Category Archives: Blogs

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

Sometimes it is all in the tweaking – immunotherapy studies

by Gomolemo Molope

In school, it goes without saying that acquiring excellent marks throughout the year is a goal most students aim to achieve. However, there is a lot more to the honours year than just bagging distinctions and simply calling it a day – or rather one of the longest years. Some lecturers emphasize that this is a year where you get to expand your knowledge by delving into the scientific work which you find most fascinating; while learning some of the most important techniques researchers use to build this body of knowledge. My supervisor on the other hand refers to it as the year of “trial-and-error”. He says it is the year wherein you’ll gain some lab experience that will either make you joyful and proud or that will just make you cry and super stressed. I couldn’t agree with him more, especially while I was standing in the lab repeating an experiment for the fourth time!

I genuinely felt like giving up at that point. But following a series of numerous attempts at the same experiment, I eventually realized that simply adding a slightly higher volume of enzyme to my reaction tubes could have produced the best results. All I needed to do was to tweak the protocol. And much like me, researchers constantly find themselves having to tweak some of their techniques and protocols to produce effective treatments that aim to alleviate numerous diseases. For instance, acute myeloid leukaemia (AML). This blood and bone marrow cancer has limited treatments with high success rates due to their lack of specificity and their association with life-threatening side effects. Additionally, some of the available treatments cannot be administered to AML patients because they lead to graft-vs-host disease. Consequently, specific and more effective treatments still need to be produced to treat this cancer.

Recently, a much greater effort aimed at developing such specific treatments is being made. The latest research has revealed the use of chimeric antigen receptor (CAR) – T cells as an alternative and novel form of cancer therapy, which boosts the immune system to fight cancer. CAR- T cell therapy has shown exceptional success rates compared to conventional treatments as it targets specific antigens which are expressed by cells known to lead to the development of a particular disease. In some cases, researchers genetically modify natural killer (NK) cells as opposed to T-cells due to their cost effectiveness, reduced side effects and longer lifespan. For instance, work done by Albinger (2022) is proof of concept of a treatment which specifically targets AML cells. Essentially, they set out to generate CD33-targeted CAR-modified natural killer (NK) cells. They focused on CD33 because it is a potential antigenic target frequently expressed on leukemic blasts and cells that prompt leukaemia.

In order for Albinger (2022) to achieve their objectives, they first collected AML cells from patients and then isolated primary NK cells from healthy volunteer donors. They then tweaked or rather genetically modified (by lentiviral transduction) primary NK cells to express a second-generation CD33-CAR. In vivo functional studies of CD33-CAR-NK cells in humanized OCI-AML2 xenograft mouse models which reflect physiological conditions of a human host were
performed. Qualitative and quantitative analysis using flow cytometry and confocal microscopy were also done.

In the end, their work showed considerable results proving that the use of CD33-CAR-NK cells could be a potential treatment for AML. In vitro experiments, in the OCI-AML2 cell line, showed that the CD33-CAR-NK cells had stronger cytotoxic activity against AML relative to untransduced NK cells. The in vivo experiments where a single dose injection of CD33-CAR-NK was administered showed effectual clearance of leukemic cells and a greater reduction in leukemic burden relative to untreated mice or mice receiving untransduced NK cells. In vivo experiments where multiple doses of CD33-CARNK cells were administered also showed minimized leukemic burden. The confocal microscopy images obtained from some of the experiments showed low GFP-positive leukemic cells and the presence of intact CAR-NK in the bone marrow of CD33-CAR-NK treated mice. Another one of the major observations made from Albinger’s (2022) work was that the use of the single and repetitive doses of CD33-CAR-NK cells in the mice did not cause any noticeable changes in weight, appearance or behaviour. Additionally, no signs of cytokine release syndrome or graft-vs-host disease were observed.

In conclusion, the results prove that CD33-CAR-NK could be a suitable treatment for AML. Moreover, targeted therapies may assist in improving the prognosis of many patients with AML. This form of therapy could also be applied in the treatment of other types of cancer. However, further research about the identification of unique antigens needs to be done to produce more effective targeted therapies while minimizing undesirable side effects in patients.

Reference:
Albinger N., Pfeifer R., Nitsche M., et al. (2022) Primary CD33-targeting CAR-NK cells for the treatment of acute myeloid leukemia. Blood Cancer J. 12, 61.

THE MALE PILL

by Husnaa Bux

Despite medical advances, uneven access to healthcare still contributes to gender inequality. The female combined oral contraceptive pill has been on the market for sixty years and has empowered women, giving us autonomy over our bodies. As reviewed by Dr. Stephanie Page and colleagues in Frontiers in Endocrinology, the variety in female contraception contrasts with male contraception which consists of condoms, withdrawal, and a vasectomy. Only 16% of global contraceptive use is male-driven, with the ‘latest’ commercially available male contraceptive being the condom, which was established two hundred years ago. Inadequate male contraception emphasises how society places the responsibility of safe sex on women.

Though the proof of concept of androgen use to suppress spermatogenesis was established by the WHO almost fifty years ago, male hormonal contraception is unavailable and pharmaceutical companies have abandoned male contraceptive development. Predictive models suggest novel reversible male contraception could decrease unplanned pregnancies by 30 to 40%, improving the mental, physical, and economic well-being of women and their families, and decreasing population growth. The perceived lack of market for male contraception highlights the commercially driven pharmaceutical industry.

Surveys show that 50-85% of men are willing to use male hormonal contraception. To date, however, only eight male hormonal contraception efficacy studies have been conducted, some of which were terminated prematurely due to mood-altering side effects. An unequal standard of healthcare between genders is seen by the side effects of the female ‘pill’ which include headaches, nausea, weight gain, mood changes, and more. Dimethandrolone undecanoate (DMAU) is an oral and injectable male hormonal contraceptive that acts on both progesterone and androgen receptors. Studies show it is safe, well-tolerated, and markedly suppresses gonadotropins and sex hormones, with few or no symptoms of hypogonadism. Yet male hormonal contraception commercial availability remains unseen.

While men bear no risks of childbirth or abortion, women are forced to use contraception as the benefits outweigh the risks. The benefits may only outweigh the risks for men if there were additional health benefits, for example, reducing long-term disease risk. Prolonging development, for an expectation yet to be explored for women, augments the burden of responsibility of pregnancy that society has already placed on women, diminishing the reality of the “shared risk”.

Through education, increased awareness, and engagement of pharmaceutical companies, male hormonal contraception can be materialised. This will improve the health and wellbeing of women, and decrease global burdens.

References
• Page, S. T., Blithe, D. & Wang, C. 2022. Hormonal Male Contraception: Getting to Market. Front Endorcrinol (Lausanne). DOI: 10.3389/fendo.2022.891589
• Roberts, M. 2019. Male pill – why are we still waiting?. BBC News (online). Available: https://www.bbc.com/news/health-47691567.

Effects of Exercise on Metabolism: More Extensive Than Previously Reported

by Anna Jellema-Butler

Regular physical activity is known to have cardiovascular-protective action mediated by improvements in lipid profiles, blood pressure, body fat, and insulin sensitivity (1). However, a recent study in Cardiovascular Research suggests that the magnitude and extent of the metabolic benefits of exercise are much more profound than previously reported. These findings have important implications for the prevention of heart disease, type II diabetes, and other cardiometabolic diseases which, together, account for over 30% of worldwide mortality (2).

In this unique study, Koay et al. (3) invited a group of 52 male military recruits of similar age and body mass index to participate in an 80-day program of daily aerobic and strength exercise. Critically, the soldiers were housed in the same domicile, allowing for careful – and previously unprecedented – control of lifestyle factors such as diet, sleep, work environment, stress, and tobacco and alcohol use.

To track changes in metabolic health, the authors compared post-exercise levels of 201 plasma metabolites to their baseline values. Global metabolism was dramatically shifted in the trained soldiers (Figure 1), with changes observed across numerous metabolic pathways and at magnitudes and significance levels heretofore unforeseen.

The largest change was a significant reduction in various fatty acid and ketone body intermediates – two substrate classes that serve as key muscle fuel. This indicates an increased capacity for and efficiency of muscular fatty acid metabolism, and to an extent that has never previously been captured. In addition to improved lipid metabolism, elevated levels of arginine and related metabolites in the post-exercise metabolomic profiles signify increased vasodilation and blood flow, reflecting improved vascular health in response to exercise.  

The scale and scope of shifts in several other metabolite classes, including gut microbiome-derived metabolites, markers of proteolysis, substrates of coagulation, endocannabinoids, nucleotides, and markers of redox stress, were similarly unanticipated and may provide novel insights into the metabolic adaptation to exercise.


However, not all the soldiers experienced the same metabolic benefits as their peers. Interestingly, an attenuated or maladaptive metabolic response was associated with increased levels of dimethylguanidino valeric acid (DMGV). This result supports a building hypothesis that DMGV, a poorly characterized metabolite, may serve as an early biomarker of subclinical metabolic dysfunction and allow for early intervention in individuals who will require strategies other than exercise to improve their cardiovascular risk (4).

As the most highly controlled metabolomic analysis of exercise to date, this study reveals the true range and magnitude of the effects of exercise across diverse metabolic pathways. Regular exercise significantly improved the overall metabolic health of young males in just three months. This result solidifies physical activity as a cornerstone of cardiovascular risk-reduction regimes. Furthermore, considered alongside demonstrated benefits for fitness, body fat, sleep, mental health, and non-communicable disease risk (5), these findings reinforce the prioritization of daily exercise for the average individual in pursuit of longevity and quality of life.


References

1.       Nystoriak MA, Bhatnagar A. Cardiovascular Effects and Benefits of Exercise. Vol. 5, Frontiers in Cardiovascular Medicine. Frontiers Media S.A.; 2018.

2.       Bhatnagar P, Wickramasinghe K, Williams J, Rayner M, Townsend N. The epidemiology of cardiovascular disease in the UK 2014. Vol. 101, Heart. BMJ Publishing Group; 2015. p. 1182–9.

3.       Koay YC, Stanton K, Kienzle V, Li M, Yang J, Celermajer DS, et al. Effect of chronic exercise in healthy young male adults: A metabolomic analysis. Cardiovasc Res. 2021 Feb 1;117(2):613–22.

4.       Robbins JM, Herzig M, Morningstar J, Sarzynski MA, Cruz DE, Wang TJ, et al. Association of Dimethylguanidino Valeric Acid with Partial Resistance to Metabolic Health Benefits of Regular Exercise. JAMA Cardiol. 2019 Jul 1;4(7):636–43.

5.       Ruegsegger GN, Booth FW. Health Benefits of Exercise. Cold Spring Harb Perspect Med [Internet]. 2018 [cited 2022 Aug 31];8. Available from: http://perspectivesinmedicine.cshlp.org/

Struggling to study? Try out Spaced Repetition Learning

by Ashraf Moosa

University students spend much of their time studying and preparing for exams. The transition from high school to university can be quite challenging with the increased volume of work and demanding time pressures. Many students struggle to get through vast amounts of content before an exam. However, a solution touted by many is spaced repetition. The idea of spaced repetition has its origins in the late 19th century when Hermann Ebbinghaus proposed a ‘forgetting curve’ (Figure 1). He noted that “frequent repetitions are indispensable in order to make possible the reproduction of a given content” (Ebbinghaus, 2013). Spaced repetition is a learning technique usually performed with flashcards. Flashcards are repeated at intervals to consolidate learning. Newer or more difficult flashcards are shown more frequently, while older less difficult flashcards are shown less frequently. This supposedly makes learning
more effective and efficient. However, is there any scientific evidence to support this technique and might it be the magic bullet to solve students’ studying woes?

A study in Australia by researchers Anton Lambers and Adrian J. Talia sought to answer this question. Their study, titled: “Spaced Repetition Learning as a Tool for Orthopaedic Surgical Education: A Prospective Cohort Study on a Training Examination”, aimed to determine the effectiveness of spaced repetition learning in postgraduate surgical trainees studying for an orthopaedic basic sciences examination. The study consisted of twelve participants who were prospectively enrolled in the study and were provided with a set of 1400 practice flashcards to use through the learning program Anki. Anki is a free and open-source flashcard programme that uses spaced repetition algorithms to enhance learning. The programme is able to track studying habits. Thus, the researchers collected data on time spent using the Anki programme, time spent studying per day, number of reviews performed per day, total number of cards reviewed, and the maturity of studied cards. After the students had written the examination, the researchers collected each student’s examination score. The researchers could then correlate the time students spent studying and the number of flashcards they reviewed with their test scores.

Out of the 12 participants of the study, 11 passed the examination. That represents a 92% pass rate, which was much higher that the overall national pass rate of 67%. It would appear that the participants fared much better than others that had not used the spaced repetition technique. This goes to show that it was effective. It was also interesting to note that the participant that did not pass the examination had only undertaken 1 hour of study time on Anki. This was well below the average of 30 hours other participants had used the programme for. The researchers found a strongly
positive correlation between time spent on the Anki program and final examination score (Figure 2). This supported the researcher’s hypothesis that spaced repetition learning using a flashcard format is an effective study strategy for learning material for Orthopaedic examinations. However, one can more broadly conclude that spaced repetition learning is an effective learning strategy for any fact-rich subject.

Whilst the results of the study are promising, it is limited by its small numbers and the fact that it was not randomised which opens it up to selection bias. In addition, the participants may have employed other studying techniques in conjunction with spaced repetition to prepare for the examination. Despite this, the findings of this study may
be of particular interest to students and those in the education community. Spaced repetition learning offers a way to learn faster and more efficiently. This would be of benefit to time-poor learners who want to maximise their learning from the limited time they have to study. Additional research is needed to further elucidate the benefits of spaced repetition learning, but why not try it out for yourself and see if you find any difference in your results?

References:
• Ebbinghaus, H., 2013. Memory: A Contribution to Experimental Psychology. Annals of Neurosciences, 20(4).
• Lambers, A. and Talia, A., 2021. Spaced Repetition Learning as a Tool for Orthopedic Surgical Education: A Prospective Cohort Study on a Training Examination. Journal of Surgical Education, 78(1), pp.134-139.

Edging closer to an idea popularized in science fiction: the culturing of embryos outside of the mother’s body

by Warwick Pitman

Both my favourite science fiction novel, Brave New World, and science fiction film Blade Runner 2049, depict a reality in which ‘humans’ can be cultured outside of the mother until the end of embryonic development. The idea stems from the allure of potentially hacking biology in a way that allows humans to create organisms with preferable capabilities. If that isn’t a recipe for a perfect science fiction novel or film, I don’t know what is! With the discovery of genetic engineering tools such as CRISPR-Cas9, the idea of introducing specific changes into the genome has indeed become a reality, but what about the culturing of embryos outside of the mother’s body? Recently a study published in Nature shows that although we are far from this reality, we are a step closer to achieving this controversial yet remarkable feat. The authors established a system that allows for the culturing of mouse embryos from an early point in embryo development, specifically known as gastrulation, through to a point at which organ development occurs.  

The purpose of developing such a culture system is to help elucidate the developmental processes of tissue and organ formation during embryo development as these processes are difficult to investigate inside the body because they occur after implantation of the embryo. An analogy for this could be a little mole that one can observe and study when it is above ground but is actually most interesting to study when it burrows itself underground where they are adapted to hunt and create tunnelling networks. The same can be said for the embryo after it embeds itself within the uterine lining of the mother, as this is when the body axes of the embryo are established and where cells change in multiple ways to form the different organs of the body.

Since the maternal environment provides the embryo with specific nutrients and availability of oxygen to aid development, the authors had to attempt to replicate this environment as accurately as possible. This was accomplished by testing different media, supplements, and pressures, before ultimately finding the goldilocks conditions that supported the growth and correct development of the cultured embryos. The authors then provided evidence that the cells of the cultured embryos expressed the same genes as those found in embryos that developed inside the mother. This suggested that the culture system was not interfering with the normal development of the embryo and therefore could be used as a tool to recapitulate what occurs within the maternal environment.

One of the major implications of the system, that the authors make mention of, is as a tool to determine the effects of different perturbations on development of the embryo. This was something Aldous Huxley, the author of Brave New World made use of, to differentiate the castes formed in his dystopian novel. For example, oxygen deprivation and alcohol treatment are used in the novel to lower the intelligence and size of individuals of the lower three castes (Gammas, Deltas and Epsilons). In contrast to this, the motives of the authors of the Nature paper are ethically superior, as they contemplate using such a system to better understand the processes leading to the formation of organs through genetic modification which can have therapeutic applications. One of which would be its use in the field of regenerative medicine, as by understanding the molecular cues that orchestrate the development of an organ can provide insight into how one could regenerate it following an injury. To better understand this idea, one could view each organ of the body as a specific building each with its own architectural plan. If you knew the exact amount of brick, wood, and glass that was used to assemble the structure, it would be much easier to rebuild it, should it ever get knocked down.  

Overall, the study established a system that prolonged the culturing of embryos outside of the mother to a point in embryo development never observed before, but also showed the current limitations in executing what was described and depicted in Brave New World and Blade Runner 2049, respectively. This may be a good thing, as with such great power comes great responsibility, and whether our society would want such a culture system to be available for use is questionable considering the dystopian worlds developed in such novels and films.

Reference:

Aguilera-Castrejon, A., Oldak, B., Shani, T. et al. Ex utero mouse embryogenesis from pre-gastrulation to late organogenesis. Nature 593, 119–124 (2021). https://doi.org/10.1038/s41586-021-03416-3

The New Genetics of Intelligence (Robert Plomin and Sophie von Stumm)

by Saleha Suleman

For centuries, humans have been defined by how intelligent they are. Although the definition of intelligence has changed with evolving times and the differences in lifestyles, the importance of intelligence has not. It is a predictor for occupational, health and overall quality of life outcomes, more than any other trait. This is because a higher intelligence involves the ability to adapt to quickly changing circumstances and undertakings that one would face in their work.

Worldwide, the most standard and widely accepted measurement for intelligence has been IQ (intelligence quotient). An IQ test is able to quantify a person’s reasoning and problem-solving abilities through various tests that the person goes through, and so should be able to account for creativity, thinking outside the box as well as skills needed in schooling subjects such as mathematics. The genetics of intelligence, however, has eluded humans for the longest time. Judging from simple logic, it can be said that there is a certain component of intelligence that is hereditary. But how much it is, and whether it outweighs other factors such as family support, schooling, socioeconomic status and others has not been determined yet. Simply put, intelligence is one of the facets of the ‘nature versus nurture’ debate.

In this paper, the authors performed a meta-analysis to accumulate the findings thus far of the effect of genetics on intelligence. They did this by reviewing results from initial genome wide association studies (GWAS) and showed how genome-wide polygenic scores (GPSs) are a better predictor of intelligence due to it’s accuracy and ability to measure the effects of thousands of DNA variants that are associated with intelligence.

The main findings of the paper are presented in the infographic bellow. Since this is a review, the authors confirmed that there have been multiple attempts to gauge the effect of genetics on intelligence, but the most recent success has come from the use of GPSs. At the time this paper was published, there was also a much larger scale GWAS study being performed that would allow identification of up to 10% of variance. Such studies would allow a clearer definition of the relationship of intelligence with socioeconomic environment, family support, educational attainment of parents and other environmental factors that have so far been attributed to nature in the nature versus nurture debate.

It is important to remember that such studies, and even any tests that would be available to take at a clinic for example, would still be probabilistic and not determinate. Because of that, despite the potential to understand the human mind more, as well as the fact that understanding measurable outcome differences in people of different genetic intelligence would be revolutionary, there have been major ethical concerns for these studies. These include four; biological determination and potential for stigmatization and discrimination, both which can see people being afforded opportunities such as in careers or social circles because of their genetic intelligence, ownership of information, and finally the emotional impact of knowing one’s own personal genetic intelligence levels. As results from current studies become available, it will be of utmost value to distinguish the benefits and shortcomings for them.

References:

Plomin, R. and Von Stumm, S., 2018. The new genetics of intelligence. Nature Reviews Genetics, 19(3), pp.148-159.

Running and Patellofemoral Pain Syndrome: What makes you weak at the knees? — Rugby Science

Patellofemoral Pain Syndrome (PFPS) is a knee condition associated with anterior knee pain when loading the knee in movements like squatting, stair climbing, running and jumping (Ferber et al., 2015). Due to its high prevalence and running becoming an increasingly common form of exercise, it is important that high quality evidence regarding treatment and preventative […]

Running and Patellofemoral Pain Syndrome: What makes you weak at the knees? — Rugby Science
« Older Entries