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).

(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

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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

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Monkey Pox: Public Health Response, Reporting and Stigma

Introduction

As of June 2022, over 2103 cases of monkeypox have been reported in 11 countries outside of areas where it is typically endemic. Prior to 2022, the UK had only ever reported 7 cases of monkeypox, but as of this month, the country has 793 confirmed cases. The strand related to the spread has been sequenced and found to be distinct from the strand typical in West Africa, which causes milder symptoms but is more infectious.

Monkeypox is a rare viral disease spread by close contact by small airborne droplets with symptoms including a fever, rash and swollen lymph nodes. The zoonotic virus earns its name from being first detected in laboratory monkeys in 1958 and is thought to transmit from wild animals to people. With a risk of death between 0-11%, there is no known cure, though the smallpox vaccine is about 85% effective against infection in close contact.

Experts believe monkeypox is unlikely to be a repetition of the devastation on the scale caused by the COVID-19 pandemic: it does not transmit from person-to-person as readily, and due to its relation to the smallpox virus there are existing treatments that can be used to combat its spread. Therefore, despite monkeypox still being a cause for concern, it is not yet a cause for widespread panic.

However, that has not prevented the public health response and discussion about monkeypox being infected with old stigmas.  

Response and Reporting

The first known case of Monkeypox in humans occurred in 1970 in the Democratic Republic of Congo. Since then, it has been primarily associated with west and central Africa, however the majority of early cases outside the region in the present outbreak occurred in gay and bisexual men.  

The causes for this are currently unknown. Presently, European authorities are investigating men’s saunas and crowded Pride festivals, such as celebrations in the Canary Islands of Spain and Belgium, as partial sources for the outbreak. The composition of the outbreak is complicated and not entirely conclusive, however, this had not stopped inaccurate health reporting from taking place. Many outlets, such as the emphasised the source of the outbreak among queer people as a ‘reason’ for the outbreak, which has been highlighted by many as being unfortunately evocative of the initial reporting of pneumocystic pneumonia in clusters of gay men with AIDs forty years ago in 1981. This is despite official health authorities such as Colin Brown, director of the clinical and emerging infections at the UK Health Security Agency, has stated that monkeypox does not spread easily nor is generally considered a sexually transmitted infection, though it can be passed in “close personal contact with an infected symptomatic person”. The World Health Organisation has also confirmed monkeypox is not a sexually transmitted infection nor exclusive to queer men.  

Irresponsible reporting in the name of accuracy can be harmful; when a disease or condition is associated with a marginalised group, people may not risk coming forward for fear of being associated or outed. This can be seen in the early days of HIV epidemic, when individuals who contracted the virus went underground and did not seek out medical care. However, the issue is complicated: while acknowledging that diseases of any kind are a wider threat that can affect anyone can reduce stigma and encourage people to come forward, it can also reduce specific resources for communities that still may genuinely need them the post. 

The LGBT community is not the only one in which misplaced reporting on the monkeypox outbreak has caused harm: racial and global economic disparities in global healthcare have also been highlighted. WHO was recently forced to change its official monkeypox pictures, after African doctors and advisors pointed out that, despite the concern being over the global outbreak, all the pictures used were of Black people.

The Democratic Republic of Congo is the country that has been dealing with the world’s largest, most persistent and most deadly strain of monkeypox outbreak by far, with at least 1238 cases and 57 deaths this year and a fatality rate of 10%. Many of these deaths are preventable, but still occur due to underfunded hospitals and lack of horses. Some African doctors feel monkeypox has only become a high priority for the medical community now that individuals in the Global North are being affected by the outbreak. The Biden administrations has purchased 119 millions dollars worth of the smallpox vaccine, which has been licensed for use against monkeypox, after the first American case of monkeypox and European countries are strongly considering stockpiling antivirals. This is reminiscent of the COVID-19 outbreak, in which Canada bought enough vaccines to vaccinate its entire population 9 times over, but countries such as Uganda and Bangladesh still faced severe vaccine shortages, with only 17% of Africans fully vaccinated. The unequal distribution of healthcare resources is a long-standing issue and continues to be seen with the outbreak of monkeypox today. 

The Way Forward

Challenges lie ahead. Despite stressing that the monkeypox outbreak does not resemble the early days of the COVID-19 pandemic because it does not transmit as easily, WHO does expect more monkeypox cases.

Reporting on monkeypox being accurate and careful is not just a matter of not perpetuating stigma, but avoiding misinformation and misleading health advice. Health officials have stressed the need to communicate very clearly to the public and the health response will likely have to look beyond vaccination and focus on quarantine, isolation and community education.

Despite comparisons to the lacking and dangerous response to the HIV/AIDS epidemic, there are important differences in the health response today and that of forty years ago. For example, UNAIDs has explicitly come out and condemned the racist reporting around the recent outbreak, with deputy executive director Matthew Kavanaugh stating, “Stigma and blame undermine trust and capacity to respond effectively during outbreaks like this one. Experience shows that stigmatising rhetoric can quickly disable evidence-based response by stoking cycles of fear, driving people away from health services, impeding efforts to identify cases, and encouraging ineffective, punitive measures.” Statements released by trusted outlets such as the BBC have also explicitly stated that monkeypox is not sexually transmitted. A related discussion most also occur in relation to the global and economic inequalities of pandemic responses and distribution of medical resources, with increased investment in deprived areas of world that may need it the most. These measures are the ones that health officials emphasises will allow for the most co-ordinated, effective and informed health response to the monkeypox outbreak.

Ishika Jha, Youth Medical Journal 2022

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