Category: Academia and Research

Zahra Mohsin, Second Year Medicine

Elizabeth Blackwell made history as the first woman in America to receive a medical degree, (Michals, 2015), as well as the first to have their name entered in the British General Medical Council’s Register in 1859, (University of Bristol, n.d.). Yet despite being a pioneer for women in the medical field, many may be unaware of the contributions which Dr Elizabeth Blackwell made towards promoting rights of women and their education in the medical profession.

Blackwell was born in Bristol, England on February 3, 1821, the third of nine children to Samuel Blackwell, wealthy owner of a sugar refinery, and his wife Hannah Lane, (Michals, 2015). Although unusual for the era, her father insisted that Blackwell and her siblings be equally well educated, (BBC, 2008), resulting in her receiving an excellent education provided by private tutors, (WAMS, n.d.). In 1832, the family emigrated from Bristol to New York after the failure of her father’s business, moving again a few years later to Cincinnati, Ohio, (Michals, 2015). Blackwell’s father died in 1838, leaving his family in financial hardship and, following his death, she and her sisters took to teaching and opened a private school to support their family, (University of Bristol, n.d.).

During her mid-20s, a close companion passed away from a prolonged illness, and prior to her passing, she had confided in Blackwell that her suffering would have been lessened had she been treated by a female doctor, (WAMS, n.d.). Following this, Blackwell decided to devote her career to studying medicine and ensuring that women received high quality healthcare. She began studying medicine privately for a few years before seeking admission to medical school, (Thakur et al., 2024). After several rejections, she was admitted to Geneva Medical College after the faculty, assuming they would not allow for a female to be enrolled, permitted the all-male student body to vote on her admission. As a joke, the student body voted “yes,” and Blackwell subsequently became a medical student, (University of Bristol, n.d.).  

Blackwell faced discrimination and hostility throughout her time at medical school, including being forced to sit separately during lectures and often being excluded from labs, (Michals, 2015). Despite these odds, she continued to persevere, ultimately ranking first in her class in 1849, (The Editors of Encyclopedia Britannica, n.d.). 

In the same year, Blackwell travelled to Paris where she studied midwifery at La Maternité. Here she contracted a serious eye infection whilst attending to a newborn, resulting in her becoming blind in one eye and ultimately compelling her to abandon hopes of becoming a surgeon, (Thakur et al., 2024). She later returned to England and worked under Dr, (later Sir), James Paget at St Bartholomew’s Hospital, (The Editors of Encyclopedia Britannica, n.d.). She became increasingly interested in social causes, particularly regarding the education of women, (Luft, n.d.). In the summer of 1851, she went back to the United States where prejudice against female physicians made practising medicine difficult, as she was refused posts and was unable to rent private consulting quarters, (The Editors of Encyclopedia Britannica, n.d.). Despite it taking a long time to develop her private practice, Blackwell opened a small dispensary in a slum district in New York in 1853, later being joined by her younger sister, Dr Emily Blackwell, and by Dr Marie E. Zakrzewska (The Editors of Encyclopedia Britannica, n.d.). In 1857, the dispensary was incorporated as the New York Infirmary for Women and Children. This was a healthcare facility dedicated to providing accessible healthcare for underserved populations, whilst also serving as a professional environment for female physicians, medical students, and nursing scholars (Thakur et al., 2024). 

During a year-long lecture tour of Great Britain, Blackwell became the first woman to have her name on the British Medical Register in 1859, (The Editors of Encyclopedia Britannica, n.d.), becoming a pioneer for British women wanting to join the medical profession. In 1861, she also helped organise the Women’s Central Association of Relief and the U.S. Sanitary Commission to help select and train nurses during the outbreak of the American Civil War, (The Editors of Encyclopedia Britannica, n.d.). As an advocate for gender equality in medical education, Blackwell argued that women should be allowed to study in the same recognised institutions as their male counterparts, (Thakur et al., 2024). Henceforth, The Woman’s Medical College of the New York Infirmary opened in 1868 with a total of fifteen students and nine teaching staff, including Blackwell as a professor of hygiene (Thakur et al., 2024). In 1869, Blackwell moved back to England, leaving the college to be run by her sister Emily, (Thakur et al., 2024).

Blackwell founded the National Health Society in 1871; this aimed to educate people on the benefits of hygiene and healthy lifestyles, something which she was passionate about (University of Bristol, n.d.). Their motto, “prevention is better than cure” is one which still holds value today, and highlights the longevity of Blackwell’s legacy.

In 1874, alongside British physicians Sophia Jex-Blake and Elizabeth Garret Anderson, Blackwell established the London School of Medicine for Women (University of Bristol, n.d.), being appointed as a professor of gynaecology. Over the next years of her life, she also spent time writing and publishing books and pamphlets on subjects including hygiene, family planning, preventative medicine, sanitation, and medication education (University of Bristol, n.d.). She died on the 31st of May 1910 in Hastings, England.

Elizabeth Blackwell spent her life dedicated to a profession which many deemed unsuitable and unattainable. Nevertheless, she spent her life advocating not only for her own prospects, but for the rights of others, with a passion and enthusiasm that helped shape a place for women in medicine. Her legacy and commitment is one that is, and should be continued to be, recognised within the medical field and beyond.

References

• BBC 2008. BBC – Bristol – History – The Bristol girl who became an American legend. bbc.co.uk. [Online]. [Accessed 9 January 2025]. Available from: https://www.bbc.co.uk/bristol/content/articles/2006/09/20/blackwell_feature.shtml.
• Library of Congress 1877. Elizabeth Blackwell, 1821-1910, oval bust, wearing wedding veil [Online]. [Accessed 9 January 2025]. Available from: https://www.loc.gov/item/2005679734/.
• Luft, E. v.d n.d. Celebrating 150 Years of Women in Medicine | Elizabeth Blackwell | HWS. http://www.hws.edu. [Online]. [Accessed 9 January 2025]. Available from: https://www.hws.edu/about/history/elizabeth-blackwell/150-years.aspx.
• Michals, D. 2015. Elizabeth Blackwell. National Women’s History Museum. [Online]. [Accessed 9 January 2025]. Available from: https://www.womenshistory.org/education-resources/biographies/elizabeth-blackwell.
• Thakur, J., Choudhari, S.G. and Gaidhane, A. 2024. Pioneering Physician: Dr. Elizabeth Blackwell and the Path to Medical History. Cureus. [Online]. 16(9). [Accessed 9 January 2025] Available from: https://doi.org/10.7759/cureus.68713.
• The Editors of Encyclopedia Britannica n.d. Elizabeth Blackwell | Biography & Facts. Encyclopædia Britannica. [Online]. [Accessed 9 January 2025]. Available from: https://www.britannica.com/biography/Elizabeth-Blackwell.
• University of Bristol n.d. Who was Elizabeth Blackwell? Bristol.ac.uk. [Online]. [Accessed 9 January 2025]. Available from: https://www.bristol.ac.uk/blackwell/who-we-are/who-was-elizabeth-blackwell/.
• WAMS n.d. Life Story: Elizabeth Blackwell. Women & the American Story. [Online]. [Accessed 9 January 2025]. Available from: https://wams.nyhistory.org/a-nation-divided/civil-war/elizabeth-blackwell/.

Lucy Longbottom, Intercalating Medical Student

Every medical student is familiar with the statistic: 1 in 25 people are carriers for cystic fibrosis (Cystic Fibrosis Trust, 2025). Many are also aware of the F508 deletion mutation commonly responsible for this disorder, which often flashes up in pre-clinical lectures. But, despite memorising the basics for exams, there is little further exploration into exactly how this disease manifests on a genetic and molecular level. Where is the affected gene located? How do mutations affect the protein’s ability to function normally? And how does this result in the clinical phenotype we see in cystic fibrosis patients? 

Gene locus, and normal protein structure and function

Cystic fibrosis is an autosomal recessive inherited disorder characterised by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene (Johns Hopkins University, 1966-2025). The CFTR gene is located on chromosome seven, specifically at position 7q31.2 (Johns Hopkins University, 1966-2025), and is approximately 6,500 nucleotides in length with 24 coding exons (Riordan et al., 1989).

The translated CFTR protein is a type of ATP Binding Cassette (ABC) transporter (Vergani et al., 2005), a superfamily of proteins which broadly function as membrane transporters, powered by ATP hydrolysis (Rees et al., 2009). ABC transporters generally possess four domains: two transmembrane domains (TMDs), spanning the cell’s lipid bilayer, and two nucleotide binding domains (NBDs), within the cell’s cytoplasm (Rees et al., 2009). ATP binds to the NBDs which induces their closure and causes flipping of the TMDs from an inward to outward facing state. Importers can then accept substrates from binding proteins, and exporters can expel substrates extracellularly (Fig. 1). Hydrolysis of ATP reverses this flipping, returning the transporter to an inward facing state (Hollenstein et al., 2007). 

Figure 1: Representation of an ABC importer, where nucleotide binding domains (NBDs) and transmembrane domains (TMDs) interact with ATP to translocate substrates across a membrane, adapted from Rees et al., 2009

The specific protein structure of CFTR is much in concordance with this general structure, consisting of two NBDs and two membrane spanning domains (MSDs). These MSDs are equivalent to the TMDs mentioned above as they span the cell’s membrane, but this different name is used when referencing CFTR’s structure specifically, so I will use ‘MSD’ from here. In addition to these, CFTR has a unique regulatory ‘R’ domain (Serohijos et al., 2008). Cytoplasmic loops (regions of the MSDs) facilitate the formation of interfaces between NBDs and MSDs, enabling synthesis of a stable tertiary structure (Fig. 2). A notable amino acid, phenylalanine, at position 508 (Phe-508), is located in NBD1 and mediates its interface with MSD2 by forming crosslinks with cysteines at cytoplasmic loop 4, resulting in the cross-linking of the two domains (Serohijos et al., 2008). As for the R domain, its role involves regulation of channel gating, whereby the phosphorylation of the R domain by protein kinases, in combination with ATP binding and hydrolysis at NBDs, is required for CFTR normal channel functioning (He et al., 2008).

Figure 2: Schema of CFTR structure (A) and corresponding 3D model of CFTR protein (B), depicting the specific interfaces that form between cytoplasmic loop four (CL4) on membrane spanning domain two (MSD2) and nucleotide binding domain one (NBD1), and cytoplasmic loop two (CL2) on membrane spanning domain one (MSD1) and nucleotide binding domain two (NBD2). Adapted from Serohijos et al. (2008). 

Functionally, the CFTR protein is an anion channel (Kartner et al., 1991) – the only known ion transporter within the ABC family (Riordan, 2008) – involved in transepithelial chloride ion transport at the apical membrane (Anderson et al., 1991). Consequentially, CFTR plays a crucial role in fluid and electrolyte homeostasis in many exocrine tissues (Sheppard and Welsh, 1999; Riordan, 2008).  

CFTR mutations

Over 2000 CFTR variants have been identified worldwide and, of a sample of 1,167 variants, ~70% were pathological for cystic fibrosis (Johns Hopkins University, 2024). The majority are missense mutations (The Hospital for Sick Children (SickKids), 2011; Bell et al., 2015) whereby a codon alteration leads to the translation of a different amino acid at that position. The most common pathological CFTR mutation is ‘F508del’ – the deletion of Phe-508 – with ~90% of the cystic fibrosis population carrying the mutation in at least one allele, and 50% of those homozygous for the mutation (Boyle and De Boeck, 2013). 

The F508del mutation is a codon deletion causing absence of Phe-508 at NBD1, reducing the strength of its interface with MSD2 and its interaction with NBD2 (McDonald et al., 2022). The resulting protein is misfolded and ultimately degraded by ubiquitin ligases at the endoplasmic reticulum (Riepe et al., 2024), meaning a functional CFTR protein fails to reach the apical membrane.

CFTR mutations can be split into six classes (Fig. 2) (Boyle and De Boeck, 2013). Crucially, regardless of mutation class or type, all mutations pathological for cystic fibrosis result in loss of function of the CFTR protein. Broadly, class one and two mutations result in the absence of a functional CFTR protein at the epithelial apical membrane, class three and four mutations result in defective channel functioning at the apical membrane, and class five and six involve reduced synthesis or stability of the CFTR protein (Boyle and De Boeck, 2013). Class two is the most common, under which F508del falls (Boyle and De Boeck, 2013).

Figure 3: CFTR mutation classes, from Boyle and De Boeck, 2013.

Clinical manifestations and therapeutics

Clinically, the dysfunctional chloride transport and fluid regulation in cystic fibrosis results in production of dehydrated, viscous secretions at exocrine surfaces, leading to obstruction, inflammation, and eventual tissue damage and impaired organ functioning (Riordan, 2008; Cutting, 2015). Key organ systems affected include the lungs, where obstructive pulmonary disease develops due to the formation of inflammatory mucus plugs and plaques (Turcios, 2020); and the pancreas, where obstruction of the ductal canal and resultant exocrine tissue loss can cause pancreatic insufficiency (Coderre et al., 2021). Additional affected tissues include the liver and bile ducts (Leung and Narkewicz, 2017), the sweat glands (causing the characteristically elevated sweat chloride concentration) (Cutting, 2015), and the male reproductive tract, where infertility from congenital bilateral absence of the vas deferens occurs in 95% of cystic fibrosis males (de Souza et al., 2018). 

Whilst there is no cure for the disorder, pharmacological agents, called CFTR modulators (Taylor-Cousar et al., 2023), have been developed that can target the proteins’ functional deficits caused by specific mutations. Ivacaftor, a CFTR potentiator, increases channel opening probability as well as chloride secretion of CFTR in cells with class three mutations (such as Gly551Asp) (Van Goor et al., 2009). Due to the nature of class two mutations, CFTR correctors such as Lumacaftor were then developed to increase CFTR trafficking to the apical membrane in F508del homozygotes and improve chloride secretion (Van Goor et al., 2011). Clinically, Ivacaftor can be used in combination with a CFTR corrector to maximise CFTR functioning in F508del variants (NICE, 2017; Taylor-Cousar et al., 2023).

Evidently, comprehensive knowledge of how mutations in the CFTR gene affect the translated proteins’ structure and function is vital to clinicians’ understanding of the disease, and the development of therapies which attempt to target and correct this loss of function. Through continued research, we can only hope to expand upon the knowledge gained over the past few decades and develop novel interventions which serve to improve the quality of life for those living with cystic fibrosis. 

References

Anderson, M.P., Gregory, R.J., Thompson, S., Souza, D.W., Paul, S., Mulligan, R.C., Smith, A.E. and Welsh, M.J. 1991. Demonstration That CFTR Is a Chloride Channel by Alteration of Its Anion Selectivity. Science. 253(5016), pp.202-205.

Bell, S.C., De Boeck, K. and Amaral, M.D. 2015. New pharmacological approaches for cystic fibrosis: Promises, progress, pitfalls. Pharmacology & Therapeutics. 145, pp.19-34.

Boyle, M.P. and De Boeck, K. 2013. A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect. The Lancet Respiratory Medicine. 1(2), pp.158-163.

Coderre, L., Debieche, L., Plourde, J., Rabasa-Lhoret, R. and Lesage, S. 2021. The Potential Causes of Cystic Fibrosis-Related Diabetes. Front Endocrinol (Lausanne). 12, p702823.

Cutting, G.R. 2015. Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet. 16(1), pp.45-56.

Cystic Fibrosis Trust. 2025. Information for carriers. [Online]. [Accessed 12 January]. Available from: https://www.cysticfibrosis.org.uk/what-is-cystic-fibrosis/diagnosis/information-for-carriers

de Souza, D.A.S., Faucz, F.R., Pereira-Ferrari, L., Sotomaior, V.S. and Raskin, S. 2018. Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis: reproductive implications and genetic counseling. Andrology. 6(1), pp.127-135.

He, L., Aleksandrov, A.A., Serohijos, A.W., Hegedus, T., Aleksandrov, L.A., Cui, L., Dokholyan, N.V. and Riordan, J.R. 2008. Multiple membrane-cytoplasmic domain contacts in the cystic fibrosis transmembrane conductance regulator (CFTR) mediate regulation of channel gating. J Biol Chem. 283(39), pp.26383-26390.

Hollenstein, K., Dawson, R.J.P. and Locher, K.P. 2007. Structure and mechanism of ABC transporter proteins. Current Opinion in Structural Biology. 17(4), pp.412-418.

Johns Hopkins University. 1966-2025. CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; CFTR. [Online]. [Accessed 8 January]. Available from: https://www.omim.org/entry/602421

Johns Hopkins University. 2024. The Clinical and Functional TRanslation of CFTR (CFTR2). [Online]. [Accessed 10 January]. Available from: http://cftr2.org

Leung, D.H. and Narkewicz, M.R. 2017. Cystic Fibrosis-related cirrhosis. Journal of Cystic Fibrosis. 16, pp.S50-S61.

NICE. 2017. Cystic fibrosis: diagnosis and management. [Online]. [Accessed 12 January]. Available from: https://www.nice.org.uk/guidance/ng78

Rees, D.C., Johnson, E. and Lewinson, O. 2009. ABC transporters: the power to change. Nature Reviews Molecular Cell Biology. 10(3), pp.218-227.

Riordan, J.R. 2008. CFTR Function and Prospects for Therapy. Annual Review of Biochemistry. 77(Volume 77, 2008), pp.701-726.

Riordan, J.R., Rommens, J.M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z., Zielenski, J., Lok, S., Plavsic, N., Chou, J.L. and et al. 1989. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 245(4922), pp.1066-1073.

Serohijos, A.W., Hegedus, T., Aleksandrov, A.A., He, L., Cui, L., Dokholyan, N.V. and Riordan, J.R. 2008. Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function. Proc Natl Acad Sci U S A. 105(9), pp.3256-3261.

Sheppard, D.N. and Welsh, M.J. 1999. Structure and Function of the CFTR Chloride Channel. Physiological Reviews. 79(1), pp.S23-S45.

Taylor-Cousar, J.L., Robinson, P.D., Shteinberg, M. and Downey, D.G. 2023. CFTR modulator therapy: transforming the landscape of clinical care in cystic fibrosis. The Lancet. 402(10408), pp.1171-1184.

The Hospital for Sick Children (SickKids). 2011. Cystic Fibrosis Mutation Database. [Online]. [Accessed 10 January]. Available from: http://www.genet.sickkids.on.ca/

Turcios, N.L. 2020. Cystic Fibrosis Lung Disease: An Overview. Respiratory Care. 65(2), p233.

Van Goor, F., Hadida, S., Grootenhuis, P.D.J., Burton, B., Cao, D., Neuberger, T., Turnbull, A., Singh, A., Joubran, J., Hazlewood, A., Zhou, J., McCartney, J., Arumugam, V., Decker, C., Yang, J., Young, C., Olson, E.R., Wine, J.J., Frizzell, R.A., Ashlock, M. and Negulescu, P. 2009. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proceedings of the National Academy of Sciences. 106(44), pp.18825-18830.

Van Goor, F., Hadida, S., Grootenhuis, P.D.J., Burton, B., Stack, J.H., Straley, K.S., Decker, C.J., Miller, M., McCartney, J., Olson, E.R., Wine, J.J., Frizzell, R.A., Ashlock, M. and Negulescu, P.A. 2011. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proceedings of the National Academy of Sciences. 108(46), pp.18843-18848.

Vergani, P., Lockless, S.W., Nairn, A.C. and Gadsby, D.C. 2005. CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains. Nature. 433(7028), pp.876-880.

Austin Keane, Fourth Year Medicine

‘Mind’ is an old word. It is a ‘supraphysical’ word: common, necessary, and widespread with meaning (Earl J. 1881: 1). The origin of the Mind ‘getting lost’ is as difficult to identify as the old word is to define. However, imagine a speaker of this metaphor: “I think I’m losing my mind.” This phrase possesses a routine lay meaning, denoting mental distress/illness, commonly characterised as ‘madness’. I argue that its widespread lay use in self-descriptive accounts exemplifies three overlapping things: a culturally-mediated individualised self; a Cartesian legacy; and confusion about the meaning of ‘madness’. 

A close reading of the phrase highlights assumptions relative to the culture that produces the metaphor—and not the specific speaker—therefore may be done. I approximate ‘mind’ (in this metaphor context) to describe an interruption in the control of cognition mediated by consciousness. While I acknowledge the broad limits of this definition, I argue they map well onto the broad images within the lay consciousness that ‘madness’ evokes (Frith C. 2016). After all, such a quality forms a lay understanding’s universality. 

The reflexive nature of ‘mind’ with its personal pronoun ‘my’ indicates not only possession but separateness, otherwise described as the ‘Western convention’ of a distinct, unique artefact, as opposed to a collective imagining of identity (Giles J. 1993). The verb form ‘lost’ affirms this: that the mind is a specific, localised entity; a single unit that can go missing. We might consider the idea of hope here: what is lost may be found; it has not been destroyed or erased. This makes sense: the mind is often accessed, or consciously experienced through practices, for example, meditation (Campion and Rocco 2009).

There is an important contradiction here. Typically, possession is binary: not here/here; lost/found. But the persistent use of the present participle (‘losing’) suggests that the process is not instantaneous, and is an illuminated halfway state. In this way, there is room for the awareness of having an altered awareness. This break in tenses, in position between illness and health states, is a common feature of ‘Illness Narratives’, and has been referred to as ‘fragmentation’ (Rimmon-Kenan S. 2002: 11). Perhaps the speaker is stuck between Sontag’s ‘Kingdoms’ of the Well and the Sick—unable to travel without a passport (1982). Otherwise, it’s an example of aporia: our speaker who says they are ‘losing their mind’ is by virtue of this an unreliable witness, an unreliable statement-maker—how to parse whether a speaker who declares ‘I am lying’ is telling the truth?

Let us vary slightly what our speaker is saying, or even in what language. In British English, “losing your mind/head” is used interchangeably. That, even in idiomatic use, the mind cannot escape conflation with the brain via the head (it contains the brain) is revealing. This is the same ‘classic’ mistake of Biomedicine in transforming mind-body divisions to body-body divisions (Scheper-Hughes N. and Lock M. 1987). Interestingly, losing the head in hiberno-english translates directly into French (je perds la tête) and Spanish (estoy perdiendo la cabeza). In Turkish, however, the equivalent literally means “I’m eating my head” (Kafayı yeycem/yiycem). To lose something holds a value judgment either of carelessness or permissible error. To eat something, however, is active, perhaps even an intentional or natural act. Cultural differences in metaphors of the body may reflect differing stigmas but needs further research as Scheper-Hughes and Lock suggested (1987).

All of these describe an embodied conflict or, as Laing describes, a ‘divided self’—a product of Cartesian thought and the focus on the ‘individual’ (1965: 44). The presence of this metaphor across different languages affirms the idea of both a confused picture of the mind-body relationship and unclear boundaries of mental distress/illness. As suggested, the metaphor has a useful function for the speaker in narratives of illness, giving room for expression even in confusion; it may even be suggestive of hope. 

‘Mind’ is an old word—and a wide one, ripe with meaning. If the speaker isn’t sure where their Mind is, what it is exactly, then there is some sense (if only poetically) in its ‘getting lost’ every now and then. 

Bibliography

• Campion, J. and Rocco, S. (2009). ‘Minding the mind: the effects and potential of a school-based meditation programme for mental health promotion’, Advancing School Mental Health Promotion, 2: 47–55
• Earle, J. (1881). ‘The History of the Word `Mind’’, Oxford University Press, 6(23): 301-320 
• Frith, C. (2016). ‘Understanding madness?’, Brain, 139(2): 635–639,
• Giles, J. (1993). The No-Self Theory: Hume, Buddhism, and Personal Identity. Philosophy East and West, 43(2): 175–200
• Laing, R. (1965). The divided self: An existential study in sanity and madness. Penguin Books.
• Rimmon-Kenan, S. (2002). ‘The Story of “I”: Illness and Narrative Identity’, Ohio State University Press, 10(1): 9-27
• Scheper-Hughes, N. and Lock, M. (1987). ‘The Mindful Body: A Prolegomenon to Future Work in Medical Anthropology’, Medical Anthropology Quarterly, 1(1): 6-41 
• Sontag, S. (1991).  Illness as Metaphor and AIDS and its Metaphors. London: Penguin Group

Holly Dobbing, Fourth Year Medicine

In a 2021 issue of Science Translational Medicine, Lattanzi et al.¹ investigated the preclinical development of a protocol to correct the HBB gene in autologous (self-derived) stem cells, aiming to identify a potential functional cure for sickle cell disease.

Sickle cell disease is a genetic disorder caused by a point mutation in the HBB gene (responsible for encoding the 𝛽-globin subunit of haemoglobin²), affecting millions of people globally¹. This altered haemoglobin produces abnormal, crescent-shaped red blood cells (RBCs), known as sickle cells^1,2. These cells can cause severely painful vaso-occlusive crises, where the irregularly shaped RBCs lodge in small vessels, causing local hypoxia and tissue damage^1,2. 

Three treatments comprise the currently approved sickle cell disease therapy². Hydroxycarbamide has been shown to reduce vaso-occlusive crises by increasing patients’ proportions of healthy haemoglobin³, however it has been repeatedly reported to have various unpleasant side-effects; notably, rashes, sore skin, and ulcers². Additionally, red blood cell transfusions have been demonstrated to improve oxygen delivery to tissues but are therapeutically limited by iron overload and haemolytic and immunogenic transfusion reactions². Stem cell transplant with a matched donor offers a curative option for sickle cell disease^1,2, however it can be difficult to find a donor and there are significant risks for both donor and patient³. This treatment is referred to as allogeneic stem cell transplant. These limitations demonstrate a significant need for safer and more effective treatments in sickle cell disease. 

Gene editing is a novel approach allowing modification of the genome at specific loci to alter disease expression⁴. In their preclinical study, Lattanzi et al.¹ investigated the safety, efficacy, and clinical manufacturing feasibility of HBB gene-corrected stem cells in the treatment of sickle cell disease. The study proposed a direct correction of the HBB point mutation that is pathognomic of sickle cell disease¹, potentially treating the disease from within the DNA of the cells, rather than via lifelong medication and repeated procedures. 

The study initially performed gene correction on healthy control stem cells and illustrated effective HBB correction, but significant off-target effects¹. This prompted alteration of the protocol, and, with a modified approach, they generated cells with more corrected HBB alleles, and fewer off-target effects. Their findings matched the threshold for cure in the standard allogenic stem cell transplants. They then repeated the experiment using sickle cell disease patient-derived stem cells and illustrated analogous results. Lattanzi et al. concluded that the patient-derived corrected stem cells were capable of clinical scale long-term correction. This demonstrated the therapeutic potential of gene correction in sickle cell disease and supported the notion that a functional cure is possible. They also assessed the toxicological and tumorigenic potential of the process and found little evidence of adverse effects, abnormal cell development, or chromosomal changes¹. 

Unsurprisingly, the relative infancy of this approach naturally generates scepticism about the long-term success of the treatment. Other similar studies face comparable criticism^5-7. The consensus is that the early-stage evidence for safety and efficacy is adequate^5-7 but the limited execution in clinical settings means that more research is critical, and clinicians may need to be prepared for unanticipated toxicities³. 

Lattanzi et al. also failed to acknowledge the cost or accessibility issues associated with such specialist technology. Regardless of the clinical potential of gene correction approaches, the findings are somewhat deemed irrelevant if integration into clinical practice is blocked by cost, so despite the exciting findings, there remains an undeniable need to develop this into a more universally accessible treatment^3,7. 

That said, this study has provided the proof of concept and foundational support for future clinical trials investigating the use of gene correction in sickle cell disease treatment. Similar studies have since corroborated the durability and efficacy of gene editing in sickle cell disease^5,6. Everette et al.⁵ used a similar strategy to illustrate correction of the sickle cell disease HBB-allele with high efficacy and minimal off-target effects. Xu et al.⁶ undertook further analysis to identify the optimal protocol and ensure patient safety. Cumulatively, this has encouraged recent approval in the UK for the use of gene correction in the treatment of severe sickle cell disease⁷ (link to BBC article – https://bbc.co.uk/news/health-67435266)). Hopefully, these promising advancements in gene correction therapy mark the beginning of a better experience for patients with sickle cell disease. 

References

(1) Lattanzi A, Camarena J, Lahiri P, Segal H, Srifa W, Vakulskas CA, et al. Development of B-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease. American Association for the Advancement of Science (AAAS); 2021.

(2) Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. Nature reviews. Disease primers. 2018; 4 (1): 18010. 10.1038/nrdp.2018.10.

(3) Crossley M, Christakopoulos GE, Weiss MJ. Effective therapies for sickle cell disease: are we there yet? Trends in genetics. 2022; 38 (12): 1284-1298.
10.1016/j.tig.2022.07.003

(4) Alayoubi AM, Khawaji ZY, Mohammed MA, Mercier FE. CRISPR-Cas9 system: a novel and promising era of genotherapy for beta-hemoglobinopathies, hematological malignancy, and hemophilia. Annals of hematology. 2023; 1
10.1007/s00277-023-05457-2.

(5) Everette KA, Newby GA, Levine RM, Mayberry K, Jang Y, Mayuranathan T, et al. Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice. Springer Science and Business Media LLC; 2023.

(6) Xu L, Lahiri P, Skowronski J, Bhatia N, Lattanzi A, Porteus MH. Molecular dynamics of genome editing with CRISPR-Cas9 and rAAV6 virus in human HSPCs to treat sickle cell disease. Molecular therapy. Methods & clinical development. 2023; 30 317-331. 10.1016/j.omtm.2023.07.009.

(7) Walsh F. Casgevy: UK approves gene-editing drug for sickle cell. BBC News. 2023 Nov 16; [accessed 17 November 2023]; Available from:
https://www.bbc.co.uk/news/health-67435266

Nithikka Senthil Kumar, Second Year Medicine

“Women are born with pain built in. It’s our physical destiny… We carry it with us throughout our lives” ⁱ.

Crafted by Phoebe Waller-Bridge for the television series ‘Fleabag’, this candid monologue helps to express the maze-like journey of navigating women’s health. In a wider context, these words provide social commentary, shedding light on the complexity of a subject that is intrinsically connected with social dogma, politics and evolving medicine.  

Historically, influences of war, fluctuating economics and societal ideologies have dictated medical discourse. The inherent mechanisms created have persisted, and continue to impact scientific knowledge and quality of life for many. Today’s evolving field of women’s health can be traced back to (arguably unsteady) foundations laid down at the beginnings of western medical history.  

From the birth of Hippocratic Corpus, medical ‘fact’ and social attitudes were contextual extensions of one another. Medical understanding of this time encircled the fundamental difference between male and female anatomy: the possession of an organ absent in a man.  This conveniently reduced a woman’s purpose in society to solely her reproductive ability. Notably, Plato’s theory of the “wandering womb”, likened the uterus to an “irrational animal” in a woman’s body, inflicting disease within those who strayed from acceptable social behaviours.ⁱⁱ Limited scientific knowledge legitimised growing social hierarchies, and vice-versa, with the fog of misinformation that then began to settle only growing thicker through time. 

The consensus that female biology was a deviant of the male form (evidenced by inferences from mythology and religion – Pandora, Eve) continued to shape ideas through to the Middle Ages.ⁱⁱⁱ Medical handbooks conveyed the idea that women were vessels, their personhood collateral to their reproductive organs. Advice to sufferers of gynaecological problems was to “not dare to reveal the anguish of their diseases… to a physician”.^iv Against a 14^th century backdrop of Plague pandemics, inherently flawed information heightened fears and shrouded women further in shame.  

In 1542, the passing of the Witchcraft Act in England inflamed medical superstitions further, finding natural physiological changes of menopause indistinguishable from pathological states, and now pursuits of magic.² Religious fervour saw the promotion of the diagnosis of “hysteria”, an all-encompassing explanation for any health concerns afflicting women. The etymology of ‘hysteria’ (Ancient Greek – “hystera”, meaning uterus^v) reflects the belief that conditions of the uterus manifested in the mind, a misinterpretation of the interconnectedness of biological systems in the body. Real health concerns were reduced to hysterical passions, or worse, grounds for conviction. Amongst much uncertainty, women existed as a contradiction: the paradoxical perception of the womb suspending them in social limbo.  

Only in the 18^th century, opposition against harmful medical attitudes began to gain motion, pursued by individuals like Mary Wollstonecraft. Successes were few and far between, however, as progress through this period was haunted by countless cases of mistreatment. This was highlighted by playwright Frances Burney’s 1812 account of her mastectomy, performed without anaesthesia. ^vi 

Social inequalities further infiltrated medicine, with effects experienced more intensely felt, and continuing to be felt, by marginalised groups. Fundamentally, incorrect concepts of black women’s insensitivity to pain, and the generalised misunderstanding of labour pain, may continue to impact women’s healthcare for many years to come.^vii 

The Victorian era saw the infectious spread of contagious diseases and beliefs, where the legally justified, yet inappropriate, use of speculums incited shame and dangerous ovariotomy surgeries entered the limelight. Continual resistance against regurgitations of older theories persisted; Florence Nightingale, Josephine Butler and Putnam Jacobi notably strived to return autonomy to women’s healthcare. Parallel to the 20^th century suffrage movement, medical myths met scrutiny, the concept of hysteria loosened its clutch on practice, and birth control was invented. Conversely, over-medicalisation was prevalent, particularly with menstruation which was viewed in relation to pathological states.  

Growing knowledge of physiology & reproductive endocrinology in the 1920s built more accurate disease profiles of gynaecological cancers, fibroids, endometriosis and other prevalent conditions. New avenues of biomedical research aided the dwindling of false conjectures, but this was not without setbacks. The 1962 Thalidomide tragedy prompted policy changes excluding large cohorts of female participants in clinical research for almost a decade. ^viii 

Nevertheless, efforts from physicians like Clelia Duel Mosher gradually shifted focus to understanding patient experiences. Although the aftertaste of older ideologies still lingered, rapid advancements following the birth of the NHS excited with improved patient outcomes.  

Change had not been radical, rather a slow-burning struggle to untangle healthcare from the knotted social and political influences which strangled its progress.   

While a condensed overview of a geographically localised history, it is evidentiary that the attitudes of today have travelled far from its progenitors. Even the existence of the recent parliamentary review of ‘Women’s reproductive health conditions’ ^ix demonstrates the time and space now given for reflection. This does not diminish ongoing issues; the contents of the report reveal concerns in a similar vein to issues of the past, but under a modern context.  

Endometriosis received particular focus in the parliamentary review. Characterised by the growth of endometrial tissue outside the uterus and often causing severe pelvic pain, this condition affects 1 in 10 women in the UK. Despite its prevalence, on average it takes around 8-10 years to be diagnosed.⁴ Reasons for diagnostic delays are multifaceted: vague symptomatic presentation, healthcare system pressures, lacking research, insufficient awareness, and entrenched inequities are contributors, and each is compounded by stigma.  

Among the public women’s health conditions are “woefully misunderstood”⁴, stemming from gaps in health education and awareness. A difficulty in quantifying pain, characterising highly variable symptoms, and individual reluctance to seek help means that conditions such as endometriosis can be a life-long burden, the weight of which is often silently carried. Even in this digital era, only 8% of women said they felt they had enough knowledge about gynaecological conditions⁴, highlighting the need for trustworthy, intersectional information resources.  

For endometriosis, definitive diagnosis can only be ascertained through laparoscopy. Until then, many patients unfortunately have to endure a pursuit of convincing clinicians of their pain.^x The enquiry reports that 80% of women feel dismissed throughout their health care journey, suggesting greater attention is needed towards understanding lived experiences. Biases in healthcare, both conscious and unconscious,to the greater detriment of certain populations, particularly black women and gender-diverse individuals.^xi Furthermore, pressures following the pandemic have exacerbated waiting times in gynaecology, lags in research endeavours and development of treatment options. ^xii  

For the person seeking help, a disconnect is formed to one’s own health.  Suppressing internalised fears through flimsy self-reassurances: “It’s probably nothing” is often a crutch for women to manage uncertainty.  

While there are intricacies to the broader issues, the problems are not insurmountable. In a recent interview with Dr Shazia Khan, a GP with special interests in women’s health based in Leeds, she expressed that improving public awareness is at the crux of the matter. She highlighted the potential of using social media platforms for greater outreach to initiate open conversations. In addition to emphasising the importance of addressing one’s own biases, her practical advice for medical students regards approaching history-taking with a wider focus. Being more conscientious with social history, learning how the patient’s symptoms may limit their daily life are pivotal to understanding with empathy. “Women all too often suffer in silence”, she says, and being more inquisitive to ask questions can provide space for people to be more forthcoming with their struggles.  

Through time, the knowledge of women’s health has grown through phases of evolving attitudes, pressures and competencies. In today’s practice, balancing celebrations of scientific accomplishment with acknowledging frustrating realities may pave the way for lasting change.  

Paraphrasing a comment from the conversation in ‘Fleabag’, future progress is “something to look forward to”.  

Thanks to Dr Khan for her time & thoughts for the article.  

References

(i) Waller-Bridge, P. and Bradbeer, H. 2019. Fleabag.  

(ii) Adair, M.J. 1995. Plato’s View of the ‘Wandering Uterus’. The Classical Journal. 91(2), pp.153–163. 

(iii) Cleghorn, E. 2021. Unwell women : a journey of medicine and myth in a man-made world. London: Weidenfeld & Nicolson. 

(iv) Green, M.H. 2001. The Trotula A Medieval Compendium of Women’s Medicine. Philadelphia University Of Pennsylvania Press. 

(v) Last, J.M., Dunea, G. and Lock, S. 2006. The Oxford companion to medicine. Oxford: Oxford University Press. 

(vi)Epstein, J.L. 1986. Writing the Unspeakable: Fanny Burney’s Mastectomy and the Fictive Body. Representations. (16), pp.131–166. 

(vii) Rao, V. 2020. Implicit bias in medicine: How it hurts Black women. TODAY.com. [Online]. Available from: https://www.today.com/health/implicit-bias-medicine-how-it-hurts-black-women-t187866.  

(viii) Balch, B. 2024. Why we know so little about women’s health. Association of American Medical Colleges. [Online]. Available from: https://www.aamc.org/news/why-we-know-so-little-about-women-s-health.  

(ix) Women and Equalities Committee 2024. Women and Equalities Committee Women’s reproductive health conditions First Report of Session 2024-25 HC 337 [Online]. Available from: https://committees.parliament.uk/publications/45909/documents/228040/default/.  

(x)Endometriosis UK 2024. Years of being ‘dismissed, ignored and belittled’: Endometriosis UK urges improvement to deteriorating diagnosis times  | Endometriosis UK. http://www.endometriosis-uk.org. [Online]. Available from: https://www.endometriosis-uk.org/diagnosis-report.  

(xi) Nuffield Department Women’s & Reproductive Health 2023. Endometriosis: black women continue to receive poorer care for the condition — Nuffield Department of Women’s & Reproductive Health. http://www.wrh.ox.ac.uk. [Online]. Available from: https://www.wrh.ox.ac.uk/news/endometriosis-black-women-continue-to-receive-poorer-care-for-the-condition.  

(xii) Smitha Mundasad and Burns, C. 2024. Gynaecology waiting lists in UK double, leaving women in pain. BBC News. [Online]. Available from: https://www.bbc.co.uk/news/articles/clyvg2157mvo.