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1. Visit my PRIMER PAGE to learn the background on Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Symptoms (MELAS) and become familiar with the terminology

2. Read my POST for scientists and non-experts summarizing this disease

3. Check out the THEME PAGES to investigate MELAS from a biochemist’s lens (me!)

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Much Ado About AdoMet

Much Ado About AdoMet

The paper can be accessed at this link:https://onlinelibrary.wiley.com/doi/full/10.1002/pro.3529

QueE is a 7‐Carboxy‐7‐deazaguanine synthase that catalyzes the radical-mediated ring contraction of 6‐carboxy‐5,6,7,8‐tetrahydropterin, forming the pyrrolopyrimidine core of 7‐deazaguanine . QueE is a member of the S‐adenosyl‐L‐methionine (AdoMet), a structurally divergent radical enzyme superfamily, which harnesses the reactivity of radical intermediates to perform its chemical reactions. Members of the AdoMet radical enzyme superfamily utilize a canonical binding motif, a CX3CXϕC motif, to bind a [4Fe‐4S] cluster, and a partial (β/α)6 TIM barrel fold for the arrangement of AdoMet and substrates for catalysis (Grell et al. 2019).

Figure 1. Radical S-adenosyl-l-methionine (SAM) enzymes are widely distributed and catalyze diverse reactions. SAM binds to the unique iron atom of a site-differentiated [4Fe-4S] cluster and is reductively cleaved to generate a 5′-deoxyadenosyl radical, which initiates turnover. 7-Carboxy-7-deazaguanine (CDG) synthase (QueE) catalyzes a key step in the biosynthesis of 7-deazapurine containing natural products.

The AdoMet radical enzymes harness the cleavage and reduction of a molecule of AdoMet ligated with a [4Fe‐4S] cluster to initiate radical chemistry, requiring a change in the resting oxidation state from +2 to +1. The intermediate generated, 5′‐deoxyadenosyl radical (5′‐dAdo•), is highly reactive and can abstract a hydrogen‐atom (H+) from many substrates, thus enabling many chemically challenging and reactions which can be generated from the reductive cleavage of SAM.

The biological reductant, flavodoxin, was first shown to be capable of this reduction in studies of pyruvate formate‐lyase activating enzyme. Flavodoxin reduces the AdoMet radical cluster as follows; firstly, radical chemistry is initiated through reductive cleavage of AdoMet since the AdoMet radical cluster needs to be reduced from the resting +2 oxidation state to the +1 oxidation state. Finally, low potentials electrons from NADPH are transferred to the AdoMet radical cluster through the action of Ferredoxin, or flavodoxin, an NADP+ reductase mechanism. The need to understand the protein–protein interactions occurring between AdoMet radical enzymes and flavodoxins are integral for exploring the determinants for activation.

The impact of this paper arises from the breadth of knowledge surrounding the catalytic activity of the enzyme, while the design for interaction with physiological reductants remains unclear. This paper examined structural differences between three 7‐carboxy‐7‐deazaguanine synthases and how their differences may be related to the interaction between these enzymes and their biological reductant, flavodoxin.

As we learned in BCM44, the flavin mononucleotide (FMN) cofactor of flavodoxin must be within electron transfer distance from the AdoMet radical cluster for cluster reduction. Therefore, the authors must consider how changes in protein folding observed in these QueE structures could explain the reductant specificity noted above for QueE enzymes. We have also learned that the N‐ and C‐terminal extensions are important for both substrate binding and dimerization in Bm

The authors present the structure of EcQueE i(n the absence of substrate) and compared this structure with previous QueE structures from Bm and Bs. Interestingly, these three QueEs, which all catalyze the exact same reaction, are farther apart in sequence space than are other AdoMet radical enzymes that catalyze completely different reaction

This paper concludes with not only a discussion but also a conclusion, posing a question that they had at the very beginning. By determining the structural data, they were able to evaluate the relationship between fold variation and AdoMet binding, substrate binding, Mg2+ ion binding, and flavodoxin binding, and propose that the QueE structural variation is most likely in response to flavodoxin variations.

Reflection Blog #3

As the acronym MELAS suggests, this disease is characterized by mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms. At the first Child Neurological Society meeting, mitochondrial encephalomyopathy was introduced as “a group of neuromuscular disorders with defects in the oxidative pathways of energy production.” It presented with encephalomyopathy accompanied by many other symptoms.

The clinical constellation of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome was first characterized in a report on two patients with the clinical presentations described in the name. In other patients reported in the literature, ragged red muscle fibers suggested an abnormality of the electron transport system, but at this time, the precise biochemical disorders in these three clinical syndromes remained to be elucidated.

Although the clinical features are relatively distinctive, the biochemical abnormalities reported so far have not been uniform across cases, therefore implying a syndrome. Again, “ragged-red fibers were seen, but biochemical analysis showed increased subsarcolemmal activity in NADH tetrazolium reductase stain. Although this patient lacked muscle symptoms initially, she was diagnosed with MELAS on the basis of her CNS symptomatology; the authors hypothesize that mitochondrial changes in some MELAS patients may be due to chronic hypoxia.

The research indicates that when the mitochondria cause defects in OXPHOS, increasing production of reactive oxygen species (ROS), this triggers the activation of the cell death pathway. Autophagy inpatient-specific induced pluripotent stem (iPS) from fibroblasts of patients with MELAS had well-characterized mitochondrial DNA mutations and distinct OXPHOS defects. An increase in autophagy was observed when compared with its normal counterpart, whereas mitophagy is very scarce contributing to decreased cellular viability.

The Power of a Name – Comment HERE

The Power of a Name – Comment HERE

As the acronym MELAS suggests, this disease is characterized by mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms. At the first Child Neurological Society meeting, mitochondrial encephalomyopathy was introduced as “a group of neuromuscular disorders with defects in the oxidative pathways of energy production.” Mitochondrial encephalomyopathies are divided into three distinct clinical subgroups: (1) mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS); (2) myoclonus epilepsy associated with ragged-red fibers (MERRF); and (3) chronic progressive external ophthalmoplegia. An A-to-G transition mutation at nucleotide pair 3,243 in the dihydrouridine loop of mitochondrial tRNALeu(UUR) that is specific to patients with MELAS (Goto, Nonaka, and Horai 1990).

MELAS is defined as a distinctive syndrome that can be differentiated from two other clinical disorders that are also associated with mitochondrial myopathy and cerebral disease. The other defining feature of this disease includes ragged red fibers in skeletal muscle, short stature, seizures, and hemiparesis, hemianopia, or cortical blindness (Pavlakis et al. 1984). Like other mitochondrial defects, this syndrome targets organ systems with high metabolic activity, including the nervous and cardiovascular systems, and clinical onset typically occurs in early adulthood (before the age of 40) and symptoms can appear after a seemingly normal childhood with development attributable to cumulative effects of chronic lactic acidosis

MELAS is one of the most common mitochondrial diseases, with an estimated incidence of 1 in 4000.(El-Hattab et al. 2015) The clinical constellation of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome was first characterized in a report on two patients with the clinical presentations described in the name. In other patients reported in the literature, ragged red muscle fibers suggested an abnormality of the electron transport system, but at this time, the precise biochemical disorders in these three clinical syndromes remained to be elucidated.

The ragged red fibers derive their name from the appearance of the degenerating granular fibers after they have been stained with the modified Gomori trichrome stain. The red staining represents growing mitochondrial elements, and the presence of these ragged red fibers suggests an abnormality of the electron transport system since these findings are regularly seen in documented biochemical deficiencies involving the respiratory chain (Pavlakis et al. 1984)

MELAS is a mitochondrial inherited genetic disorder, although it may result from a sporadic mutation with no family history. Mitochondrial genetic disorders are the result of mutations causing impaired mitochondrial function, including oxidative phosphorylation and energy production. In MELAS, mutations in tRNA are believed to cause impairment of protein assembly into respiratory chain complexes. Many different transfer RNA (tRNA) mutations can cause MELAS. The most common mutation is in the MTTL1 mitochondrial gene. A single base pair mutation, m.3243A>G, is found in 80% patients, and a second common mutation, m.3271T>C, is found in 10%. (El-Hattab et al. 2015).

Although the clinical features are relatively distinctive, the biochemical abnormalities reported so far have not been uniform across cases, therefore implying a syndrome. Most of the current diagnostic criteria on the mitochondrial disease was developed prior to the identification of molecular genetic knowledge. Muscle biopsy was the gold standard for obtaining an accurate diagnosis of mitochondrial diseases. Now, the diagnosis of MELAS is often confirmed by the presence of RRF on succinate dehydrogenase histochemical stain, as a result of diseased mitochondrial aggregates in the subsarcolemmal areas of muscle fibers.

The research indicates that when the mitochondria cause defects in OXPHOS, increasing production of reactive oxygen species (ROS), this triggers the activation of the cell death pathway. Autophagy inpatient-specific induced pluripotent stem (iPS) from fibroblasts of patients with MELAS had well-characterized mitochondrial DNA mutations and distinct OXPHOS defects. An increase in autophagy was observed when compared with its normal counterpart, whereas mitophagy is very scarce contributing to decreased cellular viability.

There is currently no cure for MELAS. Symptoms of seizures are combatted with anti-epileptic medications. Vitamins such as coenzyme Q10 or L-carnitine are thought to help increase energy production by mitochondria and may slow the effects of the disease. There are ongoing MELAS phase I and II trials of Idebenone, a synthetic coenzyme Q10, which has been shown to improve neurological function in other mitochondrial disorders (Scaglia, ClinicalTrials.gov Identifier: NCT00887562). L-arginine has been shown to attenuate the severity of symptoms when used in acute attacks and decrease the frequency of episodes. L-citrulline is also believed to be beneficial in recovery reduction of stroke risk. This relationship is theorized to be due to the correction of nitric oxide deficiency in MELAS patients, as arginine and citrulline are precursors to nitric oxide production.(El-Hattab et al. 2015)

Lipids on the Mind

Lipids on the Mind

Blog Spotlight #1

Access the article: https://www.nature.com/articles/s41598-018-26636-6.pdf?origin=ppub


Image obtained from: Lacombe, R. J. Scott, Raphaël Chouinard-Watkins, and Richard P. Bazinet. “Brain Docosahexaenoic Acid Uptake and Metabolism.” Molecular Aspects of Medicine, Dietary fatty acids, lipid mediators, cell function and human health, 64 (December 1, 2018): 109–34. https://doi.org/10.1016/j.mam.2017.12.004.

               In the United States alone, more than 200,000 people are diagnosed with brain cancer every year, a common metastasis site for patients with advanced primary lung cancer, breast cancer, or melanoma. Many of these metastases result from other primary sources and approximately 50% of lung and melanoma patients and 20% of breast cancer patients develop secondary lesions in the brain. A common feature in most brain metastases is resistance to therapy, which can be attributed to the poor penetration of therapeutics across the blood-brain barrier (BBB). This research is most impactful since there is very little understood about the mechanisms that regulate BBB permeability in normal brain tissue or brain malignancies. This prevents exploitation of the BBB for drug delivery, a method that could be useful for the treatment of many neurodegenerative or malignant brain diseases. Animal models make tumor pathophysiology comparison difficult, relying on both mouse and human cell lines for research purposes.

               Major facilitator superfamily domain‐containing protein‐2a (Mfsd2a) has recently gained the spotlight for its regulatory role in the maintenance of proper functioning of the BBB (Ocak et al., n.d.). Remarkably, Mfsd2a has been implicated in the mediation of the blood–brain barrier (BBB) permeability by selective transportation of the lysophosphatidylcholine (LPC) fatty acids (Nguyen, et al., 2014). The gene, MFSD2a plays an important role in mammalian tissue and organ growth, lipid metabolism and cognitive and motor functions. Specifically, in the brain and retina, Mfsd2a selectively transports the omega-3 fatty acid docosahexaenoic acid (DHA) across the BBB. This was confirmed by experimenting with a genetic deletion of Mfsd2a mice which led to impaired DHA transport and reduced levels of certain lipid metabolites. Loss-of-function studies provide concrete evidence in support of pursuing this pathway.

               Loss-of-function (including familial mutations) in human MFSD2A are linked to cognitive deficits and ataxia due to deficiencies in DHA transport and metabolism. As we learned in BCM441, DHA cannot be synthesized in the brain, thus it must be transported there by other means. DHA accumulated in the brain is selectively derived from the plasma where it is bound to albumin as an unesterified fatty acid or to LPC. DHA is a crucial polyunsaturated omega‐3 fatty acid required for brain development, motor, and cognitive functioning. A previous study reported down-regulation of Mfsd2a in a pericyte-deficient mouse model, suggesting that pericytes are necessary for the induction or maintaining Mfsd2a gene expression. For this reason, the authors set out to investigate the association between pericytes and endothelial cells within the vasculature of metastatic brain tumors.

Figure 1. The regulation of BBB permeability is mediated by Mfsd2a suppression of caveolae‐mediated transcytosis in endothelial cells. Essential DHA is absorbed from the intestines or synthesized, conjugated to LPC in the liver and bound to albumin forming LPC‐DHA in the plasma. The significant pathway of LPC‐DHA uptake across the endothelial cells of the BBB is controlled by Mfsd2a. The lipid composition of the plasma membrane which is highly enriched by DHA impairs the formation of caveolae vesicles. In the absence of Mfsd2a, transcytosis across the endothelial cell increases. BBB: blood-brain barrier, DHA: Docosahexaenoic acid, LPC: Lysophosphatidylcholine.

               The researchers analyzed brain metastases using patient-derived xenograft (PDX) which is a tissue graft from a donor of a different species from the recipient. In this case mouse models were used to study signaling pathways involved in disruption of the intratumoral BBB. Cells were initially grown in serum-free media, with the intention of relieving the effects of substances such as growth factors on the cells. Cultured metastatic tumor cells grew as neurosphere-like spheroids in serum-free media and expressed epithelial markers including E-Cadherin and β-catenin. Specific patterns of localization and expression of Mfsd2a in brain endothelial cells suggested a functional role that was further investigated. Since intratumoral blood vessels showed abnormal BBB properties, the authors analyzed the expression of Mfsd2a in metastatic tumors and compared these results to the opposite, non-injected hemisphere. The results evidenced a statistically significant decrease of Mfsd2a protein expression in vascular endothelial cells from brain metastases originating from primary breast cancer.

               Importantly, the results containing reduced numbers of perivascular astrocytes strongly correlated with lack of Mfsd2a expression in brain metastasis endothelial cells. The data supports the notion that endothelial cells of brain metastases are in contact or are associated with pericytes but show diminished interactions with perivascular astrocytes. As determined previously, the presence of pericytes was confirmed to be required for the expression of Mfsd2a in the brain endothelial cells. The analysis of previous microarray data of pericyte‐deficient mouse models (Armulik et al., 2010) demonstrated a significant decrease in Mfsd2a expression in pericyte‐deficient animals (Ben-Zvi et al., 2014). This data can be corroborated with reduced expression of Mfsd2a. Further, astrocytes have been known to secrete cytokines and growth factors that modulate BBB properties in the brain vascular endothelium. For this reason, the researchers examined the influence of conditioned media taken from primary mouse brain astrocytes or human astrocytes on the expression of Mfsd2a in low passage. This means that the cells were not passed or split more than five times in order to keep mutations and selective pressures at a minimum to control for mutations. This demonstrated that both mouse and human astrocytes secrete factors that promote the expression of Mfsd2a mRNA in HBMECs.

               It is also known that Mfsd2a is a transporter for DHA when it is conjugated to lysophosphatidylcholine (LPC) in circulation, as described by the pathway in Figure 2. Thus, the effects of astrocyte conditioned media on Mfsd2a-dependent uptake of nitrobenzoxadiazole-LPC (NBD-LPC) were examined using a fluorescent tracer, revealing an increased uptake of NBD-LPC by HBMECs treated with astrocyte-conditioned media compared to a control non-conditioned media. The astroglial-derived factors that positively regulate the expression of Mfsd2a were determined by treating HBMECs with different cytokines with known effects on endothelial barrier properties, such as VEGF, bFGF/FGF2, and TGFβ1. After treatment, levels of Mfsd2a gene expression were measured using qRT-PCR. It was concluded that both bFGF and TGFβ1 have the ability to induce the expression of MFSD2A in HBMECs, whereas VEGF had an inhibitory effect on MFSD2A gene expression.

Figure 2. The proposed mechanism for Mfsd2a‐mediated LPC transport across the plasma membrane is Na dependent. Na binds to Mfsd2a and LPC inserts itself into the outer membrane and diffuses laterally into the hydrophobic cleft of Mfsd2a.
this causes a conformational change in Mfsd2a to an inward‐open form while the zwitterionic headgroup of LPC is inverted within the transporter (Quek et al., 2016). Na: sodium.

               Finally, to evaluate a direct effect of DHA on metastases, the authors treated cultured primary lung and breast brain spheroids with DHA. They observed decreased growth and survival of tumor cells treated with DHA compared to controls. Additionally, DHA treatment positively impacted the growth and survival of HBMECs. Therefore, the researchers conclude that loss of Mfsd2a in metastatic tumor endothelial cells leads to decreased uptake of essential fatty acids, specifically DHA, which promotes tumor growth and survival in the brain microenvironment.

               Mediating the transport of DHA is not the only function, however. In addition, Mfsd2a suppresses caveolin-dependent transcytosis. Increased vesicles in Mfsd2a‐deficient mice have been found to be positive for caveolin‐1 (cav‐1) which is the mandatory protein coat implicated in the formation of caveolae vesicles from the plasma membrane (Ocak et al., n.d.). DHA was also previously shown to displace cav‐1 from the plasma membrane, decreasing the formation of caveolae vesicles in its presence. This was demonstrated using a genetic deletion of murine Mfsd2a leading to enhanced transcellular transport and breakdown of the vascular endothelial barrier in the brain and retina. The research shows that Mfsd2a expression as well as its transport functions are down-regulated in the metastatic brain tumor vascular endothelium and can be explained by the absence of astrocytes that use TGFβ1 and bFGF signaling to maintain expression of Mfsd2a in cerebral endothelial cells.

               Lipid transport pathways of Mfsd2a pay a critical role in the regulation of permeability and in the maintenance of the integrity of the BBB by acting as a suppressor on caveolae‐mediated transcytosis in the endothelial cells of the CNS vasculature. Therefore, loss of MFSD2A promotes metastatic tumor growth and survival in the brain microenvironment by altering DHA transport and metabolism. Mfsd2a is a novel LPC transporter selectively expressed in the endothelial cells of the CNS and provides impactful contributions to the formation, functioning, and maintenance of the BBB. Looking ahead to the future, this pathway can possibly be harnessed for pharmaceutical delivery across the BBB. Changes in Mfsd2a expression levels following different types of brain injury may be unique to the pathology, which will be an important factor to consider while creating specific targeted therapeutic strategies. Nonetheless, large numbers of in vivo and in vitro studies are warranted in order to corroborate the practicality and applicability of pharmacologic strategies based on the modulation of BBB permeability via Mfsd2a. Restoring DHA and or its metabolites to the tumor microenvironment may serve as a treatment option for patients with metastatic brain cancer.

References:

1. Ocak, P.E., Ocak, U., Sherchan, P., Zhang, J.H., Tang, J., n.d. Insights into major facilitator superfamily domain-containing protein-2a (Mfsd2a) in physiology and pathophysiology. What do we know so far? J. Neurosci. Res. 0. https://doi.org/10.1002/jnr.24327

2. Pericytes regulate the blood–brain barrier | Nature [WWW Document], n.d. URL https://www.nature.com/articles/nature09522 (accessed 2.11.19).

3. Structure and function of the blood–brain barrier – ScienceDirect [WWW Document], n.d. URL https://www.sciencedirect.com/science/article/pii/S0969996109002083?via%3Dihub (accessed 2.11.19).

4. Tiwary, S., Morales, J. E., Kwiatkowski, S. C., Lang, F. F., Rao, G., & McCarty, J. H. (2018). Metastatic brain tumors disrupt the blood‐brain barrier and alter lipid metabolism by inhibiting expression of the endothelial cell fatty acid transporter Mfsd2a. Scientific Reports, 8(1), 8267. https://doi.org/10.1038/s41598-018-26636-6

5. Nguyen, L. N., Ma, D., Shui, G., Wong, P., Cazenave‐Gassiot, A., Zhang, X., … Silver, D. L. (2014). Mfsd2a is a transporter for the essential omega‐3 fatty acid docosahexaenoic acid. Nature, 509(7501), 503–506. https://doi.org/10.1038/nature13241

Brain Squall (not a storm)

Brain Squall (not a storm)

Reflection Blog #2

While I am primarily interested in developments in the field of oncology, I think I would like to take this opportunity to investigate biochemical pathways that have biological impacts other than malignancies. I have a particular interest in neurodegenerative disorders and those that affect the brain (my brain says no bias). I am also interested in the immune system, and what happens when the body’s defenses work against itself, as well as how an understanding of these processes can help scientist develop a wide range of treatments. Here are some of the diseases I have found intriguing:

1. Immunoglobulin A (IgA) nephropathy: IgA nephropathy affects the kidneys by attacking the glomeruli which are sets of looping blood vessels in the nephrons the tiny functional units of the kidneys that filter wastes and remove extra fluid from the blood. The buildup of IgA deposits inflames and damages the glomeruli, causing the kidneys to leak blood and protein into the urine.1

2. Romano-Ward Syndrome: In people with long QT syndrome, the part of the heartbeat known as the QT interval is abnormally long. This causes abnormalities in the time it takes to recharge the heart and can lead to abnormal heart rhythms. It is characterized by syncopal episodes and other electrocardiographic abnormalities and may result from mutations encoding subunits of the cardiac ion channels. 2

3. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a condition that affects many of the body’s systems, particularly the brain, nervous system ,and muscles. This disorder is accompanied by symptoms that indicate central nervous system involvement including seizures, hemiparesis, hemianopsia, cortical blindness, and episodic vomiting. It is also caused be a series of genetic mutations and can lead to neurodegeneration.3

References:

(1)       IgA Nephropathy | NIDDK https://www.niddk.nih.gov/health-information/kidney-disease/iga-nephropathy (accessed Jan 30, 2019).

(2)       Reference, G. H. Romano-Ward syndrome https://ghr.nlm.nih.gov/condition/romano-ward-syndrome (accessed Jan 30, 2019).

(3)       Montagna, P.; Gallassi, R.; Medori, R.; Govoni, E.; Zeviani, M.; Di Mauro, S.; Lugaresi, E.; Andermann, F. MELAS Syndrome: Characteristic Migrainous and Epileptic Features and Maternal Transmission. Neurology 1988, 38 (5), 751–754.

Reflection Blog #1

Reflection Blog #1

Why Biochemistry?

“The universe is under no obligation to make sense to you.” -Neil Degrasse Tyson

I cannot ask myself the question, “why biochemistry,” without questioning my very existence. Biochemistry entered my life languidly; elementary science and math classes were my favorite subjects because the answers were always achievable. Gradually, I realized that the answers are not always apparent, and that I had many questions regarding the processes of the observable world. On a smaller scale, science allows humans to craft answers to “how?” or “why?” Those who are outside the realm of STEM, may assert that science demystifies nature by offering solutions to these questions, yet every day I am in awe of the elegance and grandeur of nature.

Biochemistry is so much more just a combination of Biology and Chemistry, it is the chemistry of biological mechanisms and interactions. This field has applications in medicine, drug development, and environmental studies. It is an integral part of food science, where biochemists study chemical composition, research ways to develop reasonable sources of nutrition, and develop methods to extract nutrients from waste products. Biochemistry is an important part of agriculture pertaining to the interaction of herbicides and insecticides with plants or pests.1 Ultimately, studying biochemistry is about understanding living systems and their functions in order to harness molecules, enzymes, genetic material, and their interactions to make the world a better place (hopefully).

I hope to use my knowledge of biochemical processes to pursue cancer research and a career as a doctor in order to preserve and protect human life, forage relationships with the suffering, or those who are greatly in need of comfort. As a volunteer EMT, I often find myself wondering how my patient will be treated after they are no longer in my care. As a biochemistry researcher, I have spent hundreds (if not thousands!) of hours in the lab. At Muhlenberg College, I work with Dr. Keri Colabroy, studying the enzyme kinetics of L-DOPA 2,3-dioxygenase from Streptomyces lincolnensis, an enzyme involved in the biosynthetic pathway of the propylhygric acid moiety of the antibiotic lincomycin. Last summer, I worked many hours with Dr. Irina Balyasnikova, performing cell-based neuroimmunology research for the treatment of brain malignancies, more specifically, employing mRNA therapeutics for the treatment of brain cancer. Cancer cells arise from the failure of different chemical pathways, and I am fascinated by immunotherapeutic treatments that harness a patient’s own artillery to combat disease.

My research directly connects my ambitions to employ biochemical knowledge and techniques to improve the lives of others as a future physician. I am further motivated to learn by the questions that I am not sure I will ever have the ability to answer. What is consciousness? Where is last Thursday? Why are endings hard? Why does the universe bother to exist? When did it start, where will it end? Is immortality the end goal? If not, what is? And why? Are we missing something that would allow us to answer these questions? Is there an answer? Why do we need one? And on and on…Unfortunately, I do not know, but I think this: existing is delightful yet painfully perplexing. Humans spend a great deal of time searching for answers as a natural quest for understanding and as distraction from existential loneliness. But then again, who am I to say?

References

  1. American Chemical Society. College to Career Biological/Biochemistry. https://www.acs.org/content/acs/en/careers/college-to-career/areas-of-chemistry/biological-biochemistry.html (accessed Jan 19, 2019).