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The Heart of the Matter
By La Rissa Vasquez, Neurobiology, Physiology, and Behavior ‘23 and Shaina Eagle, Global Disease Biology ‘24
In 1818, Mary Shelly published what is now regarded as the pioneer of the science fiction genre, the story of Frankenstein. In this novel, an ambitious scientist named Dr. Victor Frankenstein challenges the laws of nature by bringing the dead back to life. Sewn from animal and human remains, the “Creature” was sentient and desired love and acceptance like all humans but would later be known only as the infamous monster of Frankenstein. But these are no longer just stories. In recent decades, scientists have made huge strides in transplantation technology, even experimenting with the transplantation of non-human organs, redefining the laws of nature.
On January 7, 2022, David Bennett became the first person to successfully undergo the transplant of a non-human organ, or xenotransplantation. Bennett was suffering from end-stage heart disease and was ineligible for a human heart transplant, but the U.S. Food and Drug Administration granted a compassionate use for the experimental transplant of a genetically modified porcine heart [1]. The surgery was performed by Bartley Griffith, M.D. at the University of Maryland Medical Center in Baltimore [1].
The shortage of organs available for transplantation is an ongoing problem, especially for patients like Bennett in end-stage organ failure, for which transplantation is often the only option. For decades, medical geneticists and surgeons have worked to make xenotransplantation a reality. The Transplant Wait List has over 100,000 people on it in the United States alone [2]. As surgical technology and the understanding of genetics have advanced, so too has the number of patients in need of organ transplants.
‘Porkensteen:’ Bennett’s New Heart
David Bennett’s porcine heart came from Revivicor, a United Therapeutics Corporation. On their website, the organ is advertised as “UHeart ™.” Also in the United Therapeutics pipeline are xenokidneys and xenolung lobes, which are both designed to target end-stage organ failure, and are in the same pre-clinical stage as the porcine heart used in the Maryland surgery.
The heart transplanted into Bennett is not the exact heart removed straight from a pig. Revivicor altered ten genes, knocking out a few pig genes and incorporating human genes to prevent rejection by the patient’s immune system and to prevent the heart tissue from growing excessively large inside Bennet’s chest. In a collaboration between the University of Maryland School of Medicine’s cardiac xenotransplantation program and Kiniksa Pharmaceuticals, Bennet was also given KPL-404, an experimental immunosuppressant used to prevent immune-rejection of the organ by suppressing T-cell-dependent Antibody Response [3].
Genetic modifications and immunosuppressive therapies are integral to the success and scaling of xenotransplantation. After decades of experimentation with non-human primates, the domestic pig was identified as the ideal donor, due in part to the similarity in size and physiology between pig and human organs, as well as the reduced risk of zoonotic disease transmission [4]. However, genetic differences between pigs and humans serve as a complication due to an increase in the likelihood of rejection by the human immune system. Bennett’s medical team was initially able to avoid concerns such as hyperacute rejection and coagulation system dysregulation, in which the recipient’s own antibodies attack the foreign organ.
Unfortunately, on March 8, 2022, it was announced that Bennett had died [5]. The University of Maryland Medical Center has not yet announced an official cause of death but plans to publish a full clinical study in the future. Despite the outcome, Bennett lived with the transplanted organ for more than three months post-procedure. His surgery is another step in a long line of recent breakthroughs in xenotransplantation [6] and will guide researchers in their quest for sustainable and effective porcine organ transplantation in the future.
Reanimating the past
The first known xenotransplantation was the blood of a lamb into a 15-year-old French boy in 1667. Nearly two hundred years later, French physician Paul Bert warned against cross-species transplantation in “On Animal Transplantation” [7]. Cases of xenotransplantation picked up speed in the early 1900s, using organs from various species, but all ended in the death of the recipient. The first pig organ transplant on record was in Lyon, France in 1905 by surgeon Mathieu Jaboulay, using a porcine kidney; the patient only survived for three days [7]. A surgeon attempted the transplantation of a porcine heart for the first time in 1968 in London; this time, the patient only survived post-procedure for four minutes [7].
A number of attempts at xenotransplantation have been made throughout the decades, varying in levels of success, and reflecting the improvements in allotransplantation (transplantation between the same species) as well as immunosuppressive and gene-editing technology. Gene modification technology such as clustered regularly interspaced short palindromic repeat (CRISPR-Cas9) allows scientists to genetically modify genes so that transplanted organs are less likely to be immunologically rejected [4, 7]. One setback came with the discovery of porcine endogenous retroviruses (PERVs) in 1994, but in 1998, the FDA allowed porcine transplants to resume under strict guidelines after it was shown that PERV infections could be detected in recipients. In 1999, they banned the use of primate organs in xenotransplantation because the risk of infectious disease was too high [8]. The beginning of the twenty-first century saw a number of trials of pig to non-human primate transplantations, and just four months before Bennett’s surgery, surgeons in New York City transmitted genetically modified porcine kidneys to brain-dead recipients [6]. Although the recipients were being sustained on ventilators, the fact that the organs were not rejected was a milestone.
When Pigs Fly: The Future of Xenotransplantation
Ancient Greek mythology tells the story of Daedalus attaching the wings of a bird onto his son Icarus’ back, in an attempt to escape the island of Crete. Icarus falls to his death after boldly flying too close to the sun and melting his wings off: his fatal flaw was unfettered pride and ambition.
Will our pension for progress and self-congratulation in the wake of our discoveries be our downfall? An often overlooked part of the story of Icarus are the instructions that Daedelus gave to his son before their flight: “fly too low and the sea will dampen and clog the wings.” Ambition can surely lead to disappointment but so can complacency. If medical and scientific technology were not allowed to advance then we would drown in a sea of ignorance. To keep from drowning, we use our current understanding to build a raft and we preserve ethical quandaries instead of boundaries to survive the turbulent seas and ride the tides of progress.
When we think about the future of xenotransplantation, we should be excited about the possibilities of this new application. CRISPR-Cas9 allows scientists to precisely modify genes— resolving many immunological concerns while producing viable animal subjects within short periods of time; this is promising for the scaling of xenotransplantations. These engineered pigs carry fewer xenoantigens (an antigen that is found in more than one species) reducing the risk of organ rejection or the development of fatal xenozoonosis (an infectious disease that is transferred from animal to human via the transplanted organ). Reducing the risk of organ rejection caused by zoonotic diseases is paramount to the success of xenotransplantation in all human organ systems.
Xenografted porcine fetal neurons are a promising treatment for Parkinson’s disease and Huntington’s disease, in addition to biologically engineered organs grown in vitro and 3D printed organs [13]. These medical applications could shorten transplant waitlists and help those who are ineligible to receive an organ due to other illnesses [9]. Patients who are older and in a late stage of disease, like David Bennett, are also less likely to be given priority on a waitlist [10]. Xenotransplantation allows scientists to create and edit the tissue of a working animal model and tailor it to a patient’s distinct genetic disposition in abundance.
Too Close to the Sun: Ethical Concerns
“Fly too high and the sun will melt your wings:” xenotransplantation is an ambitious operation but it is not unfettered. The existence of ethics in science is not a dilemma but a framework for us to navigate the horizon of change for animal rights, the welfare of patients, and religious exemptions. The genetic engineering and subsequent raising of pigs within sterile lab conditions to prevent disease for the sole purpose of organ harvesting comes at a great cost to the animals’ welfare [11]. There are also religious considerations that could further stigmatize the practice of xenotransplantation because of the premise of mixing the human with the non-human which is often seen as a taboo [12].
The heart as an organ has philosophical and physiological definitions, but the heart as a cultural and societal symbol has carried inexplicable and global significance since ancient times. So what does it truly mean to be human? Even after being composed of dead human and animal flesh, Frankenstein’s creature still had a heart. He felt love and sorrow like any human. He was an abandoned creation who became a monster because those around him lacked the ability to show him compassion. What makes us human is our ability to adapt, advance, and most importantly, our ability to show empathy. The topic of xenotransplantation requires just as much an open mind as it does an open heart to help make the treatment more accessible to others.
Stories and fables are woven into our morality. They can help explain why we fear change at the risk of uncertainty and chase after discovery at the prospect of reward. In both tales, Dr. Frankenstein and Icarus are warned not to take pride in their intelligence because knowledge is a power equivalent to the gods. But within the realm of science and society, knowledge is not a deity or a harbinger but a vital part of our survival. As a species, we are obligated to share knowledge when it can save lives. And as humans, survival is ingrained in our biology and consciousness. It is etched in our history, pursued in our present, and foreseen in our futures. Xenotransplantation as a medical practice to save a person’s life is not inhuman nor is it hubris, but to deny ourselves a known resource in the ongoing odyssey of survival would be monstrously heartless.
References:
- In first surgery of its kind, Maryland man receives heart transplanted from genetically modified pig. Washington Post. [accessed 2022 Apr 26]. https://www.washingtonpost.com/science/2022/01/11/pig-heart-transplant-genetically-modified/.
- Organ Donation Statistics | organdonor.gov. [accessed 2022b Apr 26]. https://www.organdonor.gov/learn/organ-donation-statistics.
- Kiniksa Announces Positive Final Data from Phase 1 Trial of KPL-404 | Kiniksa Pharmaceuticals. [accessed 2022b Apr 26]. https://investors.kiniksa.com/news-releases/news-release-details/kiniksa-announces-positive-final-data-phase-1-trial-kpl-404/.
- Ryczek N, Hryhorowicz M, Zeyland J, Lipiński D, Słomski R. 2021. CRISPR/Cas Technology in Pig-to-Human Xenotransplantation Research. Int J Mol Sci. 22(6):3196. doi:10.3390/ijms22063196. [accessed 2022 Apr 26]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004187/.
- Rabin RC. 2022 Mar 9. Patient in Groundbreaking Heart Transplant Dies. The New York Times. [accessed 2022 Apr 26]. https://www.nytimes.com/2022/03/09/health/heart-transplant-pig-bennett.html.
- Thompson J. Pig Kidneys Transplanted to Human in Milestone Experiment. Scientific American. [accessed 2022 Apr 26]. https://www.scientificamerican.com/article/pig-kidneys-transplanted-to-human-in-milestone-experiment/.
- Siems C, Huddleston S, John R. 2022. A Brief History of Xenotransplantation. The Annals of Thoracic Surgery. 113(3):706–710. doi:10.1016/j.athoracsur.2022.01.005. [accessed 2022 Apr 26]. https://www.sciencedirect.com/science/article/pii/S0003497522000716.
- Fishman JA. 2018. Infectious disease risks in xenotransplantation. Am J Transplant. 18(8):1857–1864. doi:10.1111/ajt.14725. [accessed 2022 Apr 26]. https://onlinelibrary.wiley.com/doi/10.1111/ajt.14725.
- What Disqualifies You for a Liver Transplant? MedicineNet. [accessed 2022 Apr 26]. https://www.medicinenet.com/what_disqualifies_you_for_a_liver_transplant/article.htm.
- Sade RM, Mukherjee R. 2022. Ethical Issues in Xenotransplantation: The First Pig-to-Human Heart Transplant. The Annals of Thoracic Surgery. 113(3):712–714. doi:10.1016/j.athoracsur.2022.01.006. [accessed 2022 Apr 26]. https://www.annalsthoracicsurgery.org/article/S0003-4975(22)00072-8/fulltext.
- Rollin BE. 2020. Ethical and Societal Issues Occasioned by Xenotransplantation. Animals (Basel). 10(9):1695. doi:10.3390/ani10091695. [accessed 2022 Apr 26]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552641/.
- Derenge S, Rossman Bartucci M. 1999. Issues Surrounding Xenotransplantation. AORN Journal. 70(3):428–432. doi:10.1016/S0001-2092(06)62324-7. [accessed 2022 Apr 26]. https://www.sciencedirect.com/science/article/pii/S0001209206623247.
- Fink JS, Schumacher JM, Ellias SL, et al. Porcine xenografts in Parkinson’s disease and Huntington’s disease patients: preliminary results. Cell Transplant. 2000;9(2):273-278. doi:10.1177/096368970000900212. [accessed 2022 Apr 26]. https://pubmed.ncbi.nlm.nih.gov/10811399
What do scaling laws tell us about the biochemistry of life beyond Earth?
By Tammie Tam, Molecular and Medical Microbiology ‘22
Humanity has always been intrigued with the possibility of life existing elsewhere in the universe. In 1977, NASA attached the Golden Record, a detailed account of humanity and Earth, onto the Voyager 1 and 2 space probes [1]. They intended for the records to be a way to share human knowledge with intelligent life forms that may stumble upon the space probes in interstellar space. While the Voyager 1 and 2 entered interstellar space in 2012 and 2018, they have yet to encounter any intelligent life forms capable of deciphering the record [2]. But extraterrestrial life doesn’t have to be “intelligent.” Life can be as simple as a swimming bacteria.
With the broad possibility of what life can look like, most scientists rely on what they understand about life’s limits on Earth to narrow down possible markers of extraterrestrial life. In 2022, a team led by Sara Walker at Arizona State University defined the types of biochemical functions likely to be found sustaining life throughout the universe [3]. Their work is a step forward in predicting how life may exist in places that look nothing like Earth by identifying potential signs of life using chemistry.
Walker’s team did this by computing scaling laws, which represent the proportional relationship between two quantifiable variables by some power factor [3]. Often these laws are used to demonstrate the universality of phenomenons found in physics. A simple example is the relationship between the surface area and volume of a cube. Given two cubes of differing sizes, the ratio of the surface areas is equivalent to the ratio of the volumes by a power or scaling exponent of ½ [4]. What makes this a universal principle is that no matter what kind of material the cube is made of, or where the cube is found, the relationship between surface area and volume stays the same.
In biology, scaling laws are not as commonly applied, but certain biological characteristics have still been shown to be able to scale to each other. For example, scientists have defined scaling laws between body mass and other features like growth rates, metabolic rates, and life spans [5]. These scaling laws in biology are typically defined by power laws: y = axk, where y is the rate of one variable, a is a constant, x is the rate of the other variable, and k is the scaling exponent [5]. Scaling laws in no shape or form provide the mechanism of how one feature regulates another feature and vice versa. Instead, they show that no matter the differences in detail between systems of different organisms, there is an underlying commonality between them all.
One caveat is that scaling laws for these well-studied biological features like growth and mass may only apply to life forms on Earth. For instance, while the final body mass and maximum growth rate within and across many taxonomic groups generally scale with each other at k = ¾, there’s no reason that this growth scale must remain the same across extraterrestrial life [5]. Because there are many factors that contribute to growth that scaling laws don’t reveal, the growth scale may be influenced by some adaptation to living on Earth. This is evident by the fact that certain taxonomic groups don’t follow the same scaling patterns in terms of growth rate and mass. Thus, scaling laws in biology are limited in their application when examining certain biological features.
However, chemistry throughout the universe is bound by the same laws and would not change whether on Earth or Mars or an asteroid in another galaxy. Walker’s group, therefore, started thinking about how, at its core, life is run by different chemical reactions [3]. Since atoms and chemicals are universal, perhaps the chemistry of life on Earth, or biochemistry, can be generalized to include extraterrestrial life.
The group studied enzymes, which are proteins that help chemical reactions run in the body. They collated databases on all known enzymes in the tree of life. The enzyme’s associated classes, reactions, and components are systematically encoded by a unique Enzyme Commission numerical identifier. They used the ID numbers to group enzymes into classes, such as oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. ID numbers also helped them count the unique enzymes in each class [3].
By computing scaling laws as a statistical measure, they found that the number of unique enzymes within any particular class increases as the total number of enzymes from all classes increases [3]. This scaling relationship can generally be defined by y = axk, with k > 0 for all enzyme classes.
While each enzyme class demonstrated different scaling behaviors, what matters for determining the universality of a biochemical function of an enzyme class to have the same scaling behavior between all domains of life: archaea, bacteria, and eukaryotes. In their study, they found each enzyme class except for lyases to have scaling exponents within 95% confidence interval between domains, meaning the scaling behavior is similar enough to establish all enzyme classes except for lyases as universal biochemical functions [3].
The issue with lyases is resolved when lyases are grouped with hydrolases. Both enzyme classes deal with breaking down molecules. Together, their scaling behaviors between domains of life fall within a 95% confidence interval of each other, meaning lyases may potentially also constitute a universal biochemical function if reclassified with hydrolases [3].
These results reveal how these enzyme classes can inform what biochemical functions allow life to occur regardless of specific chemical components. The group reasoned that since they did not examine at the level of mechanistic details of how enzymes function, this work can be more generalizable beyond the tree of life as we know it [3].
This research will motivate others across various disciplines to propose new ideas to predict features of life outside of the immediate solar system. And until we find evidence of life (or until they find us), there are still many more ways scientists can try to bring some understanding to the unknown.
Figure 1. Here shows a conceptual schematic of how the number of unique enzymes in each enzyme class relate to the total number of enzymes across all enzyme classes, and how these scaling relationships compare between archaea, bacteria, and eukaryotes. The enzyme classes examined are oxidoreductase (EC 1), transferase (EC 2), hydrolase (EC 3), lyase (EC 4), isomerase (EC 5), or ligase (EC 6).
References:
- Voyager – what’s on the golden record. [accessed 2022c Apr 26]. https://voyager.jpl.nasa.gov/golden-record/whats-on-the-record/.
- Voyager – mission status. [accessed 2022b Apr 26]. https://voyager.jpl.nasa.gov/mission/status/.
- Gagler DC, Karas B, Kempes CP, Malloy J, Mierzejewski V, Goldman AD, Kim H, Walker SI. 2022. Scaling laws in enzyme function reveal a new kind of biochemical universality. Proc Natl Acad Sci USA. 119(9):e2106655119. doi:10.1073/pnas.2106655119. [accessed 2022 Apr 26]. https://pnas.org/doi/full/10.1073/pnas.2106655119.
- Introduction to scaling laws. [accessed 2022a Apr 26]. https://www.av8n.com/physics/scaling.htm.
- Hatton IA, Dobson AP, Storch D, Galbraith ED, Loreau M. 2019. Linking scaling laws across eukaryotes. Proc Natl Acad Sci USA. 116(43):21616–21622. doi:10.1073/pnas.1900492116. [accessed 2022 Apr 26]. https://pnas.org/doi/full/10.1073/pnas.1900492116.
Inconsistency in climate change education across K-12 grades
By Vishwanath Prathikanti, Anthropology ‘23
Author’s note: I, like many around the world, was alarmed when the Intergovernmental Panel on Climate Change released its sixth assessment report in August 2021 and delivered news of rapid and intensifying climate change. As an undergraduate with a research focus on science education, I was almost equally alarmed to find that the National Center for Science Education reported that 40% of middle and high school teachers teach climate change inaccurately. Furthermore, climate change isn’t required to be taught, or addressed in any capacity, in any state. In an era where climate change is becoming an existential threat to humanity, I wish to highlight the faults in climate change education and explain how it must improve.
In schools across the United States, teachers are teaching subjects such as arithmetics, the Revolutionary War, Shakespeare’s plays, and, more recently, climate change. However, not all teachers teach climate change, and the ones who do may be teaching it wrong.
Before we discuss climate change education, it is important to understand exactly what has caused the degree of climate change in the past few decades. All credible scientists agree that climate change is happening, and it’s human activities that are responsible for causing it. Our atmosphere is designed to keep heat from the sun inside; it’s why we don’t completely freeze at night when the sun isn’t directly on us. Greenhouse gasses, such as CO2 and methane, help our atmosphere keep this heat in. Since the mid-twentieth century, humans have been significantly increasing the amount of greenhouse gasses in our atmosphere, either by driving cars that produce carbon dioxide, raising livestock, which produce methane, or cultivating soil, which produces nitrous oxide [1]. This results in more heat being trapped in the atmosphere, causing increased floods and droughts, the destruction of coral reefs, and the displacement of animal populations.
Considering the fact that the United States had the second greatest carbon footprint in 2021, it is imperative that the next generation understands the reality of climate change [2]. If nothing is done to address climate change, irreversible damage will be dealt to the Earth, such as animal and plant populations going extinct and even human settlements being destroyed or simply deemed uninhabitable due to worsening weather conditions. People must be educated on the severity of climate change so that they may mitigate or prevent such catastrophic events.
What does climate change education look like now?
Despite climate change being an existential threat to humanity, climate change education isn’t actually required to be taught in schools. Topics discussed in school are left for states to decide, and in many states, including California, teaching climate change is not mandated, despite it aligning with state science education standards [3, 4]. This leads to varying levels of quantity and quality regarding climate change education, as it often falls into the hands of individual schools or teachers themselves to determine how much time they spend and the level of depth when discussing climate change.
A study done by Eric Plutzer and colleagues found that of their sampled high school and middle school teachers, around 75% spent at least an hour per academic year on climate change (87% of high school biology and 70% of middle school science teachers) [5]. Plutzer and colleagues note that this small amount of time dedicated is worrisome by itself, but the quality of education is cause for more concern. Thirty percent of teachers emphasized that recent rises in climate were due to “natural causes” and 12% failed to emphasize human causes. Strangely, 31% admitted to teaching that recent climate change is caused by human activity, but also that many scientists believe it is due to natural causes [5]. Plutzer and colleagues stipulate it may be an attempt to convey both sides of the argument. This is alarming when coupled with the fact that 97% of climate scientists agree that humans are causing global warming and climate change. According to NASA, “international and U.S. science academies, the United Nations Intergovernmental Panel on Climate Change and a whole host of reputable scientific bodies around the world” have expressed this fact [6].
Sarah B. Wise, a professor at University of Colorado Boulder, conducted a similar study earlier, though limited the sample to Colorado public school teachers. Wise found that while 87% of teachers addressed climate change, the method was much more variable as indicated by a free-response section. According to Wise, many teachers only have an “informal discussion” rather than an organized lecture. Meanwhile, among those that did include a formal lesson plan, more than ⅔ of them indicated the lesson was mainly on “emphasizing the ‘nature of science’ (e.g., how scientists gather evidence, arrive at explanations, and engage in peer review) … and acknowledging or discussing the presence of public controversy and skepticism around the topic of global warming” [7]. These methods of teaching climate change often give way to imagining holes in the idea that humans are responsible for climate change. For example, if a student hears the notion that some scientists disagree on climate change, and the nature of science requires us to have skepticism, their perception of climate change being driven by humans weakens.
While many teachers make sure to emphasize the scientific consensus, the fact that the number is only 54% should be cause for concern.
Why is climate change taught this way?
Plutzer and colleagues suggested that teachers may cover certain aspects of climate change and avoid others due to misinformation in their own lives. While 97% of scientists agree that human activity has been responsible for climate change, the public perception of climate change scientists’ knowledge is poor. According to a 2016 Pew Research poll, only 33% of Americans believe climate change scientists understand whether climate change is occurring or not, 28% believe scientists understand the causes, and 27% believe scientists agree that it is caused by humans [8].
When teachers were asked directly in Wise’s study, answers were a bit nebulous. The vast majority reported that a discussion of climate change would not “fit into their curriculum or standards” for various reasons, some being a lack of time, and others citing a limitation of the curriculum itself. Interestingly, unlike a subject such as evolution, very few teachers indicated they felt pressure to avoid teaching the subject by a student or member of the community. Even when teachers were directly discouraged from teaching the subject, free responses indicated it did not affect their decision to include it in the class, through an informal discussion or otherwise.
That being said, the political aspect of climate change should not be ignored. While the extent of the politicization of climate change is a somewhat complicated issue, it is undeniable that many believe climate change is a political subject, and like all political views, it is important to share “both sides” in school. While teachers were found to generally teach climate change, as discussed prior, the discrepancy was with whether they would emphasize human activity or natural causes as the main driving factor. While scientists have recognized there are patterns of climate change that occur naturally, it is also clear that after the mid-twentieth century, when cars became a family staple and humans started producing more greenhouse gas emissions, temperatures spiked much higher than they ever did naturally [9]. It is therefore commonly agreed that in the past few years, human beings are the ones mainly responsible for the increase in temperature.
Wise found that 85% believed teaching both sides was important. When asked why, 25% of teachers said it was because both views held scientific validity and 50% said it was to promote “critical thinking” and “independent decision-making.” Only 25% believed students should learn both, but school curricula should emphasize the scientific consensus that human activity is the driving force [7].
When they asked similar questions to their sample, Plutzer and colleagues found that those who believed it’s “not the government’s business to protect people from themselves” were also most willing to teach both sides [5]. In this sense, Plutzer and colleagues claimed the issue was based more on personal values of the teachers than any formalized curricula that may have been forced onto them.
What needs to be changed
It is clear that education on climate change in America must be made more robust; not only must climate change be required in school curriculums, but it should also emphasize the fact that there is a scientific consensus that human activity is the main cause. Climate change must be standardized at the state level, or at the very least, be mandated to teach. Until there is an established curriculum for climate change, the way it is presented will remain up to teachers.
While some might argue a solution is to educate teachers and allow them to retain power over the way climate change is taught, because of the personal motivations at play, Plutzer and colleagues do not believe this would solve the issue [5]. In an interview with Time Magazine, Plutzer said, “The goal of climate skeptics is very similar to the goals of evolution skeptics. They’re not attempting to prove their point; they’re merely hoping to raise doubt — enough doubt to delay [changes to education] policies” [10].
Instead, Plutzer and colleagues suggest the process of educating teachers will need to draw on science communication research, and specifically help science teachers “acknowledge resistance to accepting the science and addressing its root causes.” A failure to approach educators properly may actually lead to the strengthening of views that seek to teach both sides equally [5].
Until personal biases in teachers regarding climate change can be resolved, some researchers have turned towards extracurricular activities and games to increase climate change knowledge and bridge the partisan gap. Juliette Rooney-Varga and colleagues created a simulation for secondary (grades 6-12) and post-secondary students in which participants role-play as UN delegates who are tasked with saving the world from climate change. The researchers found that of the 2042 participants, 81% reported an increase in their desire to “combat climate change.” In particular, they pointed out the effectiveness in convincing Americans who were “somewhat or strongly opposed to free-market regulation.” This label applied to 40% of all participants, who, prior to the study, indicated lower beliefs “that climate change is caused by human activities,” “lower levels of knowledge about CO2 accumulation dynamics,” and lower levels of “a sense of Urgency” [11]. After the study, their views on climate change “showed no statistically significant differences” when compared to their fellow Americans who favored government regulation.
Similar to how schools still face difficulties teaching evolution, it is unclear exactly how much resistance teachers, schools, and textbook authors will face when incorporating a stronger climate change curriculum into K-12 education. However, with the help of educators and researchers with a desire to foster better science communication, the next generation of students may be better equipped to address climate change in society.
References:
- NASA. The Causes of Climate Change. Accessed January 30, 2022. Available from: https://climate.nasa.gov/causes/
- World population review. Carbon footprint by country. Accessed Jan 30, 2022. Available from: https://worldpopulationreview.com/country-rankings/carbon-footprint-by-country
- Johnson S. October 18, 2019. Teachers and students push for climate change education in California. Ed source. https://edsource.org/2019/teachers-and-students-push-for-climate-change-education-in-california/618239
- U.S. Department of Education. The Federal Role in Education. Accessed January 30, 2022. Available from: https://www2.ed.gov/about/overview/fed/role.html
- Plutzer E, Mccaffrey M, Hannah AL, Rose J, Berbeco N, Reid AH. February 12, 2016. Climate confusion among U.S. teachers. Science. 351(6274):. 664-665. https://www.science.org/doi/10.1126/science.aab3907
- NASA. Do scientists agree on climate change? Accessed January 30, 2022. Available from: https://climate.nasa.gov/faq/17/do-scientists-agree-on-climate-change/
- Wise SB. January 31, 2018. Climate Change in the Classroom: Patterns, Motivations, and Barriers to Instruction Among Colorado Science Teachers. Journal of Geoscience Education. 58(5): 297-309. https://www.tandfonline.com/doi/abs/10.5408/1.3559695
- Pew Research Center. October 4, 2016. Public views on climate change and climate scientists. Available from: https://www.pewresearch.org/science/2016/10/04/public-views-on-climate-change-and-climate-scientists/
- Denchak M, Turrentine J. September 1, 2021. Global Climate Change: What You Need to Know. Natural Resources Defense Council. https://www.nrdc.org/stories/global-climate-change-what-you-need-know
- Worland J. February 11, 2016. Why U.S. Science Teachers Struggle to Teach Climate Change. Time. https://time.com/4214388/science-teachers-climate-change/
- Rooney-Varga JN, Sterman JD, Fracassi E, Franck T, Kapmeier F, Kurker V, Johnston E, Jones AP, Rath K. August 30, 2018. Combining role-play with interactive simulation to motivate informed climate action: Evidence from the World Climate simulation. PLoS ONE 13(8): e0202877. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202877
The psychedelic renaissance: a review on microdosing, the routine use of low-dose psychedelics as a therapeutic
By Reshma Kolala
Abstract
Psychedelic drugs are far from what is considered to be conventional medicine. An infamous history of misuse has stigmatized psychedelics, making it difficult to garner support for its use as a potential therapeutic tool. However, among working adults, taking low doses of psychedelics has recently gained popularity in its ability to boost productivity, reduce anxiety and depression, and enhance overall well-being. Only a few studies have investigated these benefits in a controlled, randomized setting, all of which produced promising results. However, the data is far from sufficient, and significant further study is warranted before psychedelics may become a mainstream nootropic supplement.
Introduction
Psychedelic drugs such as lysergic acid diethylamide (LSD), psilocybin, and N, N-dimethyltryptamine (DMT) are notorious for their ability to induce a hallucinogenic episode or an altered state of consciousness. These effects are brought about by visual, psychological, and auditory changes following the intake of a recreational dose. In recent years, however, the profile of psychedelic drug usage has shifted to microdosing. Psychedelic microdosing is the use of low doses of hallucinogenic drugs on a chronic, relatively regular schedule. On average, users take about one-tenth to one-twentieth of a typical, recreational dosage every two to three days [1]. Anecdotal reports have shown that users experience enhanced creativity and productivity as well as improved cognitive function [2]. In an online questionnaire, Hutten et al. (2019) observed that the primary motivation for microdosing is performance and mood enhancement, symptom relief, and curiosity [3]. Despite encouraging reviews from users, there is minimal empirical evidence to support the commercialization of psychedelics for clinical purposes. The following review evaluates the practice of microdosing by examining its efficacy, application, safety, and relevance to the social and health challenges faced by individuals presently.
Microdosing as a therapeutic tool
History of clinical psychedelic drug use
The clinical use of psychedelics to treat mood disorders is not an unfamiliar avenue for hallucinogenic drugs. The discovery of LSD in the 1940s, and its wider distribution in the 1950s, began a new era of research into psychoactive compounds. Psychedelics were considered useful as a supplemental treatment to facilitate successful therapies. This prompted further research, leading to nearly 1,000 clinical studies being published by 1965 [4]. These studies reported positive therapeutic outcomes in patients suffering from various mood and substance abuse disorders. However, a cultural shift in recreational psychedelic drug usage during the 1960s and 1970s led to a relabeling of psychedelic drugs. These hallucinogens became synonymous with rebellious and dangerous behavior, leading to the criminalization of psychedelics in the United States. This severely restricted research into psychedelics as a therapeutic, causing interest and funding to diminish and ultimately stalling further advancement.
The demand for an alternative approach
Microdosing is portrayed as an alternative to traditional antidepressant or anti-anxiety medications. The prescription rates of medications treating behavioral and mood disorders remain alarmingly high, most notably in the United States. Despite this, there has been minimal improvement in the efficacy of these medications in the last few decades. These medications are slow to act, have several adverse effects, and only show improvement in ⅔ of patients [2]. This has encouraged patients to seek alternative methods of treatment, such as microdosing. Despite known unwanted effects, standard antidepressants, or SSRIs (selective serotonin reuptake inhibitors), continue to be prescribed because of the large volume of controlled, clinical trials that demonstrate their safety and efficacy. The same cannot be said for psychedelic use however, due to the controversial nature of funding research into illicit drugs, particularly those that cannot be patented by pharmaceutical companies. Therefore, the substantial anecdotal support for microdosing, notably their reported lack of relative side effects, cannot be reliably concluded. However, amidst logistical challenges, the increasing prevalence of microdosing unveils a new niche of therapeutics that target individuals who may be unreceptive to traditional modes of treatment for mood and anxiety disorders.
Chronic, low-dosage psychedelic treatment (microdosing)
Few studies have investigated the effects of microdosing in ameliorating depression and anxiety symptoms in controlled, randomized trials. One of these is a UC Davis study where DMT was administered at sub-hallucinogenic levels (1 mg/kg) on a chronic, intermittent schedule to rats (Cameron et al. 2019). This was opposed to a standard high dose (10 mg/kg) which is known to induce symptoms of anxiety. These rats were subjected to tests that quantified their anxiety levels and behavioral responses. DMT was specifically chosen for this study because of its chemical architecture, as it possesses a core indole-containing structure, present in LSD and psilocybin. These indole-containing hallucinogens are analogues of the neurotransmitter serotonin, which is known to influence mood and behavior. DMT is also known to influence rodent behaviors often affected by depressive symptoms, such as sociability, mood, and anxiety. The results indicated no significant difference between the control group and the treatment group in their ability to produce anxiogenic effects or reduced anxiety symptoms. In a test traditionally used to measure the efficacy of antidepressants, rats treated with DMT exhibited antidepressant-like responses without any impairment to working or short-term memory or social interaction. This study corroborates reports that microdosing in humans alleviates depressive-like symptoms [2]. However, anxiety reduction, enhanced sociability, and enhanced cognitive function self-reported by users in the study conducted by Hutten et al. (2019) was not observed.
Nonchronic low-dosage psychedelic treatment
Anxiogenic effects were observed, however, in a controlled, randomized study that proposed psilocybin as a treatment to reduce anxiety and depression in patients with advanced-stage cancer. Ross et al. (2016) concluded that a single dose of psilocybin (0.3 mg/kg) produced significant, immediate, and sustained (up to 7 weeks after the dose) reduction of depression and anxiety symptoms [5]. However, this study did not practice microdosing, in contrast to the study conducted by Cameron et al. (2019). In another double-blind, controlled study, patients with obsessive-compulsive disorder (OCD) were administered up to four doses of psilocybin, ranging from mildly hallucinogenic to moderately hallucinogenic (100ug/kg-300ug/kg). Results indicated that patients experienced an acute reduction in OCD symptoms immediately after treatment, at all given dosage levels [6].
Although the studies conducted by Ross et al. (2016) and Moreno et al. (2006) target different populations, both studies showed promising benefits after psilocybin treatment [5,6]. However, in both studies, psilocybin was administered minimally, not often enough to be considered microdosing. In sum, psychedelic psilocybin treatment has shown promising results when administered minimally and at low doses.
Risks of microdosing
The safety risks associated with short-term or long-term microdosing are unclear, although research into the safety of recreational psychedelic use (~10 mg/kg) suggests that it is relatively safe. In a rating study conducted by European Union (EU) drug experts, van Amsterdam et al. (2015) concluded that, based on current data, alternative substances such as tobacco and alcohol are significantly more harmful than psychedelics in a physical and societal aspect [7]. This is attributed to the addictive quality of tobacco and alcohol, and their ability to induce long-term health disorders such as lung and heart cancers.
Longitudinal studies done with higher, recreational doses have demonstrated that long-term usage of psychedelics is associated with reduced psychological distress [8]. However, it is known that both low and high doses of DMT can alter the neuronal structure of the brain, promoting structural and functional plasticity [9]. These effects were observed long after DMT was cleared from the body. The effects of psychedelic use may also have metabolic effects. The data collected by Cameron et al. (2019) indicate that the male mice who were administered low doses of DMT had a reduced appetite yet gained significantly more weight. Metabolomic profiling of these mice revealed no significant differences in serum steroid levels, implying the interplay of unknown factor(s) in microdosing.
Conclusion
Recent publications regarding microdosing and general low-dose psychedelic drug use reveal several disparities between animal trials and human reports making it difficult to recommend microdosing based on current empirical evidence. Although psychedelics as a therapeutic show promising preliminary results, further research must be conducted to determine their clinical relevance. Future studies should explore the effects of a microdose and recreational dose within the same study and use a broader range of psychedelics such as non-indole-containing compounds. Additionally, researchers may want to vary the frequency of doses within a study, ranging from frequent (Cameron et al. 2019) to infrequent administration, (Ross et al. 2016) and aim to design longitudinal studies to determine the long-term effects of practicing microdosing. By investigating alternative approaches to enhance cognitive function and minimize mood disorder symptoms, researchers can provide further insight into the future of more comprehensive, personalized healthcare for all adults.
References:
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First steps in the development of small-scale 3D printed hydrogel bioreactors for protein production in space travel
By Maya Mysore, Laura Ballou, Anna Rita Moukarzel, Alex Cherry, David Duronslet, Lisette Werba, Nathan Tran, Hannah Mosheim, Stephen Curry, Simon Coelho
Advisors: Kantharakorn Macharoen, Matthew McNulty, Andrew Yao, and Dr. McDonald, Dr. Nandi, and Dr. Facciotti
Author’s Note: My name is Maya Mysore, and I am a team lead on the BioInnovation Group’s Plant Bioprinter project. The BioInnovation Group is a student organization that creates research and leadership opportunities for undergraduates. The Bioprinter project is one of these opportunities.
I joined the BioInnovation group (BIG) in the winter quarter of 2019, as a freshman looking for ways to get involved on campus. I knew I liked research; I had been working in another lab. However, I was looking to explore different aspects of research. I heard about BIG through some friends in my major and went to an information session. There, I tried to join the more tech-based microfluidics project; however, my previous lab experience with cell culture convinced the lead for the Bioprinter project to get me involved in their work. I spent the next couple quarters investigating how to trap viruses in hydrogel. In Fall 2019, I was offered the role of lead. I was shocked, surprised, and a little out of my depth– after all, I had practically joined the project by accident! But I took on the role, excited about the leadership opportunity and the freedom. Now over a year into being project lead, I am planning to transition into the organization’s leadership. However, as a swan song to my time in charge, I wanted to compile all the hard work those involved with the project have accomplished. This paper is a celebration of the work of tens of student researchers over a period of several years. Hopefully, this paper will be the first of many for the Bioprinter project and the BioInnovation Group.
Abstract
As human space exploration expands to include potential settlement on the Moon and Mars, the ability to build shelter, manufacture food, produce medicine, and create other necessities in space will become increasingly important. Currently, the high cost and size constraints of sending payloads into space challenges us to think beyond the traditional manufacturing and agricultural tool-kit. Engineers have proposed that additive manufacturing, particularly 3D printing, is a solution to lower the payload costs and to enable the manufacturing of a variety of products in situ. This study focuses on 3D printing engineered biological cells for the production of biologics (e.g. pharmaceuticals that are living or derived from a biological source). We describe in-progress work to design, build, and test a small and affordable 3D bioprinter capable of printing 3D structured hydrogels that can carry living cells. We provide a general overview of the project, our progress in converting a low-cost and compact 3D printer from printing plastics to printing hydrogels, and preliminary work testing the compatibility of bioink formulations with genetically engineered rice cells that produce and secrete the enzyme butyrylcholinesterase.
Background
As humans continue to explore space and potentially settle in distant locations such as the Moon, Mars, and beyond, it will become increasingly necessary to build shelter, create food, and develop medicine while in space. However, the major costs (roughly $20,000/kg) and size constraints of sending payloads into space create challenges for such long-duration space travel beyond low Earth orbit [1-4]. Challenges include the manufacturing of food, shelter, and even medicine. 3D printing has been proposed as a cost-effective method for addressing some of these challenges, as it might allow the opportunity to ship only the printer to remote sites and to source the majority of the printing materials from the settlement location [5].
Biological systems may also play a large role in this approach. Microorganisms have been envisioned to help construct habitats through biocementation, a process that uses microorganisms to solidify inorganic matter into 3D structures [6-8]. Plants and microbes together are proposed as possible tools for the creation of sustainable ecosystems that recycle and detoxify waste and produce food [9-11]. A purported advantage of biological systems is that they can self-replicate, as each organism carries the full set of genetic instructions to create copies of itself. This means that biological systems could be delivered as light-weight “seeds”, i.e. self-replicating units that can be shipped in small and light quantities and grown to larger quantities upon permanent settlement at remote bases.
We and others envision that the 3D printing of engineered living systems (e.g bioprinting) may prove useful for the manufacturing of biologicals; this includes pharmaceuticals of or derived from a biological source [12]. In this context, the engineered living system serves as an on-demand expandable factory for the production of the biological while the 3D printer serves to produce custom-made culturing and purification hardware that can be produced in the geometries required for specific cells and production sizes. We were interested in exploring this concept and better understanding the challenges associated with the proposed process of drug production through bioprinting. In order to do this, we needed a bioprinter. Depending on their feature sets, commercial bioprinters can cost anywhere between $10,000 and $200,000, which was well outside our budget. Therefore, as a first step, we sought to design, build, and test a low-cost and compact bioprinter that we could later customize and use to explore novel design ideas.
FExisting modalities of bioprinting were considered and four main existing modalities of 3D bioprinting were considered: inkjet, pressure-assisted, laser-assisted, and stereolithography. For a detailed review on this subject, see Li et. al [13]. The major factors that were considered in the selection of a printer were types of usable bioinks, potential for good cell viability, cost, and complexity of the system (e.g. ease with which it can be modified). Inkjet-based bioprinting uses computer controls to drop small drops of bioink onto a surface. This type of printing maintains high short-tem cell viability and is widely available at low cost. However, it is limited in printing materials and creates high thermal and mechanical stress on cells which risks damage to cells and may affect long-term viability. Pressure-assisted bioprinters extrude bioink continuously onto a surface. While the extrusion process is slower and can lower cell viabilities immediately after printing (ranging from 40-80%, compared to 90% for inkjet printing), it allows use of a greater variety of materials and incorporates cells directly into the bioink. Laser-assisted bioprinters use a laser to irradiate a bioink such that the droplets adhere to the desired surface. This method of bioprinting is very precise and results in the highest cell viability; however, it is the most expensive, time-consuming, and has the highest risk of metal contamination. Finally, stereolithography printing uses illumination of a light-sensitive polymer to solidify 3D shapes. This method is fast, cost-effective, and has high final cell viabilities, but it is primarily limited by the need for a light-sensitive bioink, many of which are not biocompatible.
We chose to build a pressure-assisted bioprinter primarily due to practical factors: (a) the availability of low cost and compact fused deposition modeling (FDM) printers that could be used as chassis, theoretically enabling a “simple” swap of printing nozzles and pumps while taking advantage of the existing build platforms and 3D control systems; (b) the easy access to safe and low cost of compatible bioinks, and (c) the ability to incorporate cells directly into the bioink for prototyping.
This paper describes the progress of our project in developing a functional bioprinter. In addition, we describe the chemical assays used to evaluate engineered rice cell viability within hydrogels and these cells’ cell’s ability in gels to produce the pharmacologically-relevant enzyme Butrylcholinesterase (BChE), which is a complex human serine hydrolase enzyme that provides protection against organophosphorus poisoning from toxic agents such as sarin.
Figure 1. This diagram demonstrates the model methodology for seeding the cells into the hydrogel, printing out the cell-gel complex, and extracting the protein of interest from this system.
Methods
Printer selection, modification and testing
Selection of chassis
We sought to find a low-cost and compact FDM printer system that could be reasonably modified to extrude bioink rather than plastic filament. We ultimately selected the Monoprice MP Select Mini 3D Printer V2 because of its high availability, low cost ($250), and relative ease of modification. An accurate open source 3D computer-aided design (CAD) model (https://www.thingiverse.com/thing:2681912) of this printer was already available, making it easier to design new features for this specific unit.
Construction of an bioink extruder
To start converting the 3D plastic printer into a bioprinter, the printer’s original extrusion mechanism was replaced with a standard syringe/syringe-pump mechanism typical of bioprinters [14].
Incorporating the syringe-based bioink extruder required the design and construction of the entire extrusion system. An interchangeable mount was designed to hold the 10 mL syringe on the printer access, as seen in Figures 2b and 2c. In Figure 2b, the interchangeable mount design is shown with a trapezoidal connection piece, allowing the mount to swap between holding the 3D printer plastic extruder and the bioprinter syringe extruder system.
Figure 2. a) Inside of the 3D printer after all electrical components and panels were removed b) 3D printed interchangeable mount used to exchange the plastic extruder and the syringe extruder. c) The hydraulic extrusion system as connected to the bioprinter d) The hydraulic extrusion tubing system
The 10 mL syringe was connected to a hydraulic pumping system through a plastic tube. The hydraulic system is controlled using a Nema 17 Bipolar 40 mm Stepper Motor connected to an 8 mm threaded rod, forming a linear actuation mechanism. Connected to the rod is a 60 mL syringe plunger which is pushed through a 60 mL syringe. A liquid is placed in the 60 mL syringe and the bioink is placed in the 10 mL syringe also with a plunger sitting on top of the syringe. When the motor turns on, this liquid is pushed from the 60 mL syringe through the tubing and into the 10 mL syringe. This system pushes the plunger through the 10 mL syringe and extrudes the bioink onto the printing surface.
A T fitting made from 6 mm brass tubes was attached to the middle of the tubing system in order to remove air bubbles from the tube, as shown in Figure 2d.
Integration of hydraulic motors with chassis
To power the motor for the syringe extruder, the electrical components needed to be rebuilt. With this in mind, an Arduino Mega 2560 was connected with the HiLetGo RAMPS 1.4 control panel and the A4988 stepper motor driver boards using the wiring setup diagrammed in Figure 3.
Figure 3. This diagram shows the wiring for the 3D printer using the Arduino.
The Z-axis switch was then repositioned and mounted to the printer chassis directly under the print head, as seen in Figure 2c.
Firmware
For the firmware, Marlin was selected because it is open sourced and easily modified with the Arduino IDE. After the firmware and electronics were set up, a G code file was needed to determine the print pattern. Cura was used to develop the file due to its compatibility with the Monoprice 3D printer. The Cura profile used with the bioprinter tests followed a cylindrical shape with a square-shaped infill grid. With this information established, the Cura profile was exported as G Code. In the printer design, an SD card is required to flash the firmware and upload the G code to the bioprinter. With the firmware and G code loaded onto the SD card, the bioprinter could be set up to run test prints with the bioink. The final cost spent to make the bioprinter came out to $375. Further information on the process of building the bioprinter can be found at https://www.instructables.com/Low-Cost-Bioprinter/.
Hydrogels
Hydrogels are porous water-based polymers that have many valuable uses, especially in fields such as drug delivery and tissue engineering. Here, we use hydrogels for their ability to selectively trap materials on a size basis, as this is what allows us to trap cells and release the protein of interest. Our hydrogel protocol was adapted from Seidel et al., 2017. Briefly, the hydrogel mixture contained agarose (0.2275% w/v), alginate (2.52% w/v), methyl cellulose (3% w/v), and sucrose (3% w/v). Agarose, alginate, and sucrose were mixed into deionized water at room temperature until dissolved. This mixture and the methyl cellulose powder were then autoclaved in separate containers for 20 minutes at 121 C. Upon completion of the autoclave cycle, methyl cellulose was mixed into the gel. The mixture was then left for 12 to 24 hours in a 2-8 C fridge to allow swelling to occur [15]. After this, the gel was ready to be seeded.
Seeding and Crosslinking the Gels
Transgenic rice cells were supplied by the McDonald-Nandi lab. The cells were genetically modified with the addition of a human BChE gene optimized for rice cell compatibility and cloned into the RAmy3D expression system for transformation into A. tumefaciens to allow insertion into rice cells [16]. This allowed the engineered cells to produce the pharmacologically-relevant BChE protein. The provided cell suspensions were mixed thoroughly via pipetting to obtain even distribution of cells. This suspension was then added directly to the hydrogel in a 50% volume split of cell suspension and gel and gently mixed to distribute cells evenly. To crosslink the gels and create solid structures for later use, a 0.1 M calcium chloride solution was prepared. The hydrogel was loaded into a syringe and deposited into weight boats containing enough CaCl2 solution to half-cover the extruded hydrogel. The hydrogel would then cure in the solution for at least 5 minutes or until the shape solidified. Upon completion of curing, the hydrogel could be removed and used for experiments.
Tetrazolium Chloride Viability Assay on Hydrogels
The TTC (2,3,5-triphenyltetrazolium chloride) assay is a method for testing cell viability. TTC is turned red from a colorless solution in the presence of metabolizing cells, allowing for quantification of cell viability. When used with defined standards and run on a spectrometer, it can be used to monitor cell survival over time.
Preparation of the TTC solution involved mixing 0.4% w/v TTC in 0.05 M sodium phosphate buffer, pH 7.5. Once the TTC solution was prepared, the TTC assay was performed.
5-6 mL of 0.05 M sodium phosphate buffer was added to a 15 mL Falcon tube with cured gel to submerge the cured gel entirely. The gel remained in the solution for 15 minutes. Then the Ellman buffer was removed from the tube and 500 μL of TTC were added to the tube with gel while mixing slightly. This tube was stored in a dark area for 24 hours.
If the gel was not cured, roughly 5 mL of gelled cells were first centrifuged in a 15 mL conical tube at 4500 g for 20 minutes. The supernatant was removed and 1 mL of Ellman buffer was added and mixed. The sample was centrifuged again at 4500 g for 15 minutes, the supernatant was removed, and 500 μL of TTC solution were added to the gel-cell mix. This sample was stored for 24 hours in a dark area.
After the 24 hours period ended, the sample-TTC mix was centrifuged at 4500 g for 15min. The supernatant was removed and the gel-cell mix was washed with 1 mL deionized water. The mixture was re-centrifuged at 4500 g for 10 minutes. The supernatant was removed again and 1 mL of 95% ethanol was added to the gel-cell mix. The sample was transferred to a microcentrifuge tube and placed in a 60C water bath for approximately 10 minutes. The sample is then centrifuged at 21.1 g for 15 minutes to recover the final supernatant. The supernatant was then run on a colorimeter or Tecan and the absorbance value was read at 485 nm. Beer’s law was then used to determine concentration from this value.
Seeded Cell-Ellman BChE Concentration Assay
The Ellman assay was used to measure BChE concentration for a sample at a given time point. This assay uses the kinetics of a color changing reaction to quantify the amount of BChE in solution. When in the presence of specific substrates, BChE turns a colorless solution yellow; the peak rate of this reaction can be determined and used to calculate BChE mass in a sample.
After cells were seeded into a hydrogel complex with a disc shape approximately 7 cm in diameter and 1 cm thick, the complex was suspended in 40 mL sucrose-free nutrient broth (NB-S).
The flask was then covered with a cloth filter and placed in the shaking incubator (37C, 5% CO2, 80 rpm). 50 μL media samples were collected from the flask daily over 14 days and the Ellman assay was run directly following collection of each of these samples.
The Ellman assay protocol was based on the Cerasoli lab protocol, which was adapted from Ellman et al., 1961 [17]. To perform the Ellman assay, a 20 mm stock solution of 5, 5’ – dithiobis-(2–nitrobenzoic acid) (DTNB) was prepared. A 75mM stock solution of S-Butyrylthiocholine (BTCh) iodide was also prepared.
Immediately prior to performing the Ellman assay, the Ellman substrate was prepared. 60 μL of DTNB and 30 μL of BTCh were added to the phosphate buffer in the falcon tube. The tube was temporarily stored in ice with light protection.
Then the Ellman assay was performed. In a 96-well plate, 50 μL of sample containing BChE was were diluted into 0.1 M phosphate buffer, pH 7.4, to ensure the generated? outputted slope readings (mOD/min) would fall in the range of 200-1000 when read for 3-5 minutes at 25 C. This dilution was done by estimating the approximate BChE concentration and estimating the mOD/min based on the expected value. 150 μL of Ellman substrate was added to each sample containing well. The optical density of the sample was immediately read at a wavelength of 405 nm for a total of 300 s (5 min) after the measurement was started.
After collecting data from the assay, Beer’s law was used to determine the concentration of product formed. From that value, we could estimate the mass of functional BChE in the total volume of the sample collected [18].
Results
TTC-Gel compatibility
To measure in-gel cell viability, we evaluated the use of the tetrazolium chloride (TTC) assay. This assay measures metabolic activity in live cells by reducing tetrazolium chloride to red formazan through the process of cell metabolism. Effectively, it provides an indication of how well the cells survive over time. Our team modified the assay for use in gels by including extra Ellman buffer and centrifugation steps to provide more opportunity for cells in the gel to be washed.
Figure 4. This figure shows the results of the TTC assay run on the transgenic rice cells in suspension. The leftmost tube is a positive control showing the TTC assay done on cell aggregates in suspension (i.e. without gel) that have been centrifuged into a pellet after the assay was performed. The middle and rightmost tubes are cells suspended in a hydrogel; the TTC assay was performed on this combination of cells in gels. In each tube, the cells have been stained red from the assay, indicating the presence of metabolic activity. These samples can go on to be washed and suspended in ethanol to obtain a viability data value.
To qualitatively assess how different factors like cell distribution and crosslinking might influence the results of the TTC assay, we performed additional variations of the assay. We first visually examined whether cell homogeneity was impacted by the gel. Then, we performed the TTC assay on E. coli cells alone as a positive control. After that, we tested the effects of non-crosslinked and crosslinked gel to ensure neither condition would prevent the use of the assay. E. coli was used for these tests due to our group’s ability to access it more regularly and grow it more easily than the genetically modified rice cells from Dr. McDonald’s lab. All of these tests together allowed us to determine that cell survival could indeed be measured within the gel, allowing us to monitor culture health over time. This will be critical in future use of the model, allowing us to determine ways to improve cell health and protein output by providing a metric for us to test against.
Homogeneous mixing of biological sample
To determine later TTC accuracy, the first key issue to address was homogeneity of cells in a hydrogel. This would determine whether sectioned off samples of cell-gel complexes would be representative of a whole sample. To ensure that the gel mixing protocol yielded a homogeneous suspension of the cells, we first tested our procedure by mixing E. coli expressing a transgenic green fluorescent protein (GFP) and imaged the suspension under UV light. We expect E. coli to distribute homogeneously in the gel similarly to the transgenic rice cells. This mixture was observed (Figure 5a) and confirmed by visual inspection of a homogeneous mix.
Test of TTC assay with bacterial suspension
To ensure that the TTC assay in later tests would be effective with E. coli, we first tested the TTC assay on an E. coli suspension as a positive control for later tests. We ran the modified TTC assay protocol described in Methods, and observed a color change in the solution. The resultant red solution (Figure 5b) matches the literature expectations for the output of this assay on living cells and indicates the assay is effective for E. coli.
Test of TTC assay with bacteria seeded in hydrogel
After confirming the TTC assay was effective with E. coli, it became important to determine how the presence of gel would affect the assay. We suspended the E. coli cells in the hydrogel and ran the modified TTC assay. The results seen in Figure 4c show the suspension turning red, which visually indicates the presence of cell metabolic activity and the effectiveness of the TTC assay.
Test of TTC assay with bacteria seeded in a crosslinked hydrogel
Upon determining the gel did not qualitatively affect the output of the TTC assay, it became necessary to determine whether crosslinking the gel had any effect on the effectiveness of the TTC assay. We reran the same experiment as the non-crosslinking hydrogel experiment, with the only change being the crosslinking process and the different first wash step. We found that the result of the TTC assay appears to be unaffected by the presence of the crosslinked out layer, as the solution turns red in the same way it does for the positive control and the non-crosslinked gel (Figure 5d).
These experiments allowed us to qualitatively determine whether the TTC assay could be an effective measure of cell viability. They also demonstrated that the introduction of a crosslinked hydrogel will not have visible impacts on measuring cell viability.
Figure 5. Qualitative TTC assays were run on E. coli with the pMax plasmid to test homogeneity within the gel and the effectiveness of the TTC assay in different hydrogel conditions. 5a shows the bacteria mixed homogeneously within the hydrogel, which is visible in the fluorescence that is present homogeneously through the sample. 5b shows the ethanol suspension output for a TTC assay run on a pMax E. coli culture, providing a control for later experiments and showing that the TTC assay is effective for E. coli. The left image is the control and the right image is the test condition. The control is run in the same conditions as the test, except the cells are placed in a 60C water bath for ten minutes prior to adding TTC in order to kill them. 5c shows the output prior to ethanol suspension for a TTC assay on E. coli pMax cells that were suspended in an uncured hydrogel. The left tube is the control and the right tube is the experimental condition. The red color visible in the right tube shows that the presence of the hydrogel does not prevent use of the TTC assay. 5d shows the ethanol suspension output for a TTC assay run on E. coli pMax cells that had been suspended in a cured hydrogel. The left image is the control and the right image is the experimental condition. The red color of the suspension indicates the TTC assay remained effective even with the addition of the crosslinked outer layer of the gel. Throughout this figure, variation in intensity of the redness of the samples is related to variations in time spent in suspension of the TTC solution, with redder samples correlating to longer time.
Initial Attempts at Measuring BChE Production
Our second major goal was to determine whether BChE could be collected from our model system (as seen in figure 1). This would allow us to determine if our model system was an effective way to collect our protein of interest for future space travel applications, as well as confirm that our test for BChE quantity would be effective in this system. To test this, our team ran the seeded cell-Ellman assay as described in methods to assess the amount of BChE that was escaping into the media. We first prepared a hydrogel, mixed the transgenic rice cells in, and cured it into a disc shape roughly 7 cm in diameter and 1 cm in height. We then suspended this cured cell-gel complex in NB-S media to stimulate BChE production, and we kept this mix in a spinning incubator to ensure aeration and adequate diffusion of materials in and out of the gel. Media samples were collected over the course of 14 days and were run with the Ellman assay for BChE detection on a spectrometer. The Ellman assay uses the enzyme kinetics of a color-changing reaction between BChE and a substrate to quantify the amount of BChE present in a sample at a given time point.
It is important to note that this test was intended as a trial run of the system in order to ensure that the assay works and that useful data is being collected. In addition, we sought to assess if BChE could escape from the gel at all. Therefore, no negative control was run and only one run of data was collected (shown in the figure below.) As a result, we cannot conclusively state anything about the data. However, the data does show a trend worth noting for future experimentation. The This is that active BChE concentration in the media increased for the first roughly 100 hours, after which the values dropped off. At the time point marked in figure 5, 96 hours, we see the maximal BChE present. If the unusually low value seen at the roughly 120 hour time point is considered erroneous (which we suspect), the data suggests increased production of BChE over the first 4 days of culture followed by a slow decay thereafter with production ending at around day 8. This provides an early quantitative estimate of the time-dependence of BChE production in this model system. This experiment is a first attempt and will be repeated with various parameter variations in the future.
Figure 6. This plot shows the approximate active concentration of BChE released into the media for various time points over 14 days. Each sample was a 50 μL amount of media pulled from the small scale system model. This figure shows a burst in production of active BChE until the 96 hour time point (denoted with a dashed red line), after which the values drop off. The data point at t=120 hours is most likely an outlier resulting from this data being for one set of samples from one test condition.
Preliminary Bioprinter Testing
The process of building and testing the bioprinter was done in parallel with the TTC and Ellman assay testing. Detailed bioprinter testing has not been performed; however, initial testing of the printer showed its ability to print hydrogel into pre-programmed patterns. The grid pattern seen in Figure 7 was printed into a petri dish containing CaCl2 curing solution. The print shows excess hydrogel accumulation near the edges where the printhead briefly paused and reversed direction. In the center of the print, the lines in the grid averaged 1.25mm +/- 0.4 in width. Further testing and refinement is currently in process.
Figure 7. This shows a test print from our modified 3D printer using the hydrogel described in the methods section and cured in standard CaCl2 curing solution. This structure is described as a lattice shape and will be the primary pattern for future prints.
Discussion
In these experiments we determined that the TTC assay was effective in hydrogels, the Ellman assay showed the ability of protein to be detected from solution, and the bioprinter was able to create the desired lattice shape for later use.
Printer Performance
Our experiments to date have demonstrated our ability to convert a low-cost and compact FDM printer into a preliminarily functional bioprinter. The conversion of the original chassis required the modification of the printhead support, the development of a syringe-based hydraulic pump, and the modification of electronic and software control systems. Preliminary prints indicate that the printer can successfully deposit a programmed pattern with feature sizes in the range of 1.5mm. Existing conventional commercial bioprinters can achieve resolutions of 100-200µm, (some even claim filament diameters as low as 3µm), suggesting that we have room to improve the resolution of our system [19]. In addition to improving the resolution of the prints, we want to explore alternate methods for delivering the CaCl2 curing solution during alginate filament deposition to minimize user interaction and allow complete processing inside a biosafety cabinet; this should allow us to increase sterility during printing and print quality.
Cell Viability
Since it is known that pressure-assisted printing may negatively impact cell viability during printing, a key concern was the resulting cell viability of the system. As a result, our general goal for this phase of the project was to test whether a pressure-assisted bioprinter system could maintain cell viability after extrusion. We adapted the TTC assay for this purpose and tested our protocol to determine the effect of bioink and extrusion on cell viability under conditions mimicking those experienced during bioprinting.
Generally, the TTC assay demonstrated the ability of the assay to cellular viability in the crosslinked hydrogel, despite the unknown nature of how crosslinking affects pore size. Despite this success, the TTC assay remains largely qualitative as it is challenging to get quantitative measurements of cell viability when cells are embedded in a gel. This is further complicated by factors like the heterogeneous distribution of cells (or cellular aggregates) in the gel (see figure 4, rightmost sample). If homogeneity is not maintained, we need to design assays that take into account heterogeneous distribution of cells in the gel. In future experiments, we seek to determine whether samples from a large complex of cells in a hydrogel will provide a representative sample.
In later experiments, additional key variables that may potentially affect viability will be tested. These variables include media composition, culture duration, environmental conditions such as temperature, gel architecture, and the additional variables associated with the printer extrusion process (e.g. pressure, needle pore diameter, etc.). Determining how these specific factors affect viability will allow us to modify the printer design to minimize the drop in cell viability upon extrusion.
Protein production
Having confirmed the effectiveness of the TTC assay in the hydrogel, we moved forward to analyzing BChE production and its diffusion into the media. The assay we adopted allowed us to develop a standard method for data collection that can be used to analyze how various factors impact the cells’ ability to produce BChE. Figure 6, for example, shows that we can measure BChE production and diffusion out of the gel, and that under our preliminary experimental conditions, production peaks at 96 hours and then falls over the next 150 hours. While encouraging, this experiment needs to be repeated with many more samples and replicates to obtain a more reliable assessment of measurement error associated with the assay. Despite needing to replicate the experiment, we are confident that this preliminary experiment answered the core question of whether such a large protein – 85 kDa monomers and 4 units in quaternary form, with a total size of 574 monomers [20] – can effectively diffuse out of the hydrogel and avoid denaturation long enough to be collected and purified.
In addition to replication, future experiments should be explored to further improve protein escape from the hydrogel. These tests could increase the mixing speed to use centrifugal force to free proteins from the gel, increase pore size to create more physical space for protein escape, or print the 3-dimensional lattice structure to increase surface area and allow greater escape. Other relevant variables whose impact on BChE production should be tested include media composition and media changing schedules, culture duration, environmental conditions, gel architecture, and growth temperature. In our initial experiments, plant cells were grown in a shaking incubator at 37C to mimic the environment of protein production in mammalian hosts. However, this growth condition may have stressed the plant cells for which growth at 27C is more typical [16, 21]. This may explain the trend shown in figure 6, where die-off occurs after 96 hours.
Finally, in our current studies, the presence of sucrose in gel formulation (which inhibits BChE production) may have adversely impacted the amount of protein produced. While we expected that overlaying a relatively large volume of sucrose-free media would effectively dilute the sucrose to low levels, the presence of sucrose in the initial formulation could have nevertheless impacted the cells’ initial states and therefore protein production. A followup experiment that more stringently controls for the presence of sucrose in the gel than in the studies described above seems warranted.
Conclusion
In this work, we successfully modified an off-the-shelf pressure-assisted 3D printer into a working bioprinter. In addition, we established that BChE producing rice cells are biocompatible with the different bioink gel formulations and that our assays for testing cell viability and protein production are effective when analyzing the cells within the gel. Having shown that we can print gel, assess cell survival, produce BChE, and quantify its abundance, we next seek to optimize both printer function and the measurement assays for cell viability and protein concentration in ways that provide more quantitative data and more refined control over printed structures. Eventually, we expect that such advances will allow us to optimize protein production itself and ultimately develop a bioprinter suitable for protein production during space travel or in other remote locations.
Acknowledgements
Thank you to the Molecular Prototyping and BioInnovation Lab for the lab space, the BioInnovation Group for the administrative, scientific, safety, and monetary support, the McDonald-Nandi lab for materials and mentorship, and all past, present and future members of the Bioprinter team for contributing to these experiments.
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COVID-19 survivors can retrain their smell to enjoy food and wine again
By Daniel Erenstein, Neurobiology, Physiology & Behavior ‘21
Author’s Note: Last spring, I enrolled in the inaugural offering of the University Writing Program’s wine writing course. Our instructor, Dr. Alison Bright, encouraged us to report on topics of personal interest through our news stories on the wine industry, viticulture, enology, and more. In this article, which was prepared for an audience of general science enthusiasts, I examine how biologists are making sense of a puzzling COVID-19 symptom — anosmia, or loss of smell — and what COVID-19 patients with this condition can do to overcome it. Eighteen months into this pandemic, scientists continue to study cases of COVID-19-related anosmia with dreams of a treatment on the horizon. I hope that readers feel inspired by this article to follow this in-progress scientific story. I extend my appreciation to Dr. Bright, who throughout the quarter shared approaches to rhetorical awareness that elevated my grasp of effective writing.
Image caption: Anton Ego, the “Grim Eater” from PIXAR’s Ratatouille, is reminded of his childhood by Remy’s rendition of ratatouille, a Provençal dish of stewed vegetables.
With a single bite of Remy’s latest culinary creation, the eyes of Anton Ego, a notoriously harsh food critic, dilate, and Ratatouille’s viewers are transported back in time with Monsieur Ego. The meal — a simple yet elegant serving of ratatouille, accompanied by a glass of 1947 Château Cheval Blanc — has triggered a flashback to one singular moment, a home-cooked meal during his childhood. The universal charm of this enduring scene resonates; in Ego’s eyes, many recognize how our senses of smell and taste can impact a culinary experience.
Imagine how a real-life version of this scene might change for the millions of COVID-19 patients who have lost their sense of smell [1]. Anosmia, the phenomenon of smell loss, has become one of the more perplexing COVID-19 symptoms since first observed in patients during the earliest months of the pandemic [2].
What happens when we lose our sense of smell? During the pandemic, scientists have studied smell loss, which affects more than 85 percent of COVID-19 patients according to research published this year in the Journal of Internal Medicine [3]. In fact, anosmia is so common in COVID-19 patients that physicians were offered guidance for testing olfactory function as an indicator of infection last year [4].
To simplify studies of these complicated senses, taste and smell are often examined independently of one another, even though these senses are usually experienced simultaneously.
“Smell is just — it’s so crucial to taste, which means it’s really crucial to everything that I do,” said Tejal Rao, a New York Times food critic, in a March episode of The Daily [5]. “And it’s really difficult to cook without a sense of smell if you’re not used to it. You don’t know what’s going on. It’s almost like wearing a blindfold.”
Rao, who lost her sense of smell in mid-January after contracting COVID-19, began to search for answers to this mystery from scientists. Rao’s journey started with TikTok “miracle cures” and other aromatherapies — unfortunately, they were too good to be true — but she eventually discovered the work of Dr. Pamela Dalton, a scientist at the Monell Chemical Senses Center in Philadelphia [6]. At the center, Dalton studies the emotions that are triggered by our sense of smell [7].
During simple colds or viral infections, smell is normally affected when the molecules in food and other aromas are physically blocked off from chemoreceptors in our nose by congestion. Scientists have also cited Alzheimer’s and Parkinson’s diseases, head trauma, and chemotherapy as triggers for anosmia [8]. But a separate phenomenon was occurring in the case of COVID-19.
“COVID is different in that way, because most people who lost their sense of smell did so without having any nasal congestion whatsoever,” Dalton told Rao during an interview.
One study published in October of last year by Dr. Nicolas Meunier, a French neuroscientist, aimed to investigate how the SARS-CoV-2 virus, which causes COVID-19, may disrupt sustentacular cells [9]. These structural cells express the ACE2 receptor, which the virus hijacks to gain entry into our cells, at higher levels [10]. Sustentacular cells support the specialized neurons that transmit signals from the nose to the brain.
When Meunier and his team at Paris-Saclay University in France infected hamsters with the virus, tiny hair-like projections known as cilia on the surfaces of olfactory neurons began to peel back from sustentacular cells. This disruption is a possible explanation for the difficulties with smell that COVID-19 patients experience.
If it is true that damage to sustentacular cells causes anosmia, loss of smell is not an irreversible brain condition. In this case, the poor connection between incoming odors and brain networks that typically process these stimuli is at fault, not direct damage to the brain itself. The sudden onset of smell loss in COVID-19 patients supports this thinking.
“It was just like a light bulb got turned off or a switch got flicked to off,” Dalton said. “And one moment they could smell. And the next moment, nothing smelled.”
But because olfactory support cells regularly regenerate, this loss of smell is only temporary, which allows for retraining of our senses. Two months of smell training, also known as olfactory training, allowed Rao to regain her sense of smell.
Olfactory training gradually exposes patients to particularly strong smells. Spices such as cinnamon or cumin, for example, were perfect for Rao’s first smell training session [5], and AbScent, a British charity offering support to patients with anosmia, sells kits with rose, lemon, and eucalyptus [8]. Scientists have found that recurring exposure to these strong scents gives the brain time to recalibrate its networks, a feature known as neuroplasticity [11].
But “you don’t just go from hurt to healed overnight,” Rao said. “It’s more like adjusting and learning how to live in a new space. That’s really just the beginning.”
Our chemical senses have the power to satisfy, to inspire, even to cause our memory to reveal itself, as 20th-century French author Marcel Proust observed in his seven-volume novel À la recherche du temps perdu, or In Search of Lost Time. Researchers have even speculated that our sense of smell can facilitate learning in other sensory domains, including vision [12].
While scientists further investigate how coronavirus causes loss of smell, olfactory training can provide an avenue in the meantime for COVID-19 patients to recover this crucial sense. Indeed, many patients are “in search of lost time,” and smell training can help them to once again experience food and wine in its sensory entirety.
References:
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- Lechien JR, Chiesa-Estomba CM, Beckers E, Mustin V, Ducarme M, Journe F, Marchant A, Jouffe L, Barillari MR, Cammaroto G, et al. 2021. Prevalence and 6-month recovery of olfactory dysfunction: a multicentre study of 1363 COVID-19 patients. J Intern Med. 290(2):451–461. https://doi.org/10.1111/joim.13209.
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- Rao T. 2021. Will Fish Sauce and Charred Oranges Return the World Covid Took From Me? New York (NY): New York Times; [accessed 28 July 2021]. https://www.nytimes.com/2021/03/02/dining/covid-loss-of-smell.html.
- What COVID 19 is teaching us about the importance of smell, with Pamela Dalton, PhD. 17 Mar 2021, 33:31 minutes. American Psychological Association; [accessed 28 July 2021]. https://youtu.be/0pG_U13XDog.
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- Bryche B, St Albin A, Murri S, Lacôte S, Pulido C, Ar Gouilh M, Lesellier S, Servat A, Wasniewski M, Picard-Meyer E, et al. 2020. Massive transient damage of the olfactory epithelium associated with infection of sustentacular cells by SARS-CoV-2 in golden Syrian hamsters. Brain Behav Immun. 89(2):579–586. https://doi.org/10.1016/j.bbi.2020.06.032.
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- Olofsson JK, Ekström I, Lindström J, Syrjänen E, Stigsdotter-Neely A, Nyberg L, Jonsson S, Larsson M. 2020. Smell-Based Memory Training: Evidence of Olfactory Learning and Transfer to the Visual Domain. Chem Senses. 45(7):593–600. https://doi.org/10.1093/chemse/bjaa049.
Transgender Health: Barriers to Healthcare and Physiological Differences
By Ana Nazmi Glosson, Neurobiology, Physiology & Behavior ‘21
Author’s Note: I initially wrote this literature review for UWP 104F in Winter 2020. I chose to focus on a topic that was, and is, very dear to me. I believe that readers would benefit from an overview of transgender specific health, as it is a subsection of science that is often unknown or overlooked. I wrote this while personally researching TGD healthcare and the availability of transitional therapies, and realizing firsthand the barriers to access, and lack of available information.
ABSTRACT
Transgender and gender diverse (TGD) individuals are people whose gender identity does not match the biological sex they were assigned at birth. Transgender is an umbrella term for many gender identities, and individuals may identify as male, female, or outside the gender binary. This population faces more barriers to healthcare access than cisgender individuals, or people whose gender identity does match their sex assigned at birth. Lack of access to knowledgeable healthcare providers, as well as provider bias, creates an environment of hostility for a TGD patient. Transgender people have unique health needs that healthcare professionals must be educated on in order to properly serve this community. Emerging literature is beginning to identify health concerns among transgender people who have undergone hormone replacement therapy (HRT) that may require specialized treatment and attention. This review attempts to answer the following question: What does current research tell us about barriers and educational gaps in healthcare of transgender individuals, and what physiological differences in this population, compared to cisgender individuals, make this research important? Further studies are essential to properly providing healthcare to this population.
Key Concepts: Transgender and gender diverse, hormone replacement therapy, culturally competent healthcare.
INTRODUCTION
Historically, TGD individuals have faced many barriers to healthcare access—and many of these barriers still exist [1-9]. This paper aims to review the specifics of these barriers and educational gaps. Current research suggests that a lack of education from physicians and provider biases against transgender people are primary reasons why transgender individuals—especially TGD youth— struggle to access safe and culturally component heathcare [3,5-7]. Transgender people are less likely to seek healthcare, and if they do seek it, they are less likely to receive proper, unbiased access with educated professionals [1,3]. This review also presents literature on unique physiological differences between transgender and cisgender individuals in order to properly express why clinical research is needed to increase baseline education [10-16]. The critical health differences between the TGD population and other groups means a team of doctors and specialists—primary care physician, gender specialist, surgeon, and endocrinologist—must collaborate to provide culturally competent care. TGD individuals may choose to medically transition and undergo gender-affirming therapies such as gender-affirming surgery (GAS) or hormone replacement therapy (HRT). Given the nature of this topic, it is important to note that much of the research in this review is from ground-breaking preliminary studies that have not yet been repeated with larger sample sizes beyond initial investigation.
DISCUSSION
Healthcare Access Among TGD Individuals
TGD individuals of all ages face challenges to healthcare on both a personal and institutional level. Increasing numbers of TGD people, including older adults, are openly living with their gender identity, meaning this is a critical area of research. TGD adults frequently struggle with insurance access; they are less likely to have insurance access compared to non-TGD LGBTQ+ individuals, and those that do have access are more likely to face healthcare discrimination [7,8]. One study found that individuals with Medicaid were more likely to be refused hormone replacement therapy, and more likely to lack a surgeon to perform gender-affirming surgery in their network, as compared to individuals with private insurance [7]. TGD adults who are part of other disadvantaged communities, such as being an ethnic minority or having lower socioeconomic status, face additional obstacles and higher levels of healthcare refusal [1,8]. Older LGBT adults are far more likely to have physical and mental health struggles than their non-LGBT counterparts, but older TDG adults are the most likely to have those struggles within the LGBT community [9,17]. Older TGD adults are more likely to live alone and have a community of “chosen family” instead of partners or children, which adds a layer of complexity to difficult end-of-life care decisions and increases senior care costs [9,17]. These circumstances show the need for thoughtful and individualized care for TDG individuals of all ages, necessitating competent and knowledgeable providers to navigate these sensitive topics.
Adolescence is a very stressful time in people’s lives, and recent literature shows that young TGD individuals are especially vulnerable [3,5,11]. Surveying the adolescent population directly allows researchers to analyze experiences and suggestions from youth to further improve healthcare. Currently, there is not much information on transgender youth, though the field of research has begun to grow rapidly in the past few years. In everyday life, TGD individuals are often misgendered or referred to as names that they do not identify with anymore. In the context of medical care, this leads to individuals being less likely to seek continuing care. Even without malicious intent, these actions may be incredibly damaging to the TGD individual. In a medical setting, misgendering patients may foster unspoken feelings of distrust and alienation between the patient and their doctors. This is critical because transgender individuals are less likely to continue seeking routine and specialized healthcare if they feel uncomfortable in the medical environment [2,3]. In order for healthcare professionals to serve this population, practices must be as friendly as possible. Requesting and consistently using the individual’s pronouns and preferred name is a critical first step [2-3,5]. Surveyed youth suggested that healthcare providers should ask all individuals these questions, instead of only those known or assumed to be LGBTQ+ [2]. This will lead to the subpopulation not being immediately singled out in a healthcare environment, as well as creating a welcoming space for patients who may not otherwise volunteer this information. Another suggestion was healthcare providers using gender-neutral decor in exam rooms [4]. In settings such as a gynecologist office, traditionally feminime or masculine imagery and furnishings can further alienate TGD individuals and reduce the likelihood of patient continuation. The language used in medical forms should be adjusted to encompass diverse gender expressions. Given the fact that many TGD individuals identify outside of the gender binary, medical records should allow patients to write in their identity rather than check one of two boxes [3]. The gender binary is essentially the rigid classification system of two genders, male or female, a system which is commonly rejected by members of the LGBTQ+ community and their allies. Since gender identity and the language that individuals use to express their personal sense of self is incredibly varied, giving patients more freedom to define and communicate their gender identity would allow them a greater sense of expression. This may also require reform of electronic healthcare systems to include this information, which is currently not common practice. In one study, the vast majority (79%) of TGD youth indicate they would appreciate the professional record of preferred name and pronouns [5].
A common method of surveying the adolescent population is in-depth interviews of a small sample size. These thorough accounts of real experiences are very useful, as researchers can gain a more holistic insight into the individual’s life and experiences. The downside of this research approach is the small sample size, which may lead to results that are not as applicable to larger audiences as would be the case with a larger sample size. In order to best reach this population, researchers target LGBTQ+ programs, but for many reasons, a large subset of the TGD population cannot safely participate in those programs, and therefore are not included in reviews such as this. Voices of closeted LGBTQ+ community members in general are rarely heard, meaning this subset of the population is almost always left out.
Research also suggests that preferences regarding the inclusion of gender identity information in medical records differ greatly if the patient is closeted or “out” [2]. There are factors that should be taken into account with medical records disclosing transgender identity. For instance, a TGD minor may privately disclose their gender identity or preferred pronouns to their healthcare provider. If this TGD youth was not “out” to their parents, and the healthcare provider made a note, their parents might find this while viewing their medical records. This could potentially be damaging or even dangerous to the patient, so healthcare providers should be careful with handling such delicate information. Additionally, TGD care—especially for patients that are in the process of transitioning—involves many aspects of healthcare; a team of culturally competent therapists, physicians, specialists, nurses, and staff must all be properly informed to contribute to a holistically supportive team.
Sexual Health Needs
Research into sexual health needs of young transgender people demonstrates TGD youth have unique sexual health needs that are not currently being met by their healthcare providers. Healthcare providers tend to be less knowledgeable about TGD-specific health issues, which differ from cisgender individuals [3,13,15]. Distinct aspects of TGD individuals include hormone replacement therapy (HRT), gender-affirming surgery (GAS), reversible puberty blockers, and same-sex STI transmission. Compared to previous generations, youth today are more likely to come out as transgender at a younger age, but many healthcare providers are not properly relaying healthcare information to their patients [3]. When providers fail to relay crucial information to their patients, it poses risk to the patients that could otherwise be avoided. For instance, a doctor who is unknowledgeable on STI transmission among two people that were assigned the same sex at birth, or even a doctor with personal prejudices against TGD patients, might not inform patients of essential sexual health information, thus putting the patients at higher risk. Sexual education information for teenagers is lacking, and this issue is amplified for TGD youth, many of whom receive absolutely no relevant information from professionals and alternatively turn to unvetted online sources. Healthcare providers need to stay up to date on the current literature for LGBTQ+ patients and have an obligation to confirm their patients receive adequate and age-appropriate information on topics of sexual health.
Transgender men or non-binary individuals who have been prescribed testosterone, a gender-affirming hormone replacement therapy, may suddenly experience an ovulatory event after a long period of time [15]. Testosterone can stop ovulation by suppressing the hypothalamic-pituitary-adrenal axis, but this research study is the first to show that after an extended period of time, such as several years, some individuals may “overcome” these suppressed hormones and suddenly ovulate [15]. This is important for healthcare professionals to be aware of because their patients may not be on contraceptives and will likely not expect this after suppressed ovulation. Unplanned pregnancy may result among patients who partake in sexual intercourse with sperm-producing individuals. Healthcare providers have an obligation to inform their patients of medical issues such as this, as pregnancy for a transitioning TGD individual can be an extremely emotionally stressful event, especially in the face of body and gender dysphoria.
An emerging branch of literature involves TGD patients and gynecological care. TGD patients are less likely to seek this type of care, and when they do, healthcare providers may have personal biases against treating transgender patients [4,6-7]. Transgender men or transmasculine individuals were found less likely to seek cervical cancer screenings, the main preventative test against cervical cancer. This is because of a variety of barriers on both a personal level and a wider institutional level. On a personal level, traumatic experiences with past healthcare, misgendering, and overall gender dysphoria contribute to transgender men not seeking cervical cancer screenings [4]. Institutionally, research suggests incompetent provider education is a primary barrier to accessing satisfactory healthcare. This leads to a reduced number of transgender men or transmasculine individuals continuing cervical cancer screening [4].. Healthcare professionals should focus on ways to retain transgender men as patients throughout their transition and changing gender identity, as well as providing culturally competent healthcare to this population.
In a study on gynecological health of transmasculine people, healthcare professionals were surveyed on their willingness to provide healthcare to TGD individuals. It was found that personal biases and attitudes against TGD individuals were the greatest barriers [6]. This contradicts other studies, which indicate healthcare providers’ lack of knowledge to be the biggest obstacle to accessing safe healthcare. Professional training should account for transphobic beliefs among healthcare professionals [6].
Much of the research on TGD populations are groundbreaking pilot studies, and conducting more large scale clinical studies and research is highly recommended for improving healthcare for transgender individuals [2,5,17]. Another recommendation is to standardize inclusive and informed education on transgender topics in medical school curricula and continuing education programs [3,5,8]. Informed and supportive healthcare professionals are absolutely vital in addressing health and continued patient retention among TGD individuals. More research must be done to determine the extent of additional training needed to properly serve this population.
HRT and Physiological Differences
Literature has begun to explore and emphasize that physiological differences exist between transgender individuals who are undergoing gender-affirming hormone replacement therapy (HRT) and cisgender individuals [11-17]. Hormone replacement therapy is suggested to be gender-affirming to a patient with gender dysphoria by helping their body match their preferred gender identity, and has been found to be correlated with better body- and self-perception, as well as lower sexual distress [13]. This is incredibly important in increasing the holistic wellness of a transgender patient. Limited available research suggests that transitioned TGD individuals are at greater risk for certain cardiovascular diseases, such as heart attacks, compared to the general population [16]. When researching the impact of HRT on adolescents, one pilot study found key body composition differences in regards to cardiovascular health, suggesting this population has unique cardiometabolic needs that differ from both cisgender males and cisgender females [11,16]. Similarly, in regards to resting state network, individuals on HRT were found to have “intermediate” levels of physiological values unique and distinct from cisgender male or female individuals [11,16]. For the purpose of this paper, we can think of resting state networks as networks and patterns of activity between spatially separated areas in the brain, which are helpful in analysing organization, when the brain is not processing a specific task.. This information is preliminary—and it is important to keep up with developing research—but it suggests the extreme importance of larger repeat studies. Questions for further research include long-term effects of HRT on adolescents. Additionally, research should be conducted on the distinct physiological values of individuals on HRT. In particular, do these values (the intermediate state) change the longer the individual is on HRT? If a patient were to stop HRT, would this “intermediate” state revert to values similar to their gender assigned at birth?
Another question to consider would be whether or not this intermediate state is reversible if the patient were to stop HRT for a period of time. However, such a question would bring up many ethical concerns for the psychological well-being of the study participants, as well as physical concerns of abruptly stopping medical therapy. One longitudinal pilot study found that transgender individuals on HRT had altered resting state functional connectivity in emotional, cognition, and sensorimotor ways after undergoing gender-affirming surgery [15]. These studies suggest that the brains of TGD individuals have the ability to form altered synaptic connections in a way that is different from cisgender people. Much more research is required in order to pinpoint any major connections and the implications of treating this population. These medical differences could be very important in areas such as proper drug dosage. Healthcare professionals must recognize these differences, and continue to push for more research to ensure transgender patients receive the competent care they need. Much of this research contributes to some sense of a gender binary, given that this “intermediate” state is defined as being between “the two” genders; furthermore, a TGD individual may not aspire to follow a binary gender, and providers should be thoughtful and individualized in the language they use with patients. The majority of these studies were composed of very few individuals. These results suggest that healthcare professionals must stay informed with research findings in order to keep their patients updated.
CONCLUSION
Transgender individuals face discrimination in everyday life, as well as in the medical world. This is a large problem because transgender patients have specific healthcare needs that differ from cisgender patients and must be approached and treated differently. Many of these studies are pilot studies and were only published in the last several years. Several recent studies have attempted to classify barriers transgender individuals face, specific health differences, and what steps healthcare providers need to be taking. As research in transgender healthcare continues, it is important to note that not all transgender people can be grouped under one umbrella. Subpopulations exist within the TGD community, each with their own healthcare concerns, physiological health differences, and types of care they seek and receive. In order to better treat these populations, healthcare professionals cannot treat every transgender person with identical care. This emerging research, especially on topics of physiological differences, should not be used to discourage TGD individuals from their necessary transitional therapies. Rather, a more comprehensive understanding should help healthcare providers give their patients stronger, evidence-backed information about their medical choices. In addition, there are barriers that this discussion barely touched on, such as cost, insurance issues, and overall accessibility. Many more studies are required to identify the best ways to combat transgender barriers to healthcare access in order to address the physiological differences between TGD and cisgender individuals.
References:
- Cicero EC, Reisner SL, Merwin EI, Humphreys JC, Silva SG. 2020. The health status of transgender and gender nonbinary adults in the United States. PLoS One [Internet]. 15(2):e0228765. doi: 10.1371/journal.pone.0228765
- Eisenberg ME, McMorris BJ, Rider GN, Gower AL, Coleman E. 2020. “It’s kind of hard to go to the doctor’s office if you’re hated there.” A call for gender-affirming care from transgender and gender diverse adolescents in the United States. Health Soc Care Community [Internet]. 28(3):1082-1089. doi: 10.1111/hsc.12941.
- Haley SG, Tordoff DM, Kantor AZ, Crouch JM, Ahrens KR. 2019. Sex Education for Transgender and Non-Binary Youth: Previous Experiences and Recommended Content. J Sex Med [Internet]. 16(11):1834-1848. doi: 10.1016/j.jsxm.2019.08.009.
- Johnson M, Wakefield C, Garthe K. 2020. Qualitative socioecological factors of cervical cancer screening use among transgender men. Prev Med Rep [Internet]. 17:101052. doi: 10.1016/j.pmedr.2020.101052.
- Sequeira GM, Kidd K, Coulter RWS, Miller E, Garofalo R, Ray KN. 2020. Affirming Transgender Youths’ Names and Pronouns in the Electronic Medical Record. JAMA Pediatr [Internet]. 174(5):501-503. doi: 10.1001/jamapediatrics.2019.6071.
- Shires DA, Prieto L, Woodford MR, Jaffee KD, Stroumsa D. 2019. Gynecologic Health Care Providers’ Willingness to Provide Routine Care and Papanicolaou Tests for Transmasculine Individuals. J Womens Health [Internet]. 28(11):1487-1492. doi: 10.1089/jwh.2018.7384.
- Bakko M, Kattari SK. 2020. Transgender-Related Insurance Denials as Barriers to Transgender Healthcare: Differences in Experience by Insurance Type. J Gen Intern Med [Internet]. 35(6):1693-1700. doi: 10.1007/s11606-020-05724-2.
- White Hughto JM, Murchison GR, Clark K, Pachankis JE, Reisner SL. 2016. Geographic and Individual Differences in Healthcare Access for U.S. Transgender Adults: A Multilevel Analysis. LGBT Health [Internet]. 3(6):424-433. doi: 10.1089/lgbt.2016.0044.
- Stinchcombe A, Smallbone J, Wilson K, Kortes-Miller K. 2017. Healthcare and End-of-Life Needs of Lesbian, Gay, Bisexual, and Transgender (LGBT) Older Adults: A Scoping Review. Geriatrics. [Internet]. 2(1):13. https://doi.org/10.3390/geriatrics2010013
- Clemens B, Junger J, Pauly K, Neulen J, Neuschaefer-Rube C, Frölich D, Mingoia G, Derntl B, Habel U. 2017. Male-to-female gender dysphoria: Gender-specific differences in resting-state networks. Brain Behav [Internet]. 7(5):e00691. doi: 10.1002/brb3.691.
- Nokoff NJ, Scarbro SL, Moreau KL, Zeitler P, Nadeau KJ, Juarez-Colunga E, Kelsey MM. 2020. Body composition and markers of cardiometabolic health in transgender youth compared to cisgender youth. J Clin Endocrinol Metab [Internet]. 105(3):704–714. doi: 10.1210/clinem/dgz029.
- Oda H, Kinoshita T. 2017. Efficacy of hormonal and mental treatments with MMPI in FtM individuals: cross-sectional and longitudinal studies. BMC Psychiatry [Internet]. 17(1):256. doi: 10.1186/s12888-017-1423-y.
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- Schneider MA, Spritzer PM, Minuzzi L, Frey BN, Syan SK, Fighera TM, Schwarz K, Costa ÂB, da Silva DC, Garcia CCG, Fontanari AMV, Real AG, Anes M, Castan JU, Cunegatto FR, Lobato MIR. 2019. Effects of Estradiol Therapy on Resting-State Functional Connectivity of Transgender Women After Gender-Affirming Related Gonadectomy. Front Neurosci [Internet]. 13:817. doi: 10.3389/fnins.2019.00817.
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Among Virions
By Jordan Chen, Biochemical Engineering ‘24
What are viruses? Miniscule packages of protein and genetic material, smaller than all but the smallest cells, relatively simple structures on the boundaries of what we consider living. Undetectable to the human eye, these invisible contagions are rarely on the minds of the average person, occupying a semantic space in public consciousness more often than they are understood for their material reality. Stories are more likely to be described as “viral” than an actual virus, yet when the COVID-19 pandemic washed over the world at the end of 2019, the public suddenly had to confront that which was seemingly abiotic, simple, and small. However, the impact of the COVID-19 pandemic exceeded that unassuming material reality. With the shuttering of the global economy, mass death, political crisis, confusion, hysteria, and science without immediate answers, it’s become clear that the sum of COVID-19’s viral components is much more than the whole.
To emphasize this idea in the piece, coronavirus virions are depicted as massive and detailed larger than earth bodies, in a vital bloody red, surrounding and overwhelming the relatively simply shaded globe. What was formerly small, simple, and nonliving, can now be dramatically understood as larger than life, having created complex predicaments, and having taken on a life of its own in its assault against the world. This digital artwork was created in Blender.
Psychedelics Herald New Era of Mental Health
By Macarena Cortina, Psychology ‘21
Author’s Note: As a psychology major who used to be a plant biology major, I’m very interested in the arenas where these two fields interact. Such is the case with psychoactive plants and fungi that produce significant alterations in brain chemistry and other aspects of the human psyche. That is why I chose to write about psychedelics and their rebirth in both research and culture. In the past few months, I have seen increasing media coverage of new scientific findings about these substances, as well as legal advancements in their decriminalization, making this a relevant topic in the worlds of psychology and ethnobotany. The history of psychedelics is a long and complicated one, but here I attempt to cover the basics in hopes of demystifying these new powerful therapeutic treatments and informing readers about the latest horizon in mental health.
After decades in the dark, psychedelic drugs are finally resurfacing in the world of science and medicine as potential new tools for mental health treatment. Psychedelics, otherwise known as hallucinogens, are a class of psychoactive substances that have the power to alter mood, perception, and cognitive functions in the human brain. They include drugs such as LSD, magic mushrooms, ayahuasca, MDMA, and peyote [1]. The US has a long and complex history with these drugs, and the resulting criminalization and stigma associated with them have kept psychedelics in the shadows for many years. However, a major shift in society’s opinions of psychedelics is taking place, and a reawakening is happening in the scientific community. Researchers from various disciplines are becoming increasingly interested in unlocking the therapeutic powers of these compounds, especially for those who are diagnosed with mental disorders and are resistant to the treatments that are currently available for them. Whether or not the world is ready for it, the psychedelic renaissance has begun.
Psychedelics have been used by Indigenous communities around the world as part of their cultural, spiritual, and healing traditions for thousands of years. In the Western world, psychedelics were rediscovered in the 1940s by Swiss chemist Albert Hofmann, who accidentally absorbed LSD through his skin while conducting tests for a potential medicine [2]. What followed was an “uninterrupted stream of fantastic pictures, extraordinary shapes, with intense, kaleidoscopic play of colors” [7]. Once LSD was disseminated throughout the world, psychologists began to experiment with it as a psychotomimetic, or a drug that mimics psychosis, in hopes of gaining a better understanding of schizophrenia and similar mental disorders [2, 3]. In the 1950s, as a result of the US government’s fear that communist nations were using mind control to brainwash US prisoners of war, the CIA carried out the top-secret project MK-Ultra, drugging even unwitting subjects with psychedelics in an attempt to learn about potential mind control techniques [4]. Recreational use of psychoactive substances proliferated in the counterculture movement of the 1960s, eventually leading to their criminalization and status as Schedule 1 drugs [5]. This classified them as substances with no medical value and a high potential for abuse—two descriptors we know are not factual [6].
Now, people seem to be reevaluating their outlook on these formerly demonized drugs and are instead looking for ways to harness psychedelics’ medicinal properties for mental and physical improvement. Momentum is building quickly. Clinical trials are beginning to show real potential in the use of psychedelics for the treatment of depression, anxiety, post-traumatic stress disorder (PTSD), addiction, eating disorders, and emotional suffering caused by diagnosis of a terminal illness. The US Food and Drug Administration (FDA) has already approved the use of ketamine for therapeutic purposes with MDMA and psilocybin set to follow [7]. Psilocybin has also been decriminalized in cities across the US and was completely legalized for medical use in the entire state of Oregon in November 2020. Entrepreneurs and investors are flocking to startups such as MAPS Public Benefit Corporation and Compass Pathways, which are currently developing psychedelic drugs for therapeutic application. Research centers have been cropping up across the country as well, even at prestigious institutions like John Hopkins School of Medicine and Massachusetts General Hospital.
So how do psychedelics work? In truth, scientists still don’t know exactly what happens to neural circuitry under the influence of these mind-altering drugs. While more research is required to fully understand how psychedelics affect the brain, there are some findings that help clarify this mystery. For example, the major group of psychedelics—called the “classic psychedelics”—closely resembles the neurotransmitter serotonin in terms of molecular structure [8]. This group includes psilocin, one of the important components of magic mushrooms; 5-MeO-DMT, which is present in a variety of plant species and at least one toad species; and LSD, also known as acid [8]. What they all have in common is a tryptamine structure, characterized by the presence of one six-atom ring linked to a five-atom ring [8]. This similarity lends itself to a strong affinity between these psychedelics and serotonin receptors in the cerebral cortex, particularly the receptor 5-HT2A [8]. The implication of this is that psychedelics can have a significant and widespread influence on brain chemistry, given that serotonin is one of the main neurotransmitters in the brain and plays a major role in mood regulation [9].
What follows is a poorly understood cascade of effects that causes disorganized activity across the brain [10]. At the same time, it seems that the brain’s default-mode network gets inhibited. British researcher Robin Carhart-Harris recently discovered this by dosing study participants with either psilocybin or LSD and examining their neural activity with the help of fMRI (functional magnetic resonance imaging). Rather than seeing what most people expected—an excitation of brain networks—Dr. Carhart-Harris found a decrease of neuronal firing in the brain, specifically in the default-mode network. According to Michael Pollan, author of the best-selling book on psychedelics How to Change Your Mind, this network is a “tightly linked set of structures connecting the prefrontal cortex to the posterior cingulate cortex to deeper, older centers of emotion and memory.” Its function appears to involve self-reflection, theory of mind, autobiographical memory, and other components that aid us in creating our identity. In other words, the ego—the conscious sense of self and thus the source of any self-destructive thoughts that may arise—seems to be localized in the default-mode network. This network is at the top of the hierarchy of brain function, meaning it regulates all other mental activity [10].
Therefore, when psychedelics enter the system and quiet the default-mode network, suddenly new and different neural pathways are free to connect, leading to a temporary rewiring of the brain [10]. In many cases, this disruption of normal brain functioning has reportedly resulted in mystical, spiritual, and highly meaningful experiences. Psychedelics facilitate neuroplasticity, thereby helping people break negative thinking patterns and showing them—even temporarily—that it’s possible to feel another way or view something from a different (and more positive) perspective.
This kind of experience can be immensely helpful to someone who is struggling with a mental health disorder and needs a brain reset. While other techniques, such as meditation and general mindfulness, can help cultivate a similar feeling, they require much more time and effort, something that is not always feasible—and never easy—for those who are severely struggling with their mental health [10]. Psychedelics can help jump-start the process of healing, and their effects can be made even more powerful and long-lasting when coupled with psychotherapy [11]. Talking with a psychiatrist or psychologist after the drug treatment can help integrate and solidify a client’s newly acquired thinking patterns [11].
In a study published in The New England Journal of Medicine in April 2021, researchers found that psilocybin works at least as well as leading antidepressant escitalopram [12]. In this double-blind, randomized, controlled trial, fifty-nine participants with moderate-to-severe depression took either psilocybin or escitalopram, along with a placebo pill in both cases. After six weeks, participants in both groups exhibited lower scores on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16), indicating an improvement in their condition. The difference in scores between the two groups was not statistically significant, meaning that a longer study with a larger sample size is still required to show if there is an advantage to treating depression with psilocybin over conventional drugs [12]. However, one notable difference was that psilocybin seems to take effect faster than escitalopram [13]. As an SSRI (selective serotonin reuptake inhibitor), escitalopram takes a couple months to work, something that’s not helpful for those with severe depression. Psilocybin, then, is suggested to provide more immediate relief to people battling depression [13].
In June 2020, a team of researchers at John Hopkins published a meta-analysis of nine clinical trials concerning psychedelic-assisted therapy for mental health conditions such as PTSD, end-of-life distress, depression, and social anxiety in adults with autism [14]. These were all the “randomized, placebo-controlled trials on psychedelic-assisted therapy published [in English] after 1993.” The psychedelics in question included LSD, psilocybin, ayahuasca, and MDMA. Following their statistical meta-analysis of these trials, they found that the “overall between-group effect size at the primary endpoint for psychedelic-assisted therapy compared to placebo was very large (Hedges g = 1.21). This effect size reflects an 80% probability that a randomly selected patient undergoing psychedelic-assisted therapy will have a better outcome than a randomly selected patient receiving a placebo” [14].
There were only minimal adverse effects reported from this kind of therapy and no documentation of serious adverse effects [14]. When compared to effect sizes of pharmacological agents and psychotherapy interventions, the effects of psychedelic-assisted therapy were larger, especially considering the fact that participants received the psychedelic substance one to three times prior to the primary endpoint, as opposed to daily or close-to-daily interventions with psychotherapy or conventional medications. Overall, results suggest that psychedelic-assisted therapy is effective—with minimal adverse effects—and presents a “promising new direction in mental health treatment” [14].
At UC Davis, researchers in the Olson Lab recently engineered a drug modeled after the psychedelic ibogaine [15]. This variant, called tabernanthalog (TBG), was designed to induce the therapeutic effects of ibogaine minus the toxicity or risk of cardiac arrhythmias that make consuming ibogaine less safe. TBG is a non-hallucinogenic, water-soluble compound that can be produced in merely one step. In an experiment performed with rodents, “tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behavior, and produce antidepressant-like effects.” These effects should be long lasting given that TBG has the ability to modify the neural circuitry related to addiction, making it a much better alternative to existing anti-addiction medications. And since the brain circuits involved in addiction overlap with those of conditions like depression, anxiety, and post-traumatic stress disorder, TBG could help treat various mental health issues [15].
As the psychedelic industry begins to emerge, members of the psychedelic community are voicing their concerns about the risks that come with rapid commercialization [7]. Biotech companies, researchers, and therapists should be careful about marketing psychedelics as a casual, quick fix to people’s problems. Psychedelics can occasion intense and profound experiences and should be consumed with the right mindset, setting, and guidance. There are still many unknowns about psychedelic use, especially its long-term effects. Not all individuals should try treatment with psychedelics, especially those with a personal or family history of psychosis. It will also be important to move forward in a way that is respectful to Indigenous traditions and accessible to all people—particularly people of color—without letting profit become the main priority. Some advocates worry that commercialization and adoption into a pharmaceutical model might strip psychedelics of their most powerful transformational benefits and that they will wind up being used merely for symptom resolution [7]. As long as psychedelics’ reintroduction to mainstream medicine is handled mindfully, the world may soon have a new avenue for effective mental health therapy that honors its Indigenous heritage and is accessible to all.
References:
- Alcohol & Drug Foundation. Psychedelics. October 7, 2020. Available from https://adf.org.au/drug-facts/psychedelics/.
- Williams L. 1999. Human Psychedelic Research: A Historical And Sociological Analysis. Cambridge University: Multidisciplinary Association for Psychedelic Studies.
- Sessa B. 2006. From Sacred Plants to Psychotherapy:The History and Re-Emergence of Psychedelics in Medicine. Royal College of Psychiatrists.
- History. MK-Ultra. June 16, 2017. Available from https://www.history.com/topics/us-government/history-of-mk-ultra.
- Beres D. Psychedelic Spotlight. Why Are Psychedelics Illegal? October 13, 2020. Available from https://psychedelicspotlight.com/why-are-psychedelics-illegal/.
- United States Drug Enforcement Administration. Drug Scheduling. Available from https://www.dea.gov/drug-information/drug-scheduling.
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- Pollan M. How to Change Your Mind: What the New Science of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression, and Transcendence. New York: Penguin Press; 2018.
- Bancos I. Hormone Health Network. What is Serotonin? December 2018. Available from https://www.hormone.org/your-health-and-hormones/glands-and-hormones-a-to-z/hormones/serotonin#:~:text=Serotonin%20is%20the%20key%20hormone, sleeping%2C%20eating%2C%20and%20digestion.
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