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What a rollercoaster ride!

by Kayla Lesch

In 2021, I completed my BSc degree in Biotechnology at the University of the Western Cape with a Magna Cum Laude and did exceptionally well in all my modules. Although everything was online due to COVID-19 including lectures and exams, it was still tough. Somehow, 2021 was one of my greatest academic years. This was probably due to me working at my own pace and having discipline. It all paid off, as it landed me quite a few jobs and most importantly my acceptance for honours at the University of Cape Town. 

My honours year (2022) has been anything but easy. However, I’m thankful that I’ve been given this opportunity. I’m proud to say that I’m one of four students in the BMedSci (Hons) Biomedical Forensic Science, Department of Pathology, Division of Forensic Medicine and Toxicology. 

Throughout the year, I never thought I was capable of being an honours student. At the beginning of the year, I wanted to drop out, but something told me not to give up. The toughest part was initially the overall workload. I experienced plenty emotions and had a lot of ups and downs with my academics. During this year, the BMedSci honours students done coursework (lectures, tests and exams), assignments, and project-related work simultaneously. We had presentations and assignments due straight after one another. I was afraid that I could never meet any of the deadlines, yet I did! 

Honours was a massive leap from my undergraduate degree. Mainly since my two years out of the three-year undergraduate degree was online-based and this included exams. This year was the first year since 2019 that I wrote in-person exams, and it was tough! I forgot entirely how to study word for word and retain information. However, somehow, I managed to write each exam and it wasn’t as bad as I thought it would be. To my surprise, I happened to get extremely good marks in all my modules.

This opportunity has also allowed me to meet amazing and educated people! The individuals within my honours programme overall were very friendly and helpful. Each individual within my division was extremely welcoming and supportive. Everyone was willing to share their experiences and knowledge. I appreciated how each of them also gave their advice on ways to cope, handle stress, calm the nerves and mentioned tips for growth in the specific Forensic Science field.  I would’ve never thought that my classmates, would now be a few of my closest friends. Honestly, without these people, I don’t think I would’ve been able to cope with this year as well as I am. 

Honours has coached me to be independent and take initiative. It has shown me that it’s okay to make mistakes but learn from them, and that you’re definitely not the smartest in the room! It has taught me that hard work pays off and to always do the that best you can, as your best is enough. It has taught me that I am capable and educated and lastly, it has shown me how strong I am. Honours has also taught me a lot about the research sector and how important research is overall. It helped me focus solely on my education and my goals, and in some strange way, it helped me evolve. Honours improved my reading, writing, my critical analysis, and so much more. I was told by many, that honours are one of the worst years in post-graduate studies, and according to my knowledge I must agree. Even though being in honours is a tiring, bitter-sweet journey, I can honestly say it is worth all the stress! 

Forensic Science has always fascinated me since I was young! I loved the fact that the individuals involved aimed to solve cases for justice. I loved that they aimed to serve and help others. Honours in Biomedical Forensic Science made me even more intrigued, experiencing first-hand how the field of Forensic Science works in South Africa! Surprisingly Forensic Science is way more complicated and diverse than the CSI TV shows we grew up watching. Did you know, Forensic Science consists of science, law, and medical aspects!? It makes me feel so important, to be involved with real-life cases and learn all the things that’s needed as a forensic scientist. In the beginning, we learnt the different disciplines within forensic science which included Entomology, Medico-legal Death Investigations, Genetics and lastly Toxicology which is what my honours project titled “Retrospective Analysis of Routine LC-QTOF/MS Toxicological Screening Results in Post-Mortem Casework” entails. I never knew forensic science was so diverse and that it had so much room for professional development. I cannot wait to one day contribute to this field and positively impact the lives of others.

Regardless of the rollercoaster of emotions I’ve been on during this year, experiencing both good and difficult times, I’m grateful. Without this experience, I wouldn’t have been this resilient and shaped into the woman I am today, and one day will be. I still have 6 weeks left of my honours year and I’m ready to face it head-on!

A student’s job is to learn, not know

by Imraan Dixon

There’s a cognitive bias called the Dunning-Kruger effect first described by two aptly named researchers, David Dunning and Justin Kruger (funny how things always line up like that, huh?). Essentially, it causes people with limited knowledge to overestimate the extent of that knowledge. Regardless of how true to life the Dunning-Kruger effect is, there is a popular interpretation of it that looks something like this:

When we’ve explored the tip of the knowledge iceberg, ignorant of what lies beneath, we assume we are more knowledgeable than we actually are. Once we are able to see into the depths and how far out of our reach it is, we realise that what we know is a but a droplet in the grand scheme of things.

Honours really gives us the freedom to search and learn about the topics we want to. Undergrad coaxed us with the gentle guide of lecture material. But Honours is conservative on that front, opting to encourage us to seek out knowledge autonomously, bounded only by our own eagerness and deadline constraints. It is through this that I’ve plummeted into the so-called “Valley of Despair”.

Aware of how little I really know, thoughts creep in. Thoughts that I’m not living up to the Honours standard. See, I wasn’t originally accepted into Honours. The only reason I made it here is because space opened up from other admittees leaving. Where does that put me amongst my peers? An off cut that was only put in the final product, because the packaging still had some free space in it…

You know what, though? That’s a bit self-centred, isn’t it? Tsk, tsk, tsk. Let’s not pretend that there aren’t people out there who feel like they are underperforming. I’m not saying there’s definitely people out there who feel like that – I speak only for me, myself, and I – but chances are that I’m not the only one with these insecurities. It makes sense, in a way. Students are integrated into labs where it’s likely that the majority of their interactions are with people on a higher level than them. They’re constantly exposed to Master’s and PhD students who are more experienced. In a way, perhaps those students start to be seen as peers regardless of the degree they hold.

What’s comforting for me to think about is that it’s okay to feel incompetent. It’s okay to feel like I don’t have it all or that I’m lacking knowledge that I assume is supposed to be basic. It’s okay if there’s some things that I can’t do with my current skillset. I’m a student. I’m not here to do. First and foremost, I’m here to learn. The practical aspect is there to facilitate this. The idea that, just because I’m a postgraduate, I’m supposed to be a full-fledged researcher swimming in grants and sleeping in sheets made up of hundreds of my published papers is absurd.

The takeaway, for me, is that I should be a lot more forgiving on myself for my gross inaptitude. Sure, I shouldn’t be complacent, but shooting myself in the foot by psychologically punishing myself like this will hamper my ability to walk forward. After all, I could very well be at the level of knowledge I’m expected to be at and I’m just looking at things through murky lens. Such a preposterous idea! But maybe I just need new glasses…

Learning experiences in 2022

by Caylin Mc Farlane

I realized I needed to pace myself when it comes to how much I put into my studies. People had told me Honours was going to be difficult, but this is much more difficult than what I expected.

The course I chose is Clinical Anatomy and we had our first techniques exams in March. Most of our learning was crammed into 2 months of intense studying and understanding of human anatomy. This would be the first time I had written a test in 5 years, so I had decided to give it my all, because I had wanted great marks. Yet, after the techniques exam was done, I felt I had failed. It felt as if all the hard work I had put into studying was for nought. I had to accept that I wasn’t cut out for academia or lower my expectations of myself.

With all the intense learning and studying for techniques, I had stopped taking care of my mental health. Therefore, I had a breakdown. I was burnt out and the year wasn’t finished. I didn’t realise how much I had put into getting great marks. Yes, I enjoyed myself, and yes, I received great marks, but the cost wasn’t worth it. I had to find a way to balance my studies and the other parts of my life, otherwise I wouldn’t survive 2022.

It’s been a few months since then and I’m getting better at finding the balance. Now, I’m working to achieve good marks. The lesson I learnt was to be realistic about my expectations regarding Honours and myself. Yes, Honours is difficult, intense and sometimes crazy, but that doesn’t mean I won’t enjoy Honours.

Mary Poppins (1964) said, “In every job that must be done, there is an element of fun. You find the fun and ‘snap’, the job’s a game.”

Finding the fun in writing this, was finding a way to incorporate the quote.

Goodluck to all the future Honours students. Remember to take care of your mental health and yourself.

I would be just fine, right?

by Gomolemo Molope

Hey, I am Gomolemo. A young individual from Gauteng who is aspiring to be a scientist. I cannot share a whole lot more about myself right now, but I will share something in particular. The final semester of my undergraduate studies was the most nerve-wracking time of my life. I would try to make the most of my days but my thoughts were always about doing well on my final exams, ultimately getting my degree and then furthering my studies. On top of that, I would check my email regularly to see if any of the universities I had applied to do my honours at had
accepted me.

Once the exam season had finally ended and the long-awaited festive season was approaching. I received an email confirming my admission to UCT. To say that I was happy would be an understatement. I was over the moon! I could not wait to share these amazing news with my family and friends. As excited as I was though, I realised that going to UCT would mean that I would have to move to a different province and stay in a place that was completely new to me. Extremely far from friends, family and home – my comfort zone. However, I will admit that in high school my friends and I would constantly say, “I can’t wait to leave high school. I will finally feel grown and independent.” Needless to say, that is every teenager’s dream. However, it started to feel like everything was suddenly happening way too fast and I felt like I was no longer ready to be grown and independent. On the other hand, I kept thinking that it really could not be all that bad. I would be just fine, right?

Soon after New Year’s Day, I finally made it to Cape Town. I was overwhelmed with a feeling of excitement and a dash of fear. But surely I would be just fine, right? A few days into my stay I eventually got to meet my stream convenor and
classmates for the first time. Surprisingly, many of my classmates were just like me, in that they had now moved to a place which was totally unfamiliar to them. It was during our orientation that we realised that the journey we were now embarking on would not be as terrifying as we had imagined. Although we had all just met, we discovered that together we would form the best support system for one another. Our similarities would be what allow us to form a strong bond which would make those days away from family and friends slightly bearable. Our connectedness would be the source of strength and courage needed to help us through the eventful year ahead of us.

It certainly did not take me months to finally believe that I would be just fine. All my uncertainties and fears were slowly overcome with each passing day. That was all thanks to my stream convenor, lecturers and most importantly my
classmates. A small group of compassionate and friendly people who somehow showed me that change is not always scary. They revealed that stepping out of your comfort zone allows you to live a fulfilling life in which you discover your
abilities and potential. You learn to stand on your own and experience moments that will allow you to grow as an individual. So with all that I have shared, trust me when I say that throwing yourself into the unknown seems daunting. But take that leap of faith because in the end, you will be just fine.

The Mystery Behind Neuronal Death in ALS

by Imraan Dixon

Imagine the things your body is capable of. Imagine even the little things like stretching, scratching that itch, talking, and eating. Now, imagine not being able to do any of that, each ability you’ve had for as long as you can remember slowly eroding away. Every little thing we may take for granted like being able to swallow, being able to speak, or just being able to move our bodies is a gift that a person with amyotrophic lateral sclerosis (ALS) soon loses.

ALS is a neurodegenerative disease characterised by the progressive death of motor neurons in the spine and the brain that control voluntary muscle movements. The death of these neurons leads to the subsequent death of muscle cells. The loss of motor neurons spreads to other parts of the body leading to the inability to move, eat and swallow, and speak. Eventually, this fatally leads to the muscle and nerve cells of the diaphragm – the most important muscle involved in breathing – also dying. Now, symptoms and disease progression may vary, but ultimately one’s life and loved ones are affected severely.

There is unfortunately no current cure for ALS. All that can be done right now is supportive care that can potentially increase life expectancy but at the cost of quality of life. The difficulty in finding effective long-term treatments is due to our lack of understanding of how this disease occurs. There are a multitude of genetic and environmental factors that play a role in ALS, so the picture is quite complex. One fundamental question underpinning ALS pathogenesis is:
“Why do those neurons die?”

Firstly, cell death is divided broadly into two categories. We have accidental cell death that is uncontrolled and typically caused by direct chemical or physical injury. Then, we have regulated cell death (RCD) that is controlled and regulated by our own cells. One major kind of RCD is “apoptosis” which is typically triggered by death ligands (molecules that signal cells to undergo RCD) and a caspase cascade (a chain reaction of caspase molecules that result in apoptosis). It
was originally thought that motor neuron death was caused by apoptosis, but inhibiting it did not protect neurons in ALS. Then, “necroptosis” was suggested as a mechanism. It’s another form of RCD that’s typically caspase-independent and driven by inflammation. However, if we get rid of MLKL – a critical component of necroptotic signalling – we find no changes in neuronal death.

A group of researchers in Australia aimed to find a mechanism underlying neuron death in ALS. That led them to “ferroptosis”. Ferroptosis is a relatively newer discovery and also a form of RCD that is iron-dependent and caspase-independent. Ferroptosis is typically caused by iron dysregulation and glutathione peroxidase 4 (GPX4) depletion that result in lipid peroxidation and cellular membrane damage (lipids are a major component of cell membranes). GPX4 is a major regulator of ferroptosis as it is acts as a defense against lipid peroxides, preventing widespread cellular damage. It does require glutathione (GSH), an antioxidant, in order to do so. See, as it turns out, accumulated iron, lipid peroxidation, and glutathione depletion were found in spinal cord and brain tissue of affected ALS individuals. See the link here?

To test if ferroptosis was indeed the cause of cell death in ALS, the researchers tested the effect of GPX4 on neurons from ALS mice. The result? ALS mice had lower levels of GPX4, and iron levels were dysregulated as expected. Overexpressing GPX4 in these mice showed a positive effect. There was a decrease in lipid peroxidation, therefore cell death was decreased, and disease onset was delayed thereby extending the mice’s lifespan. Additionally motor function was somewhat preserved although disease progressed as usual upon onset.

Does it really amount to much though?

These might not seem like groundbreaking discoveries. After all, the ALS mice still displayed neurodegeneration, indicating that we’re yet to uncover the full picture, let alone find a suitable long-term treatment. But we’ve made progress. Highlighting ferroptosis’s role in ALS opens up new avenues for treatments and discovery. Just from the researcher’s suggestions alone, perhaps selenium (a component of GPX4) or GSH treatments may be useful; iron chelation to remove excess iron might also hamper degeneration. Just knowing that ferroptosis exists and is involved in ALS gives us the power to target it in the future. Perhaps this is just the beginning. Ferroptosis is slowly being linked to other neurodegenerative diseases. Understanding it and how to influence it has the possibility of building the foundation upon which we can treat other diseases as well. Every step we take towards learning more and more about the diseases that plague us is a step towards building a world where people don’t have to suffer from them.

Reference

Wang, T., Tomas, D., Perera, N.D., Cuic, B., Luikinga, S., Viden, A., Barton, S.K., McLean, C.A., Samson, A.L., Southon, A. and Bush, A.I., 2022. Ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis. Cell Death &
Differentiation, 29(6), pp.1187-1198

Are cerebrospinal fluid pharmacokinetics able to predict brain target concentrations of drugs?

by Bianca Rijkmans

Are the pharmacokinetics of cerebrospinal fluid (CSF) able to predict brain target concentrations of various drugs? What role does the blood brain barrier (BBB) play in the distribution of drugs within the central nervous system (CNS)? What is the relationship, in terms of drug distribution, between the different compartments of the brain? These are some of the questions explored in a review paper by de Lange and Danhof (2002).

Knowledge about distribution within the central nervous system is important for drugs that have brain target sites, such as antidepressants, anticonvulsants, anaesthetics, antibacterials and anticancer agents. In the clinical setting, direct measurement of the concentration of these types of drugs poses many challenges. Historically, most often drug concentrations within lumbar CSF were used as a proxy for the concentrations achieved in the brain – however the role of the blood-brain barrier and blood-CSF barrier in the complex relationship of drug distribution within the different compartments of the CNS requires further research. The compartments of note include the brain extracellular fluid (ECF), intra-cellular brain compartments, as well as ventricular and lumbar CSF.

There are multiple factors that may affect drug distribution within the CNS. Firstly, the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) affect the entry and distribution of drugs into the different CNS compartments. The BBB is found at the cerebral endothelial capillaries, which have tight junction proteins that restrict the movement of mainly hydrophilic drugs. The BCSFB is slightly more permeable than the BBB. The characteristics of these barrier systems have significant implications for the distribution of drugs in the CNS. Secondly, there may be distinct differences in the pharmacokinetics of drugs within lumbar CSF compared to ventricular CSF, due to diffusion as well as CSF dynamics. Thirdly, in terms of the physicochemical properties of drugs, the size, charge and lipophilicity of the drug affect its ability to passively diffuse. In this case, lipophilic, small and non-charged drug molecules are favoured when it comes to transcellular diffusion. On the other hand, hydrophilic, large and charged drug molecules rely more on paracellular diffusion, although this type of transport is mediated by the tight-junctions of the BBB and BCSFB, that preclude molecular transport based on size. Cerebral blood flow could also affect drugs crossing the BBB, with an increase in blood flow resulting in a greater influx of highly permeable drugs across the BBB. In addition, the extent of plasma-protein binding of a drug will affect its transport across the BBB and BCSFB. The turnover rate of CSF will also have an effect. Enzymes found at the BBB and BCSFB affect drug metabolism, which acts as a barrier for drug entry into the brain. In addition, pathological brain conditions can affect the permeability of the BBB. This creates repercussions for the transport of drugs across the barrier into the brain. Drugs can also cross the BBB and BCSFB by active transport, which involves the use of ion channels and pumps, including influx and efflux transporters. Some endogenous influx transporter proteins may assist drug entry into the brain, and efflux transporters may actively pump drugs out of the brain.

Considering the multitude of factors that affect drug distribution within the different CNS compartments, it seems logical to try to find a method of measuring drug concentrations as close to their presumed site of action as possible. This is important for antibacterial drugs, where a minimum inhibitory concentration (MIC) needs to be reached in order to kill off the bacteria – for example when treating bacterial meningitis. If we are still only using lumbar CSF concentrations as a proxy for brain drug concentrations, we are in the dark about the actual drug concentrations being achieved in the affected brain tissue. This has significant implications for determining whether sufficient dosages are being prescribed in the clinical setting in order to achieve the best patient outcomes.

Most drugs that target the CNS have their target sites within extracellular regions, thus extracellular brain concentrations of these drugs provide the most relevant information. Cerebral microdialysis is a method, although invasive, that may be able to measure drug concentrations achieved at specific regions in the brain. Imaging techniques, despite having significant limitations, may be non-invasive methods for obtaining better drug concentration information as well. These techniques include positron emission tomography and magnetic resonance spectroscopy.

The review concludes that the value of CSF concentrations of drugs in predicting the effect of the drugs in the brain is highly limited, and thus methods to measure drug concentrations closer to their site of action in the brain need to be further developed.

Reference

de Lange, E. and Danhof, M., 2002. Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting. Clinical pharmacokinetics, 41(10), pp.691-703.

Early bird or night owl?

by May Krause

Do you consider yourself a night owl? Do you struggle to fall asleep and wake up early in the morning, hitting the snooze button a few too many times? This may be the cause of a genetic mutation, meaning we now have a medical excuse for missing that 8 am lecture.

Researchers from The Rockefeller University discovered a genetic mutation, altering the timing of the biological clock. The result of this is a common sleep syndrome called delayed sleep phase disorder (DSPD) or “Night Owl Syndrome”.  It is estimated that a whopping 15% of people in the United States struggle with this disorder.

Normally the intrinsic circadian clock promotes 24-hour rhythms, that are essential for daily human activity and body functioning. The 24-hour cycle consists of a negative feedback loop where transcription factors, Clock and Bmal1, produce inhibitors (of the Per and Cry family). These inhibitors gradually repress the transcription factors which are eventually silenced and therefore no longer produce inhibitors. Once all the inhibitors have degraded, the transcription factors regain their maximum potency, thus starting the cycle all over again.

The researchers sequenced the genes that form the mammalian circadian clock from the DNA of a patient thought to have DSPD. A mutation in the CRY1 gene was found, a gene already implicated in the circadian cycle. This gene mutation results in an altered protein expressed leading to the inhibitor being hyperactive. A hyperactive inhibitor causes the activators to be repressed for too long, extending the circadian cycle by at least half an hour.

To test whether the circadian abnormalities in this individual were related to the observed modification of CRY1, information on sleep patterns was obtained from the proband’s family members. The individuals were genotyped for the presence or absence of the candidate allele. Delayed sleep behaviour was found to be common among family members of both sexes and across several generations. This led the researchers to conclude an autosomal-dominant inheritance pattern.

So besides being an easy excuse as to why you overslept, this discovery may lead to the development of drugs in the future based on this mechanism that has been uncovered. Perhaps a drug that would reduce the activity of the hyperactive CRY1 protein in individuals with this disorder. Additionally, I believe that more research should be done around this since the human circadian cycle is known to not only regulate sleep but also hunger and levels of metabolites and hormones. How does the CRY1 mutation in people with DSPD affect this? Hopefully, the answer to this becomes clear soon, but until then I’ll carry on hitting my snooze button a few too many times. 

Reference

Patke, A., Murphy, P. J., Onat, O. E., Krieger, A. C., Özçelik, T., Campbell, S. S., & Young, M. W. (2017). Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder. Cell, 169(2), 203-215.e13. https://doi.org/10.1016/J.CELL.2017.03.027

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