cells get damaged and die; heart cells have little to no capability to regenerate (make more of themselves). The zebrafish heart, on the other hand, has the capability to regenerate and replace injured heart tissue after damage. Therefore, scientists are using the zebrafish to figure out what factors or pathways are involved in that process, so they may be able to help the human heart heal itself after being damaged during a heart attack. Heart disease is the leading cause of death in the U.S. and worldwide; so, many lives can be saved with the help of a little striped fish, like Dory.

With that in mind, it’s probably safe to say that fish are friends (and not just food).

 

Peer edited by Breanna Turman.

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Diet Soda: Providing Insight into a Rare Metabolic Disorder

https://pixabay.com/en/beach-soda-diet-coke-ocean-sand-2752753/

Diet Coke is advertised as a sugar free alternative to regular Coke Cola, using aspartame as a sweeteners

Have you ever read the Nutrition Facts on a diet soda or sugar-free gum? If so, you might have noticed a bolded sentence that reads: PHENYLKETONURICS: CONTAINS PHENYLALANINE. In the U.S., this sentence is present on every commercially available medicine, food, or beverage that contains the artificial sweetener aspartame. Often, this warning goes unnoticed, partly because it is nestled quietly at the foot of the list of ingredients and partly because it only applies to 1 in every 10,000 individuals in the United States. Nevertheless, this subtle message is essential for this subset of consumers.

 

Typical nutrition facts label for a product that contains phenylanaline

Phenylketonuria  (Phe·nyl·ke·ton·uria)

Those people are “Phenylketonurics,” or people with a rare metabolic disorder called Phenylketonuria (PKU). PKU is a genetic disorder that results in the inability to convert the amino acid phenylalanine (Phe) into the amino acid tyrosine (Tyr), both essential amino acids that are found in most protein. Phe’s most important biological function is its role as a precursor to Tyr, which is involved in many processes such as the synthesis of neurotransmitters. Without the ability to convert Phe to Tyr, there is less Tyr available for the synthesis of dopamine, norepinephrine, and epinephrine (all important neurotransmitters) and Phe can accumulate in the brain, resulting in local metabolic dysfunction. PKU can result in severe developmental complications and mental retardation if left untreated. Fortunately, PKU can be successfully managed by abiding by a strict low-protein diet, avoiding foods that contain sources of phenylalanine such as meats, fish, dairy, and nuts.

Now, you might ask, “How does PKU have anything to do with the Nutrition Facts on my Diet Coke?” Good question. The answer lies in the chemical structure of the aforementioned artificial sweetener, aspartame.

Image Credit: Blaide Woodburn

Aspartame, an artifical sweetener in Diet Colas, is broken down into phenylalanine, methanol, and aspartate

Aspartame, sold under the brand name NutraSweet, is a dipeptide that contains the amino acids aspartic acid and phenylalanine. Aspartame is rapidly hydrolyzed (i.e. split in two by water) into its respective amino acids in the small intestine, serving as a source of aspartic acid and phenylalanine. Thus, it is important to communicate the presence of aspartame in all artificially sweetened products, especially since the products that usually contain aspartame (soft drinks, candies, etc.) are not typical sources of phenylalanine.

Yet, nutrition labels aren’t just important for Phenylketonurics. With the increased incidence of heart disease, it’s more important now than ever to understand the nutritional value of the foods you’re eating. But, do not fear! Stay up to date on some of my upcoming articles for The Pipettepen and Nutrition at UNC and Translational Science where I’ll outline the basics for healthy eating and overall wellness!

Peer edited by Amanda Tapia.

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One Cancer Drug to Rule Them All?

As early as 1999, a scientific study in Denmark found that patients with Huntington’s disease (HD) are less likely to develop cancer when compared to their healthy relatives and the overall population. A decade later, another independent study looked into forty years of patients’ information from the Swedish Cancer Registry and identified a similarly low risk of cancer in patients with HD and related neurodegenerative diseases. Strikingly, this association was not limited to one specific type of cancer but applied to many different tumor types.

What is the connection between cancer and these neurodegenerative diseases, which cause a progressive loss in the structure of the nerve cells? Researchers at Northwestern University think the answer to this puzzle lies in HD-associated ribonucleic acids (RNA), molecules responsible for important biological functions like expression and regulation of genes.

An overabundance of repeated RNA sequences in HD can suppress genes crucial for the survival of nerve cells. A team of scientists led by senior author Dr. Marcus E. Peter at Northwestern recently discovered that these RNA sequences are also highly toxic to a broad variety of cancer cells, and thus have the potential to be a uniquely lethal weapon in the fight against cancer.

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Triplet CAG repeats in Huntington’s Disease can be highly toxic to cancer

All major forms of life on the earth use the nucleic acids like DNA and RNA to perform critical biological functions. The nucleic acids are sequences of five basic building blocks called nucleobases, which are commonly represented by the Roman characters A, G, C, T, and U.  Sequences in nucleic acids can encode information and direct functions in a living system. In HD, a defective genetic alteration causes a “stutter” in a gene called huntingtin, resulting in a prolonged stretch of triplet repeats of C-A-G.

In the earlier phases of their study, Dr. Peter and his team tested a family of RNAs containing these CAG repeats in multiple human and mouse cancer cells. Within hours of treating the cells with the RNAs, the cancer cells stopped growing and eventually most of the cells died. Encouraged by these results, the researchers moved on to test the RNAs in a preclinical mouse model of ovarian cancer. They used small particles, known as nanoparticles, to enable better delivery of the RNAs to the tumor. The treatments were able to reduce the growth of the tumor and did not cause any prominent toxicity to the mouse.  Further, the cancer cells were not observed to be resistant to the therapy even after multiple treatments.

These “suicide” RNA molecules can be a breakthrough in cancer therapy. However, there’s a long journey ahead. The effect of the RNAs on normal cells is not quite clear yet. While a short-term therapy of a few weeks will probably not result in the neurological toxic effects of the repeated tri-unit RNAs, a transient therapy may not be adequate for long-term cancer remission. In fact, mice were observed to have a persistent tumor progression once the therapy was discontinued. Further, to achieve a robust tumor control, the mice had to be daily dosed with the RNAs for two to three weeks. The dosing can be a further delivery challenge in hard to penetrate solid tumors. Nevertheless, these issues can be addressed by rigorous optimization of the RNA formulations and using approaches like gene therapy to ensure long-term availability of the toxic RNAs in the tumor. Finally, it is rare to see a drug so effectively target so many different types of cancers, across species. Whether this is a “moonshot” against cancer, time will tell.

Peer edited by Paige Bommarito and Laetitia Meyrueix.

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Mimicking Electric Eels to Provide Power to Medical Devices

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The electric organ of eels has inspired researchers to develop biocompatible power sources that could be used to power medical devices

While the shock of an electric eel sounds like more of a medical nightmare than a fortunate asset, researchers at the University of Michigan were inspired to simulate the power of these slick creatures in hope of creating power sources for a variety of medical devices. With society’s heavy reliance on technology, it’s not surprising that medical treatments have continued to rely more and more on electrical devices including wearable and implantable sensors, pacemakers, and prosthetics. Just as with any piece of technology, these devices require an electrical power source. However, medical devices face the added requirement of being biocompatible, meaning they must function safely and effectively in the human body. Eel-inspired power sources may achieve this goal of being biocompatible while supplying medical devices with the electricity they need to function.  

The inspirational efficiency with which an eel uses its electrical shock, to help catch prey and protect itself against predators, is the result of natural selection. Electrophorus electricus, know commonly as a knifefish or an electric eel, possesses an electric organ that extends through the back 80% of its body. The organ contains parallel stacks of special cells called electrocytes. When a situation arises that warrants a shock from the eel, its nervous system generates an electric current by activating thousands of electrocytes at the exact same time. As the cells are activated, the positively charged sodium and potassium ions, in and around the cells, move toward the head of the eel. The movement of these ions allows each of the electrocytes to act like small batteries. The activated end that lost the ions has a negative charge, while the opposite side that acquired the sodium and potassium ions carries a positive charge. The battery-like cells can each generate a small, innocuous voltage (less than that of a AAA battery). But when combined, the eel’s shock can be over 600 volts! For reference, a US household outlet supplies 120 volts. While a significant portion of this voltage is lost to the water around the eel, its prey or attacker will still get a nasty shock.

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By developing this work further, researchers hope to successfully use their artificial electric organ to run medical devices like pacemakers

The University of Michigan team has successfully created an artificial electric organ that can potentially be used by humans to power devices. To make the electrical power supply biocompatible, it was necessary to efficiently mimic the features of the eel’s electric organ. This was achieved by preparing hydrogel membranes that could be layered to replicate the structure of the organ. To mimic the movement of ions in and out of the cells, the hydrogels were filled with dissolved table salt, which is made of sodium and chlorine ions. Half of the cells were designed to allow only positively charged sodium ions out and the other half would only allow negatively charged chlorine ions to exit. The gels containing the salt water were alternated on the membrane sheet with gels containing pure water, which allows the sodium and chlorine to move in opposite directions. This flow of ions generates an electric charge with an electrical potential of 110 volts. While this voltage is less than that of the inspirational eel organ, in its current state the artificial organ may be sufficient to power some low-power devices.

Though pleased with the engineering of a potentially biocompatible power source, the researchers acknowledge that there are plenty of opportunities to improve its design. By increasing the efficiency of these artificial organs, researchers believe their utility will increase, as they will become more suitable for use in combination with implantable devices.

Peer edited by Erika Van Goethem.

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