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Health and Disease Narrative

Heart xenotransplantation: A Story of Progress and Setbacks

Introduction

At present, due to a worldwide shortage, 17 people die every day while waiting for an organ transplant—nearly a third of the people on a waiting list. Xenotransplantation (transplantation of animal organs into humans) could greatly reduce this shortage if fully actualised—with a significantly in-demand and crucial donor organ being the heart.

Studies suggest the animal organ donor would likely be a pig. Baboons have been considered, but are more impractical as potential donors given their smaller body size, experience infrequent occurrence of blood group O (the universal donor), their long gestation period and small number of offspring. This affects their overall availability. Pigs, on the other hand, have a decreased risk of cross-species disease transmission due to their phylogenetic distance from humans and are more readily available. Even still, with the advent of CRISPR-Cas9 genome editing, replacement hearts can be genetically edited with human genes to deceive the patient’s immune system into accepting it. 

Heart xenotransplants have been attempted many times before with little success. However, recent novel advancements have led to an overview of its scope and potential, as well as what hurdles still remain. If heart xenotransplantation truly is an option, they are a potentially more effective and readily available alternative to allotransplants, that could become safe, accessible and truly life-extending.  

Trials, Failures and Successes

There have been multiple attempts at animal heart-to-human transplants in the past. One of the earliest attempts was in 1984, when an America infant girl, Stephanie Fae Beuclair or “Baby Fae”, was born with hypoplastic left heart system in which the left side of the heart is severely underdeveloped and unable to support the system circulation. The procedure performed at Loma Linda University Medical Centre involved a baboon heart and was the first successful infant heart transplant ever. However, three weeks later, Baby Fae still died of heart failure due to rejection of the heart transplant. This is thought to have been caused by an unavoidable humoral response due to an ABO blood type mismatch. Type O baboons (universal donors) are very rare, and all the baboons involved were type AB. the rarity of type O baboons.

The first transplant of a non-genetically modified pig heart xenotransplantation happened in India in December 1996. The patient was Purno Saikia, a 32-year-old terminally ill man who died shortly after the operation due to multiple infections. The procedure was condemned by medical institutions due to the unethical conditions and malpractice. The instance was accepted by the scientific community because the findings were never scientifically peer-reviewed.

In more recent years, researchers have successfully transplanted pig hearts into baboons and saw them survive for 945 days. However, these transplanted hearts were not essential to the life of the recipients, and life-supported pig-to-baboon transplants have only lasted about two months. Nevertheless, researchers found that organ survival after transplantation could be improved by intermittently pumping (perfusing) a blood-based, oxygenated solution containing nutrients and hormones through the hearts at a low temperature. (Fig. 1).

Diagram

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(Fig. 1)

This optimised protocol was tested in five more baboons. First, they reduced the baboons blood pressure to resemble that of pigs, before giving the baboons temsirolimus (a drug that combats heart overgrowth by stifling cell proliferation). Finally, they modified the standard hormone-treatment regimen. Out of five, two baboons lived healthily for three months, another two lived for over six months before being euthanised for non-health related reasons, and one died after 51 days. The survival rate was highly impressive and a cause for hope.

Finally, in the most recent occurrence, in January 2022, doctors led by surgeon Bartley Griffith at the University of Maryland Medical Center performed a heart transplant from a genetically modified pig heart into a terminally ill patient, 57-year-old David Bennet Sr., who was ineligible for a standard allotransplant. Bennett had been on cardiac support for almost two months and could not receive a mechanical heart pump because of an irregular heartbeat. He could not receive a human transplant, because he had a history of not complying with treatment instructions. Since he otherwise faced certain death, the researchers received special permission from the FDA to carry out the procedure under compassionate use criteria. 

The pig involved had undergone ten genetic modifications. The company who owned the pig, Revivicor, removed three pig genes that would produce enzymes responsible for producing sugar antigens that would lead to hyperacute organ rejection. They also added six human genes to help the body accept the organ. To modify  the pig heart used in the transplant, the company removed three pig genes that trigger attacks from the human immune system, and added six human genes that help the body to accept the organ. A final modification aimed to prevent the heart from responding to growth hormones, ensuring that organs from the 400-kilogram animals remain human-sized.

The surgery initially succeeded and the patient was well. The heart was not immediately rejected and continued to function for over a month, surpassing a critical milestone for transplant patients. However, two months after the transplantation, the recipient died. The exact cause of death is currently unclear, but there are many limitations inherent to xenotransplantation that could be the cause. 

Limitations & Setbacks

The most prevalent and reoccurring limitation of xenotransplantation is organ rejection and immune system response. Some degree of rejection is inevitable, but can be limited with drugs that suppress the immune system. ‘Xenozoonoses’ are the biggest threat to rejection, as they are xenogenetic infections which can lead to fatal infections and then rejection of the organs. There are several types of rejection organ xenografts face, including hyperacute rejections, acute vascular rejection, cellular rejection and chronic rejection. 

Hyperacute rejection is rapid and violent and occurs within minutes to hours from the time of the transplant. Strategies to overcome it include interruption of the immune system response of the complement cascade by the use of cobra venom factor. However, the toxicity of cobra venom factor could be harmful and could potentially deprive the individual of a functional complement system. Transgenic organs in which the enzyme that could for immune system ‘flags’ and express human complement regulators instead are also an option. Even if this is surpassed, there is still acute vascular rejection, which can occur with 2 to 3 days and can be dreamed with immunosuppressive drugs, and cellular rejection, due to the response of the humoral immune system, are still highly likely to occur. 

Furthermore, if all these stages of organ rejection have been surpassed, there is still the poorly-understood prospect of chronic rejection, which David Bennet Sr. is likely to have suffered from. Chronic rejection is slow and progressive, and scientists are still unclear on how precisely it works. It is known that XNAs and the complement system are not primarily involved. Chronic rejection leads to pathologic changes of the organ, and why transplants must often be replaced after many years. It is likely that chronic rejection will be more aggressive in xenotransplants than allotransplants. 

There is one final major risk: porcine endogenous retroviruses, or PERVs. These are pig-viruses which could be transmitted to humans. While the risk of PERV-related complications are considered to be small, regulatory authorities worldwide view the possibility with caution. However, on this front, genome-editing technology such as CRISPR-Cas9 has led to researchers being able to produce live, healthy pigs in which PERVs and their related genes have been deactivated, indicating one way in which PERV-transmission can be circumvented. Regardless, there are still many hurdles before heart xenotransplantation is fully realised. 

Conclusion

The journey of animal-to-human heart transplantation is a long and convoluted one, and one that is likely to continue facing challenges and setbacks. Nevertheless, promising advancements have been made in the past few years alone. Even in the most recent case of David Bennet Sr.’s unfortunate death after his pig-heart transplant, there is the consideration that he multiple pre-existing health conditions may have had just as much to play in his untimely death as the transplant itself. Researchers and doctors alike will have many things to take into account, from informed patient consent to the possibility of disease transfer from animals to humans, but consideration of risks should not stop safe research into a field with much power to help those in need.

 Ishika Jha Youth Medical Journal 2022

References

[1] Healy, D. G., Lawler, Z., McEvoy, O., Parlon, B., Baktiari, N., Egan, J. J., Hurley, J., McCarthy, J. F., Mahon, N., & Wood, A. E. (2005). Heart transplant candidates: factors influencing waiting list mortality. Irish medical journal98(10), 235–237.

[2] Michler R. E. (1996). Xenotransplantation: risks, clinical potential, and future prospects. Emerging infectious diseases2(1), 64–70. https://doi.org/10.3201/eid0201.960111

[3] Sachs D. H. (2018). Transplantation tolerance through mixed chimerism: From allo to xeno. Xenotransplantation25(3), e12420. https://doi.org/10.1111/xen.12420

[4] Bailey LL, Nehlsen-Cannarella SL, Concepcion W, Jolley WB. Baboon-to-Human Cardiac Xenotransplantation in a Neonate. JAMA. 1985;254(23):3321–3329. doi:10.1001/jama.1985.03360230053022

[5] Cooper D. K. (2012). A brief history of cross-species organ transplantation. Proceedings (Baylor University. Medical Center)25(1), 49–57. https://doi.org/10.1080/08998280.2012.11928783

[6] Banerjee, Ruben (January 15, 1997). “Pig heart transplant: Not many are buying the Assam doctor’s story yet”. India Today. Retrieved May 21, 2022.

[7] “Why the US Pig Heart Transplant Was Different From the 1997 Assam Doc’s Surgery”. The Wire Science. January 13, 2022. Retrieved May 21, 2022.

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[12] Roberts, M. (2022, January 10). Man gets genetically-modified pig heart in world-first transplant. BBC News. Retrieved from https://www.bbc.com/news/world-us-canada-59944889

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[14] Neergaard, L., & K. Johnson, C. (2022, March 9). US man who got 1st pig heart transplant dies after 2 months. Retrieved from AP NEWS website: https://apnews.com/article/pig-heart-transplant-patient-dies-bc3b304de3c8d3bf3acbb3c221960ecf

[15] Rabin, R. C. (2022, March 9). Patient in Groundbreaking Heart Transplant Dies. The New York Times. Retrieved from https://www.nytimes.com/2022/03/09/health/heart-transplant-pig-bennett.html

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[17] M Andacoglu, O. (2018, November 13). Xenotransplantation: Overview, Choosing the Donor Species, Immunologic Barriers to Xenotransplantation. Retrieved from Medscape.com website: https://emedicine.medscape.com/article/432418-overview

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[19] Vanderpool H. Y. (1999). Xenotransplantation: progress and promise. Interview by Clare Thompson. BMJ (Clinical research ed.)319(7220), 1311. https://doi.org/10.1136/bmj.319.7220.1311

[20] Patience, C., Takeuchi, Y., & Weiss, R. A. (1997). Infection of human cells by an endogenous retrovirus of pigs. Nature Medicine, 3(3), 282–286. https://doi.org/10.1038/nm0397-282

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[22] Xenotransplantation: How Pig Organs Could Be Transplanted into Humans |. (2018, November 6). Retrieved from web.archive.org website: https://web.archive.org/web/20181106004635/https://www.animalbiotech.com/blog/xenotransplantation-how-pig-organs-could-be-transplanted-into-humans/

[23] Le Page, M. (2022, May 6). Man who received pig heart transplant has died after pig virus found. Retrieved September 1, 2022, from New Scientist website: https://www.newscientist.com/article/2319108-man-who-received-pig-heart-transplant-has-died-after-pig-virus-found/#:~:text=David%20Bennett%20died%20in%20March

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Biomedical Research Narrative Neuroscience

Brain Organoids: A Narrative Review of Potential, Limitations and Future

Introduction

The rapid development of stem cell technology has opened up unprecedented avenues for studying human neurodevelopment. One of such avenue is the study of brain organoids, or “mini-brains”. These are three-dimensional, stem-cell derived suspension cultures, capable of self-assembling into organized forms with features resembling the human brain. 

While considerable progress has been made for in vitro models of organoid development for other systems—namely the intestine, pituitary and retina—three-dimensional culture modelling of the brain had for long remained out of reach, until a breakthrough study in 2013. In this study, led by postdoctoral student Madeline Lancaster, researchers developed innovative new methods to generate “cerebral” organoids, inspired by past work in the field with a focus on improving conditions for growth and higher-level development of cells. ‘Organoids’, in this sense, refer to stem-cell-derived, three-dimensional cultures that self organize to some extent and include multiple cell types and features of a particular organ. These developing tissues were placed in a rotational bioreactor. Within a few weeks, they yielded organoids containing anatomical brain structures resembling those of a 9-week-old human foetus. In the years since, developments in the field of stem cell research has allowed for other teams of researchers to give cerebral organoids increased degrees of structural complexity: from transplanting small organoids into mice to expose them to a greater supply of blood vessels, to making several organoids that mimic various parts of the brain and combining them for more complex cytoarchitecture. This provides immense potential for the study of human foetal brain development, neurodevelopmental disorders and degenerative diseases. 

However, it remains unclear precisely what cell types arise in these brain ‘organoids’, how much individual organoids vary, and whether mature neuronal networks can form and function in organoids. Many limitations and hurdles lie in the way of growth for this novel field, and even further, ethical questions await on the question of sentience and autonomy.

Technical Advances and Methodology 

To make an organoid in 2013, Lancaster’s team began with an embryoid body, floating aggregates of cells that resemble embryos. These could be obtained either from natural, embryonic stem cells (from the inner cell mass of a blastocyst) or from induced pluripotent cells, which were made from adult cells (typically skin cells) that would have been treated with four crucial biochemical factors which caused them to be reprogrammed to forego their original function and behave like embryonic cells. (See: Fig. 1) These embryoid bodies were differentiated into neural tissue and then transferred into three-dimensional gel matrix droplets. Once these ‘aggregates’ had reached a certain size, they were placed in a rotational bioreactor where they were spun to enhance to flow of nutrients into the medium without being shaped by the constraint of a vessel such as a Petri dish. 

With minimal external interference, this approach produced cerebral organoids possessing human pluripotent stem cells with the most freedom in regards to self-organisation and construction, exhibiting a variety of cell lineage identities, ranging from the forebrain, midbrain and hindbrain, to the retina, choroid plexus and mesoderm. 

This is known as the ‘unguided approach’ for the production of cerebral organoids. Although cell-type diversity offers a unique opportunity to model interactions between different regions of the brain, the high degree of variability and unpredictability present significant challenge for reproducibility and systemic studies.

On the other hand, in the ‘guided’ or ‘directed’ method for generating brain organoids, small molecules and growth factors are applied to developing organoids throughout the differentiation process to instruct human pluripotent stem cells to form cells and tissues resembling certain regions. These directed organoid cultures are sometimes capable of generating mixtures of cell types with relatively consistent proportions with less variation. However, they typically contain relatively small neuroepithelial structures and their architecture is often not well-defined. Nevertheless, the guided method remains the most common one for generating brain organoids today. 

There is also the avenue of advanced techniques that allow for greater complexity. This includes used organoid technologies, in which pluripotent stem cells are differentiated into region-specific organoids separately and then fused together, forming an end result with multiple distinct regional identities in a controlled manner. An example would be fused dorsal and ventral forebrain organoids, together forming an ‘assembloid’. These structures reveal the manner in which migrating interneurons connect and form microunits. 

The choice between guided and unguided methodologies will be dependent on the focus of the investigation. Where unguided organoids are suitable for exploring cell-type diversity during whole-brain development, brain region-specific organoids better mimic brain cytoarchitecture with less heterogeneity, and assembloids allow for the investigation of interactions between different brain regions.

With there being many routes to obtaining organoids that can then proceed to act as ‘models’, the logical next step in their development is their capability to, in fact, model the brain and study it, and what new avenues of treatment and application this can lead to.  

Potential Application 

As the organoids contain striking architectures strongly reminiscent of the developing human cerebral cortex (evolutionarily the most complex tissue), they display great potential for the effective modelling of neurodevelopmental brain disorders. As it would in the native brain, the cortical areas segregate into different layers, with radial glial cells dividing and giving birth to neurons in the innermost and subventricular zones, from which the quantity of neurons to develop the larger cerebral cortex is generated. 

This process presents fascinating opportunities for the study and treatment of microcephaly in particular. Microcephaly is a developmental conditions in which the brain of young infants remains undersized, producing a small head and debilitation. Replicating the condition is not suitable for mice models, as they lack the developmental stages for an enlarged cerebral cortex possessed by primates such as humans. Naturally, this means the disease would be impossible to show in a mouse model, as they do not have the developmental stage in which microcephaly is expressed in the first place. In this instance, brain organoids provide the most ideal model for study. 

Other studies involving brain organoids have been able to provide glimpses into the cellular and molecular mechanisms involved in brain development. For example, forebrain organoids derived from cells of individuals with ASD (autism spectrum disorders) display an imbalance of excitatory neuron and inhibitory neuron proportions. They have also developed great interest as potential neurodegenerative diseases models, even though attempts so far have had minimal success. This is mainly due to the fact that many neurodegenerative diseases, such as Alzheimer’s, are age-related and late onset, therefore brain organoids with mimic embryonic brain development may not possess the ideal characteristics to reproduce such development. 

In addition to genetic disorders, brain organoids can also provide models for neurotrophic pathogens such as the Zika virus. When brain organoids are exposed to the Zika virus, it results in preferential infection of neural progenitor cells (which suppress proliferation and cause an increase in cell death) leading to what is ultimately drastically reduced organoid size. They then also display a series of other characteristics identified in congenital Zika syndrome, such as the thinning of the neuronal layer, disruption of apical surface junctions and the dilation of the ventricular lumens. This highlights direct evidence of the causal relationship between exposure to the Zika virus and the development of harmful neurological conditions. In this way and many others, brain organoids provide optimistic prospects for the study of various neurodevelopmental diseases—though not without some considerations. 

Limitations

The fundamental limiting factor that prevents organoids from being able to fully replicate the late stages of human brain development is their size. Cortical organoids are much smaller in size compared with the full human cerebral cortex. Whereas cortical organoids can at most expand to approximately 4mm in diameter containing 2-3 million cells (about the size of a lentil), the human neocortex is about 15cm in diameter, with the thickness of gray matter alone being 2-4mm. This is a difference of about 50,000 in order. Furthermore, owing to a lack of circulation due to the limited metabolic supply, lack of a circulatory system and the physical distance over which oxygen and nutrients must diffuse, the viable thickness of organoids is restricted.  

Notably, cortical folding (gyrification) remains an unachieved ‘holy grail’ for cortical organoids. Gyrification is an essential and unique stage in the development of the human cortical brain in which the cerebral cortex experiences rapid growth and expansion. Due to the stressed of spatial confinement, the cortical layer buckles into wave-like structures, with outward ridges known as gyri and inward furrows called sulci. This stage is unique to humans and some other primates, theorised to be essential to complex behaviours such as language and social communication. In contrast, the brains of small such as rodents exhibit little to no gyrification—and neither do cerebral organoids. This may be because they are unable to reach the stage at which gyrification occurs (the demarcation of ‘primary’ gyri and ‘secondary’ gyri does not occur in humans until the second and third trimester, which is a later stage than what most brain organoids can replicate). Attempts have been made to induce ‘crinkling’ or ‘pseudo-folding’ in early organoid differentiation, but this has not led to the formation of gyrus- and sulcus- like structures. 

A better understanding of the mechanism under with gyrification occurs could lead to progress in existing methodologies to engineer the phenomenon in cerebral organoids, however, it is unlikely that the current organoid structure can fully replicate the folding of the human neocortex soon. Statistical analyses have suggested that the degree of folding across mammalian species is scaled with the surface area and thickness of the cortical plate, and organoids—at least in their current form—may simply be too small to achieve this result.

Due to these limitations, many ethical considerations concerning sentience and consciousness remain premature. The vast majority of scientists and ethicists are in agreement that consciousness has never been generated in a lab. Still, concerns over lab-grown brains have highlighted a blind spot: neuroscientists have no agreed upon definition or measurement of consciousness. Furthermore, certain experiments have still drawn scrutiny. In August 2019, a paper in Cell Stem Cell reported the creation of human brain organoids that produced co-ordinated waves of activity, resembling those seen in premature babies. While this was to a very small degree, it still prompted a wave of questions in relation to ethics, autonomy and ownership. Regardless, the waves only continued for a few months before the team shut the experiment down. Though moderate amounts of electrical activity is a sign of consciousness, the vast majority of brain organoids developed today are too far away in sophistication to be considered conscientious, autonomous beings.

Conclusion

Despite compelling data and innovative methodology, the formation of ‘a brain in a dish’ remains out of reach. Current models of brain organoids remain far from reproducing the complex, six-tiered architecture of their natural counterpart, even a foetal one. Presently, the organoids stop growing after a certain period of time and areas mimicking different brain regions are randomly distributed, often lacking the shape and spatial organisation seen in a sophisticated brain. Furthermore, there is also an absence of a necessary circulatory system means their interiors can often accumulate dead cells deprived of oxygen and nutrients. 

Yet, even with significant limitations, the potential for cerebral organoids are great. For certain questions, the model provided by this innovation could provide interesting answers and mechanism with which to study early human brain development and the progression of neurodevelopmental disorders. The brain organoid field has made exciting leaps to empower researchers and scientists with new tools to address old questions, and while there is a long path before more faithful in vitro representation of a developing human brain is reached, it is important to consider that no model will likely ever be perfect. 

Ishika Jha, Youth Medical Journal 2022

References

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Narrative

CRISPR Technology Today

By Katelyn Crawford

Published 8:50 EST, Mon October 25th, 2021

The CRISPR/Cas9 technology is continually advancing and improving with rigorous scientific testing. This technology leads the scientific community closer to finding cures for genetic diseases, but it also creates more questions and ethical concerns. CRISPR technology is one method of genetic engineering that cuts out and replaces or repairs specific segments of DNA sequences, including sequences that code for specific monogenic diseases. This emerging technology holds many potential lifesaving benefits but fails to address long-standing societal concerns about the dangers of genetic engineering.

The CRISPR technology is expected to cure many single-gene diseases such as Sickle Cell Anemia or Cystic Fibrosis. For example, CRISPR could be used to alter the gene responsible for Cystic Fibrosis, called the CFTR gene; this technology would correct known mutations that give rise to Cystic Fibrosis. However, thousands of different mutations could cause the disease, and not all of these mutations can be targeted with our current technologies. Therefore, genetic sequencing would need to be performed on each patient to identify which cases could be cured with gene therapy and which are currently genetically inaccessible. Due to CRISPR making permanent changes to the genetic code, much research must be performed before the technology can be approved for testing on human patients with specific CF-related point mutations. Furthermore, in 2018 a new version called base editing was created, which was able to fix some CF mutations without cutting the DNA sequence. The original CRISPR technology would cut the DNA strand, potentially harming the person by damaging the DNA sequence with inappropriate DNA repair; instead, this new technology directly repairs the mutation site without cutting the DNA sequence [1]. This base editing technology is a safer way to use CRISPR to edit gene sequences to treat Cystic Fibrosis and eventually many other diseases. 

One crucial aspect of successful treatment is identifying this new CRISPR enzyme to target the correct cell types within specific organs. This is important because genes often play critical roles in developing or functioning multiple cell types or organs. A mutation may be harmful to heart function but benign or helpful to brain function. One example of this dichotomy is the intended targeting of survival genes in cancer cells that unintentionally harm the immune cells responsible for clearing the cancer cells; this unintentional harm then decreases the treatment efficacy. So while these advancements to the CRISPR technology are beneficial to patients and will revolutionize the treatments of some diseases, a lot is still unknown. One area of active research focuses on the removal of white blood cells from a patient, followed by gene editing and then inserting the edited cells back into the affected patient. Scientists believe this approach could be used to treat certain kinds of cancer and infectious diseases, like HIV. It combines CRISPR technology with the technology to insert the CRISPR raw materials into a cell [4]. Scientists now argue that they can use electrical fields instead of viruses to introduce gene-editing materials into immune cells to treat various cancers. These newly edited immune cells then are inserted back into the body, where the cells find and attack the tumor. Many questions must be answered before it can be approved for human use. For instance, how long would it take for the modified cells to find and destroy the tumor? Will these cells show autoimmune behavior and also destroy healthy tissue? The technology should allow for the quicker treatment of diseases like HIV and Cancer, where weeks to months make a significant difference for patient survival. 

Since all of the changes made to the genome sequence by CRISPR are permanent, it is important to note that the technology is only being considered for use in somatic cells. These are cells in the body that do not get passed down to any children. There is concern that CRISPR use in germline cells may permanently adjust the genes in humans passed down to children, including any mistakes that the editing technology may have made. This brings up the idea of how technology would change genetic diversity. The prevention or treatment of life-threatening diseases is helpful technology, but beyond unintentional mistakes getting introduced into the gene pool, where does the editing stop? Is there any way for people to prevent the use of CRISPR for editing medically insignificant traits, such as eye color? Due to these concerns, the scientific community is attempting to hold off on all genetic engineering of embryos to allow time for ethicists and the law to catch up with scientific progress. Clear guidelines will need to be provided before using these technologies. There is limited funding for research available, so studying CRISPR to treat life-altering diseases takes top priority; introducing the possibility of researching medically insignificant mutations would waste resources better served to prevent or correct life-threatening conditions. People’s lives could depend on this treatment, and many ethical issues arise as a result.

Pending future approval of CRISPR for medical cures, another significant drawback is the cost. This technology is new and very expensive. Researching and repairing one protein could cost millions of dollars, including the cost of many stages of trials needed for FDA approval, animal care for testing, the cost of patents, and licensing to a company. Paying the researchers and other employees leads to a significantly higher price, which is prohibitive to many families. Additionally, the time to conduct the necessary research before use in patients may nullify the need for treatment if the process takes too long or cannot be scaled up effectively. Thus, the costs associated with CRISPR are not accessible to most families, which raises the question “If only some patients can afford treatment with CRISPR, what makes these people more qualified or deserving of treatment?”. To illustrate this point, in 2019, Novartis released a gene therapy called Zolgensma to treat Spinal Muscular Atrophy. In the base-case analysis, the company’s subjective value was estimated at $900,000 per treatment [2]. This is the cost of a single treatment, but it is hard to determine how many treatments a single patient will need with the unknowns of gene therapy. As a result, only 700 patients were approved for the treatment. In the future, where CRISPR has received approval for a broader range of genetic diseases, it will not be cheap at its current scale, and therefore many people will not be able to afford it. As the technology changes and is streamlined, cost-effectiveness may also improve, but if the costs fail to decrease, what are the determining factors in who will get this life-saving treatment? CRISPR is controversial, costly, and time-consuming to bring from start to finish; with CRISPR’s potential to yield so many treatments weighed against its considerable drawbacks, how can the overall impact of CRISPR truly be determined? And will CRISPR turn out to be the silver bullet of gene therapy, or will it fall short of expectations?

Katelyn Crawford, Youth Medical Journal 2021

References

[1]Inacio, Patricia. “New CRISPR Tool Fixes CFTR Mutations in CF Patients’ Stem Cells, Study Finds.” Cystic Fibrosis News Today. Last modified March 16, 2020. Accessed July 21, 2021. https://cysticfibrosisnewstoday.com/2020/03/16/new-crispr-tool-fixes-cftr-mutations-in-cf-patients-stem-cells-study-finds/.

[2]Irvine, Alison. “Paying for CRISPR Cures: The Economics of Genetic Therapies.” Innovative Genomics Institute. Last modified December 16, 2019. Accessed July 21, 2021. https://innovativegenomics.org/blog/paying-for-crispr-cures/.

[3]John J. Mulvihill, Benjamin Capps, Yann Joly, Tamra Lysaght, Hub A. E. Zwart, Ruth Chadwick, The International Human Genome Organisation (HUGO) Committee of Ethics, Law, and Society (CELS), Ethical issues of CRISPR technology and gene editing through the lens of solidarity, British Medical Bulletin, Volume 122, Issue 1, June 2017, Pages 17–29, https://doi.org/10.1093/bmb/ldx002

[4]Kolata, Gina. “Swift Gene-Editing Method May Revolutionize Treatments for Cancer and Infectious Diseases.” New York Times. Last modified July 11, 2018. Accessed July 21, 2021. https://www.nytimes.com/2018/07/11/health/gene-editing-cancer.html?hp&action=click&pgtype=Homepage&clickSource=story-heading&module=second-column-region.

Categories
Narrative

Lessons from Aviation

By Rhea Agarwal

Published 11:18 EST, Sat October 23rd, 2021

What is Power Distance?

The concept of power distance was first developed by the Dutch social psychologist, Geert Hofstede; it was one of the first theories of Hofstede’s Cultural Dimension Theory in which Hofstede attempts to quantify the differences in cultural behaviours. Power Distance is a term that expresses the distribution of power in an organization or industry (Kenton, 2021). The Power Distance Index (PDI) is a measure of the power distance in a country; the numbers of a PDI convey the degree to which unequal distribution of power is accepted in a culture or nation. The elucidation of a number on a PDI scale tends to be rooted in cultural norms and legacy (Pettit Whisenant, 2019).

Individuals in an industry demonstrating a high power distance, generally embody people that do not challenge figures of authority and are accepting of hierarchical culture; contrarily, individuals demonstrating a low power distance do not hesitate in questioning figures of authority and expect their views to be holding some weight when making decisions. These behaviours are not only evident within the culture of a nation but also within the culture of certain professions such as aviation and healthcare (Pettit Whisenant, 2019).

Power Distance in Aviation

In the book, Outliers: The Story of Success, author Malcolm Gladwell discusses how a high PDI culture in aviation had severe reverberations on aviation safety (Gladwell, 2009).

In the period 1988 to 1998, Korean Air’s “loss” rate was 4.79 per million departures. An airline’s loss rate is the frequency with which crashes or aviation accidents occur. Relatively, the loss rate for the American carrier United Airlines in the same period was 0.27 per million departures; Korean Air’s record was more than seventeen times higher than that of United Airlines’. However, today Korean Air is a certified 5-star airline and its safety record since 1999 has been immaculate. In recognition of this transformation, Korean Air has received the Phoenix Award in 2006 (Gladwell, 2009).

In retracing Korean Air’s transformation, we see how decreasing a high PDI played a significant role in minimising the airlines’ loss rate and thus ameliorating its reliability and reputation. According to aviation experts, a plane crash is multifactorial and often a culmination of errors that leads to a crash. Astonishingly, these errors are rarely problems of knowledge or flying skill, rather they are errors of teamwork and communication (Gladwell, 2009).

“The whole flight-deck design is intended to be operated by two people, and that operation works best when you have one person checking the other, or both people willing to participate. You will have a safer operation than if you have a single pilot flying the plane and another person who is simply there to take over if the pilot is incapacitated.”

(Earl Weener, Chief Engineer for Safety at Boeing)

In Korean Air, it was the captain on the “flying seat.” The first officer simply worked as a substitute rather than a supplement in the cockpit (Gladwell, 2009).

On August 5, 1997, Korean Air Flight 801 departed for Guam; the flight crashed on August 6, 1997. Among other reasons such as bad weather, the National Transportation Safety Board, nonetheless, cites poor communication between the flight crew and the captain’s poor decision-making skills as the main cause of the crash (Wikipedia, 2021). Upon subsequent inspection of the black box, by psychologists, the most unusual feature of the conversations between the captain, first officer, and first engineer was the lack of explicitness in the language used by the subordinates in informing their captain of an emergency. The speech used by these officers is identified by psychologists as “mitigated speech (Gladwell, 2009).”

Mitigated speech is indirect communication inherent in communication intended to be polite or deferential to authority; it involves implicitly suggesting or referring to something and often uses subtle hints to convey a message. In a critical situation, mitigated speech coming from a subordinate is very likely to be ignored or looked over. The use of mitigated speech by subordinates during this emergency not only demonstrates a high power distance relationship between the captain and the officers but also indicates that such conduct may deeply be entrenched in cultural legacy. Helmreich and Merritt once measured the PDI of pilots from around the world; South Korea ranked second (Gladwell, 2009).

After experiencing several preventable aircraft accidents, aviation recognized the need for change. Reducing “mitigation” has become one of the greatest crusades that aviation has striven for by changing a bureaucratic culture to one that epitomizes collaboration and safety. Aviation experts contribute the decline in airline accidents to the battle against mitigation (Pettit Whisenant, 2019).

Substantial sociological research on the repercussions of a high power distance in aviation has been performed. However, such research is not as readily available for the medical field. In this article, we attempt to draw similarities in the critical situations of both professions. Thus, just how aviation integrated research results to improve safety, the healthcare profession can draw on tips to do the same. Both of these professions share certain features: high-level thinking and quick decisions with no room for error; mistakes in critical situations can have severe safety repercussions. 

Power Distance in Healthcare

The cockpit, with its intricate manoeuvres, can, to some extent, simulate the exacting environment of an operating room; the two professions share a strong resemblance in their administration. In a healthcare setting, the physician has the authority and the final say in most operations. However, a hospital setting does not only involve physicians –  there are nurses, residents – in – training, and assistants – all of which have received official training. A high PDI invalidates their observations and assessments; a low PDI, however, demands participation from all positions. A low PDI work environment involves communication and the transfer of necessary information among different departmental positions. This makes the system efficient, thus indirectly promoting better health outcomes. Literature confirms that a high power distance culture reduces worker wellbeing and commitment thus negatively impacting a positive work atmosphere (Rafiei & Sadeghi, 2018).

Let’s compare the healthcare systems of Denmark and the US. Denmark’s healthcare system is known to be able to provide its citizens with efficient and low-cost healthcare with better health outcomes than the US. Immediately, one may presume that the Danish government may be having higher funds allocated towards healthcare or may have rolled out better healthcare policies. False! In fact, on a percentage of GDP on a per capita basis, Denmark spends less money on healthcare than the US; also no unique policies have been rolled out which may distinguish one healthcare system from the other. The root of the issue is the culture in the workforce. Denmark has a relatively lower power distance culture than the US  (Matus, 2017).

The diminished bureaucratic system in Denmark’s healthcare system optimizes the capacity of the workforce thus enabling an efficient system to operate; additionally, it recognizes the contribution of all healthcare providers (Matus, 2017).

To conclude, a healthcare system can greatly benefit from dismantling a hierarchical system within its administration thus promoting a positive and efficient workplace environment.

Rhea Agarwal, Youth Medical Journal 2021

Conclusion

There is limited research examining how a high power index affects the healthcare environment. Yet, we can draw parallels between the two industries in the sense that both involve complex procedures with little or no room for error. As one begun its crusade against an entrenched, detrimental cultural behaviour, the other should take lessons to do the same. It is only in this way can healthcare promote active participation from all its constituents, thus ensuring an efficient system with better health outcomes.

“Bureaucracy is the death of all sound work.” ~ Albert Einstein

Rhea Agarwal, Youth Medical Journal 2021

Bibliography:

Gladwell , M. (2009). The Ethnic Theory of Plane Crashes . In Outliers: The story of success (pp. 206–261). essay, Back Bay Books/Little, Brown.

Hofstede Insights . (2017). Comparison of Pdi between Denmark and Usa. How does Denmark have better healthcare than the US for less money? https://sciencenordic.com/culture-denmark-forskerzonen/how-does-denmark-have-better-healthcare-than-the-us-for-less-money/1451158.

ICSB. (2020). Geert Hofstede . ICSB takes a moment to remember Geert Hofstede. https://icsb.org/geerthofstede/.

Kenton, W. (2021, July 14). What is the power Distance Index (PDI)? Investopedia. https://www.investopedia.com/terms/p/power-distance-index-pdi.asp.

Matus , J. C. (2017, December 10). How does Denmark have better healthcare than the us for less money? ScienceNordic. https://sciencenordic.com/culture-denmark-forskerzonen/how-does-denmark-have-better-healthcare-than-the-us-for-less-money/1451158.

Meyers – Reuters , M. (2019). The Tragedy of Flight 801. http://content.time.com/time/covers/asia/0,16641,19970818,00.html.

Pettit Whisenant, D. (2019). Power distance in Healthcare: Learning from aviation to decrease power distance and improve Healthcare Culture. stti.confex.com. https://stti.confex.com/stti/congrs19/webprogram/Paper98235.html.

Rafiei , S., & Sadeghi , P. (2018). Personnel Attitude toward Power Distance in Hospitals Affiliated by Qazvin University of Medical Sciences. Evidence Based Health Policy, Management & Economics.

Wikipedia . (2021, August 7). Korean air flight 801. Wikipedia. https://en.wikipedia.org/wiki/Korean_Air_Flight_801.