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Human Cryopreservation: An Opportunity for Rejuvenation
By Barry Nguyen, Biochemistry & Molecular Biology ‘23
Author’s Note: I became interested in ways to bypass built-in lifespans after taking HDE 117, a longevity class with Dr. James Carey. During the course of the class, I was exposed to many different ways to extend the human lifespan. However, I was most interested in cryogenics and its prospects of human rejuvenation, prompting me to explore the possibilities of human cryopreservation.
Summary
This paper is focused on exploring the prospects of human cryopreservation. The first section discusses cryogenics and its relevance in the discussion of human cryopreservation. The following section utilizes empirical modeling to support the relationship between temperature and reaction rates. Next, the paper discusses the cryopreservation procedure itself and explores how the definition of death can be reimagined. We then transition to discussing cryopreservation’s possibility for rejuvenation. Specifically, we redefine the definition of aging itself and discuss aging phenomena on the molecular scale and use both of these as a basis for the discussion of immortality. The succeeding section is concerned with the limitations of human cryopreservation. Finally, the paper concludes with a brief discussion of the possible future of cryogenic technology.
Cryogenics
Cryogenics is a field of study focused on material behaviors at very low temperatures, ranging from -150°C to -273°C. At these extremely low temperatures, chemical properties are altered, and molecular interactions are halted [1]. By halted, it is not correct to say that all molecular interactions have been stopped. Rather, the molecular interactions have come as close to theoretically possible to ceasing and are at the lowest possible energy state. At these temperatures, chemical properties are also altered and unique phenomena emerge, allowing for extensive applications, most notably human cryopreservation. Because heat is related to the motion of particles, at these temperatures the biochemical activities within living systems are effectively reduced [9]. The prospects for preserving an individual at extremely cold temperatures have been increasing throughout the years as research within the field continues to develop. As of now, human cryopreservation seems more of a speculation than reality. Freezing an individual is one thing, but there is no guarantee that the individual will wake up from such an extensive period of suspension. Although extremely low temperatures serve as an appropriate basis for human cryopreservation, many more factors must be considered to avoid consequences that may occur during the procedure and after revival.
Empirical Modeling
The rates of biochemical processes at extremely low temperatures can be modeled mathematically [4]. The Arrhenius equation, proposed by Arrhenius in 1889, establishes a relationship between temperature and reaction rates. In figure 1, K is the reaction rate, Ea is the activation energy, A is the frequency factor (related to the orientations of molecules necessary to produce a favorable reaction), R is the universal gas constant, and T is the temperature. Manipulating the equation, we produce a form that directly shows the relationship between the reaction rate and temperature, as depicted in Figure 2. We will use the enzyme lactate dehydrogenase to illustrate the relationship between K and T [4]. With its activation energy defined as 54, 810 J/mol, we can explore the enzyme’s reaction rate at a 10°C difference. With T1 and T2 at 40°C and 30°C respectively, we get a reaction rate ratio of 2.004. This tells us that a 10°C difference is enough to cut the reaction rate of the enzyme exactly in half.
The relationship between reaction rates and temperature, as expressed by the Arrhenius equation, lends weight to the viability of cryopreservation. If a 10°C difference is enough to cut a reaction rate in half, imagine how much the reaction rate would be reduced within cryonically preserved individuals at extremely low temperatures. Furthermore, the biochemical processes that are occurring in the body at these levels are paused—not in the sense of being physically stopped, but rather the time needed for the processes to go to completion is relatively infinite.
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| Figure 1. The Arrhenius equation | Figure 2. Manipulation of the Arrhenius equation to compare reaction rates at two different temperatures |
Human Cryopreservation
By understanding that at these extremely low temperatures, biochemical reaction rates are suppressed, the practice of cryogenically preserving a whole individual became a reality [14]. For this process to begin, the individual must be induced in the death state. Once an individual enters the initial stages of death, the human body initiates its decomposition phase. The body’s cell walls begin to break down and in turn, release digestive enzymes that process the tissues in the body [11]. Because the body begins to break down at such a rapid pace, it is imperative that the patient, once induced in the death stage, be worked on immediately.
The process of chilling the human body to extremely low temperatures is a delicate and slow process and is very important in the initial steps of the cryopreservation procedure. Once the patient arrives in the death state, the circulation and respiration of the cryonic subject is restored and they are ready to be cooled [4]. First, the subject’s blood is replaced with 10% cryoprotectants to prevent ice formation. A small percentage of cryoprotectants are added initially to avoid an elevated osmotic shrinking response. Once the intracellular and extracellular cryoprotectant volume reaches equilibrium, the cells are ready for cooling which is done at a very slow pace (1°C/min) [5].
The cryoprotectant used typically consists of nutritional salts, buffers, osmogens, and apoptosis inhibitors, ingredients necessary in the maintenance of isotonic concentrations of the cell [5]. In doing so, cells within the human body can avoid swelling and shrinking. Additionally, another key formulation of cryoprotectant mixture is non-penetrating cryoprotectants which are typically large molecular polymers. These play a large part in the inhibition of ice growth and prevention of injury due to being subjected to the extreme cold [5].
To understand the prospects of human cryopreservation, it is helpful to redirect ourselves back to the definition of death. In 1988, the scientific community reviewed and redefined the definition of death from being in cardio-respiratory arrest to brain death [8]. In cryonically preserved patients, the extremely cold temperatures are thought to preserve the neural structures, which store long-term memory and the identity of the person. In this way, utilizing extremely low temperatures to preserve neural structures and prevent them from being compromised is a prospect worth noting. Individuals who are cryonically preserved should not be viewed as being dead or alive, but rather be viewed as being temporarily suspended in time [8]. The normal cycles of biological processes such as growth and decay are paused, providing an opportunity for resuscitation and reanimation in the future [10]. To give a new perspective, cryopreservation can be viewed similarly to frozen embryos: just as embryos preserved in extremely cold temperatures gain life once implanted in a uterus, the cryopreserved patient may reenter the living state through the process of human reanimation.
Prospects for Immortality
The process of human cryopreservation aims to allow individuals to escape imminent death by first being induced into a transient death state [8]. Essentially, individuals are given the opportunity to bypass human mortality. Dr. James Hiram Bedford, a former psychology professor at UC Berkeley had his life threatened by renal cancer. He decided to undergo the cryopreservation process and became the first human to be cryonically preserved in 1967 [13]. By agreeing to enter this process, he hoped that, in the future, technology would be advanced enough to revive him and cure his illness. Ever since interests in cryopreservation have increased substantially, and as of 2014, about 250 corpses have been cryogenically preserved in the US [13].
Shifting Views on Aging
Aging is a degradative process that entails a whole array of pathologies. If we were to view aging as a disease itself that can be treated, cryopreservation opens a wide range of possibilities. Specifically, the process of cryopreservation allows an individual to avoid the effects of aging pathologies by having the opportunity to be treated once technology has advanced enough. This provides hope to bypass the mechanically built-in lifespans of humans, and essentially, provides prospects for immortality.
On a larger scale, as we age, the probability of dying increases significantly [7]. To put it simply, as we age, there are more health factors in place to compete for our lives and the chance of survival through older ages decreases. In such cases, aging can be correlated with functional decline. Similarly, on the molecular scale, aging can be seen as a direct consequence of telomere shortening [6]. Telomeres are nucleoprotein structures that exist at the ends of chromosomes and are essential to the integrity of our DNA. During the process of DNA replication, telomeres protect the ends of chromosomes and prevent loss of genetic information [16]. However, as we age, and as our body continues to undergo DNA replication, the telomeres shorten leading to the joining of ends of various chromosomes, pathological cell division, genomic instability and apoptosis.
In short, the health consequences that come with aging are inevitable but human cryopreservation can be seen to offset these inevitable aging phenomena. The process allows an individual who is suffering from a presently incurable disease to be temporarily frozen in time. In this way, they may be revived when society is advanced enough to deal with the disease successfully. In essence, the human cryopreservation process can be seen to bypass inevitable health consequences, providing rejuvenating possibilities for any individual.
Technological Limitations
Although successfully preserving an individual through extreme temperatures is certainly an exciting prospect, little evidence exists to indicate that successful preservation and remanimation is possible [15]. At present, there are many challenges that need to be overcome to even support the viability of such an extensive process. According to Professor Armitage, the director of tissue banking at the University of Bristol, preserving the whole human body is an entirely new challenge [15]. Society is not even at the stage of cryopreserving organs. Organs, alone, are very complex, containing different types of cells and blood vessels that all need to be preserved. Similarly, Barry Fuller, another professor at the University of College London, has stated that before exploring the prospects of human cryopreservation, society must be able to demonstrate that human organs can be cryopreserved for transplantation [15]. Hence, as of current, there is close to zero evidence that a whole human body can survive cryopreservation.
In the previous section, we discussed the arrhenius equation which derived the relationship between temperature and metabolic rates. However, the equation itself does not explore the consequences of raising the temperature of the human body during reanimation. While thawing, the frozen tissues and cells can experience physical disruptions which can damage them [3]. To a greater extent, an individual’s epigenetic markers can even be affected, causing epigenetic reprogramming, which can change the expression of certain genes. However, the biggest hurdle is the successful preservation of the brain. The human brain is arguably one of the most important organs in the body, and cryopreservation must be successful in preserving the integrity of the neural structures. Prospects of successfully cryopreserving whole human brains are slim due to minimal research. Moreover, experiments with frozen whole animals’ brains have not been reported since the 1970s [3]. Obviously, research on this matter is severely limited.
Discussion
Despite the overwhelming uncertainties surrounding human cryopreservation and society’s current limits, the prospects of being able to defy death or possibly avoiding it in the future are becoming a topic of increasing interest. When an individual is brought to the brink of death, the uncertainties around the cryopreservation procedure, specifically its unproven track record of success, seem inconsequential in the long run. If society were to overlook the field of preservation based purely on unsubstantiated results and the unlikelihood of success, advancements would never occur. All in all, the increase in technological advancements and research within cryogenics is making the prospects of reviving a frozen individual in the future ever so likely.
References:
- Britannica, T. Editors of Encyclopaedia. “Cryogenics.” Encyclopedia Britannica, May 26, 2017. https://www.britannica.com/science/cryogenics.
- “What Is Cryogenics? “Gaslab.com. Accessed May 2, 2021. https://gaslab.com/blogs/articles/what-is-cryogenics.
- Stolzing, Alexandra . “Will We Ever Be Able to Bring Cryogenically Frozen Corpses Back to Life? A Cryobiologist Explains.” The Conversation, March 26, 2019. https://theconversation.com/will-we-ever-be-able-to-bring-cryogenically-frozen-corpses-back-to-life-a-cryobiologist-explains-69500.
- Best, Benjamin P. “Scientific Justification of Cryonics Practice.” Rejuvenation Research 11, no. 2 (2008): 493–503. https://doi.org/10.1089/rej.2008.0661.
- Bhattacharya, Sankha. “Cryoprotectants and Their Usage in Cryopreservation Process.” Cryopreservation Biotechnology in Biomedical and Biological Sciences, 2018. https://doi.org/10.5772/intechopen.80477.
- Blasco, M. A. “Telomere length, Stem Cells and Aging.” Nature Chemical Biology, 3, no.10 (September 2007): 640–649. doi:10.1038/nchembio.2007.38
- Carey, J.R. 2020, June 13. Limits of morbidity compression. Longevity (HDE/ENT 117) lecture notes, UC Davis.
- Cohen, C. “Bioethicists Must Rethink the Concept of Death: the Idea of Brain Death Is Not Appropriate for Cryopreservation.” Clinics 67, no. 2 (2012): 93–94. https://doi.org/10.6061/clinics/2012(02)01.
- Jang, Tae Hoon, Sung Choel Park, Ji Hyun Yang, Jung Yoon Kim, Jae Hong Seok, Ui Seo Park, Chang Won Choi, Sung Ryul Lee, and Jin Han. “Cryopreservation and Its Clinical Applications.” Integrative Medicine Research 6, no. 1 (2017): 12–18. https://doi.org/10.1016/j.imr.2016.12.001.
- Lemke, Thomas.“Beyond Life and Death. Investigating Cryopreservation Practices in Contemporary Societies,” Soziologie, 48. No. 4 (April 2019):450-466.
- Lorraine. “The Stages of Human Decomposition.” Georgia Clean Services.” Georgia Clean, April 6, 2020. https://www.georgiaclean.com/the-stages-of-human-decomposition/.
- Luke Davis. “The Difference between Cryonics and Cryogenics,” August 10, 2020. https://logicface.co.uk/difference-between-cryonics-and-cryogenics/.
- Moen, Ole Martin. “The Case for Cryonics.” Journal of Medical Ethics 41, no. 8 (2015): 677–81. https://doi.org/10.1136/medethics-2015-102715.
- Purtill, Corinne. “Fifty Years Frozen: The World’s First Cryonically Preserved Human’s Disturbing Journey to Immortality.” Quartz. Quartz. Accessed May 2, 2021. https://qz.com/883524/fifty-years-frozen-the-worlds-first-cryonically-preserved-humans-disturbing-journey-to-immortality/.
- Roxby, Philippa. “What Does Cryopreservation Do to Human Bodies?” BBC News. BBC, November 18, 2016. https://www.bbc.com/news/health-38019392.
- Trybek, Tomasz, Artur Kowalik, Stanisław Góźdź, and Aldona Kowalska. “Telomeres and Telomerase in Oncogenesis (Review).” Oncology Letters 20, no. 2 (2020): 1015–27. https://doi.org/10.3892/ol.2020.11659.
Unnoticed Adverse Childhood Experiences in COVID-19
By Vishwanath Prathikanti, Political Science ‘23
Author’s Note: While doing research for a paper on the mental decline in adults during the pandemic, I discovered something alarming occurring in younger people. While young adults are still the most susceptible to acquire depression in the pandemic, an unprecedented number of K-12 students were as well. Furthermore, K-12 students facing parental abuse were not being recognized as often as before due to the new virtual learning environment they are in. In this paper, I identify what this can lead to, and why we should be doing a better job protecting our younger students.
As college students, we often take for granted the fact that, if we do not have a positive relationship with our parents, many of us can live on campus during the pandemic. Children do not have this luxury, and in fact, the pandemic has made the threat of child abuse arguably even more dangerous.
Part 1: Adverse Childhood Experiences and their effect on the biological development of adolescents.
An Adverse Childhood Experience (ACE) can be any traumatic experience in a child’s life from the ages of 0-17, ranging from the death of a family member to abuse or neglect [1]. ACE’s are relatively common in the US, with around 61% of adults reporting to have experienced some form of an ACE in their lifetime [1]. Apart from the psychological damage, chronic stress caused by ACE’s has a number of harmful effects on a biological level, including a weakened immune system, which can result in premature death [2].
First and foremost, ACE’s cause a fear response in multiple parts of the brain; the amygdala mediates the response, the prefrontal cortex is involved with the cognitive response, and the hypothalamic-pituitary-adrenal (HPA) axis is critical in the stress response [3]. In a developing brain, extra stressors can cause dysregulation of the HPA system, which inhibits hippocampal neurogenesis, or the growth of new neurons [3]. These stressors have been found to cause cognitive defects in children resulting in lower attention span, lower scores in problem-solving, and lower scores on the California Verbal Learning Test long delay-free recall, which tests learning and memory [4]. Children who suffer from these stressors are often diagnosed with PTSD as a result of the ACE.
Part 2: How COVID-19 makes these situations more difficult to notice and likely more frequent
An important fact to note is that child abuse is more likely to occur in households with parentswho are chronically stressed or have mental illnesses such as depression [1]. COVID-19 has seen a general rise in mental illnesses and general stress across the world, with one study reporting a rise in depression from 14.6 percent to 48.3 percent and stress increasing from 8.1 percent to 81.9 percent [5]. Unsurprisingly, experts are concerned that this has resulted in a surge in domestic abuse. It is important to note is that while reports of child abuse have gone down by 20-70 percent (depending on the area), it is very likely that this is because the primary reporters were teachers, doctors, and social workers who had higher access to children before the pandemic [6, 7]. Furthermore, while the visits themselves have decreased, visits that result in hospitalization increased from 2.1 to 3.2 percent, suggesting that injury severity is getting worse [6].
Normally, teachers are one of the most important ways of identifying and reporting child abuse. Rashes and bruises are easily identifiable by teachers when a child is at school for the majority of the day. On the less physical side of things, when a student is distressed or is showing signs of poor mental health, such as inattentiveness or stress, teachers will address it with a personal conversation with the student. However, it is much more difficult to observe these signs of abuse over online platforms, such as Zoom. Rashes and bruises are much harder to detect due to limited to no visibility of a child’s body, and when students mute themselves or turn off their camera, it is extremely difficult to gauge attention and recognize when there is a problem. The zoom format of group meetings is also naturally less conducive to one-on-one meetings with teachers and students that would normally be very flexible and easy to conduct in person.
Dr. Kevin Gee from the UC Davis School of Education spoke about K-12 education and dealing with the challenges COVID has posed for this age group during a UC Davis live event. According to Gee, the more support schools can provide to kids the better. “I know of schools that did one-on-one home visits; socially distanced with masks just to check in on how kids are doing,” Gee said [8]. Gee went on to further explain how schools often have many strategies for recovering “academic learning losses, but we still don’t know a lot about how one goes about recovering socio-emotional losses that have been incurred over the past year and a half” [8].
Part 3: Implications for adults
In abuse-related PTSD specifically, adults have been shown to have smaller hippocampal volumes after experiencing an ACE followed by chronic stressors [3, 9]. This smaller volume results in a myriad of memory-related effects. The most significant were deficits in verbal short-term memory, or the ability to remember words that were just spoken, and a failure to activate the hippocampus during memory tasks, leading to poor memory or the inability to make new memories [3]. This reduction in volume can be seen in the other aspects of the brain that contribute to a fear response, including the prefrontal and frontal cortices, cerebellum, and corpus callosum [3]. Neuronal survival and synaptic connectivity generally decreased, resulting in abnormalities in brain structure, possibly leading to psychotic disorders such as schizophrenia and bipolar disorder [10, 11].
The implications of this data are grim, indicating that COVID-19 may produce a generation suffering from mental illness brought on by ACE’s on a scale never before seen. With no way of knowing exactly how many children are affected, it is crucial to focus on preventing abuse rather than intervening when signs appear. This shift can be seen in the passing of the Family First Prevention Services Act of 2018, which is still being updated and improved today. The act focuses on giving states the option to spend money on “prevention services that would allow ‘candidates for foster care’ to stay with their parents or relatives” given the candidates create a “written, trauma-informed prevention plan” that is evidence-based [12]. So far the process for actually implementing these changes has been slow, and not all states have approved the reimbursement of medical charges for families [13]. It’s a relatively small step, and many more must be made to prevent a rise in ACE’s and the health detriments that accompany them in COVID-19.
References:
- “Adverse Childhood Experiences” CDC. https://www.cdc.gov/violenceprevention/aces/fastfact.html#:~:text=Adverse%20 childhood%20experiences%2C%20or%20ACEs,in%20the%20home%20or%20community
- Bellis et al. “Adverse childhood experiences and sources of childhood resilience: a retrospective study of their combined relationships with child health and educational attendance.” BMC Public Health. 2018; 18: 792. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020215/#CR2
- Anda, et al. “The enduring effects of abuse and related adverse experiences in childhood” Eur Arch Psychiatry Clin Neurosci. 2006 Apr; 256(3): 174–186. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232061/
- Beers, Sue R. and De Bellis, Michael D. “Neuropsychological Function in Children With Maltreatment-Related Posttraumatic Stress Disorder.” The American Journal of Psychiatry. March 2002. 159(3): 483-486. https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.159.3.483
- Xiong, J. et al. “Impact of COVID-19 pandemic on mental health in the general population: A systematic review.” Journal of Affective Disorders. December 2020. 277(1): 55-64. https://www.sciencedirect.com/science/article/pii/S0165032720325891
- “Trends in U.S. Emergency Department Visits Related to Suspected or Confirmed Child Abuse and Neglect Among Children and Adolescents Aged <18 Years Before and During the COVID-19 Pandemic — United States, January 2019–September 2020” CDC. https://www.cdc.gov/mmwr/volumes/69/wr/mm6949a1.htm#:~:text=During%20the% 20COVID%2D19%20pandemic%2C%20the%20total%20number%20of%20emergency, hospitalization%20increased%2C%20compared%20with%202019.
- Eberman, Sarah. “Identifying and Addressing Child Abuse During the Coronavirus Pandemic.” Hackensack Meridian Health. April 23, 2020. https://www.hackensackmeridianhealth.org/HealthU/2020/04/23/identifying-and-addressing-child-abuse-during-the-coronavirus-pandemic/
- “UC Davis LIVE: Covid’s Impact on Education” https://m.facebook.com/events/2815426028773876
- Bremner, J.Douglas. “Long-term effects of childhood abuse on brain and neurobiology.” Child and Adolescent Psychiatric Clinics of North America. April 2003. 12(2): 271-292. https://www.sciencedirect.com/science/article/abs/pii/S1056499302000986?via%3Dihub
- Read, J. et al. “The contribution of early traumatic events to schizophrenia in some patients: a traumagenic neurodevelopmental model.” Psychiatry. Winter 2001;64(4):319-45. https://pubmed.ncbi.nlm.nih.gov/11822210/
- Aas, et al. “The role of childhood trauma in bipolar disorders.” Int J Bipolar Disord. 2016; 4: 2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712184/#:~:text=Childhood%20 traumatic%20events%20are%20risk,suicide%20attempt%20and%20substance%20misuse).
- National Conference of State Legislatures. “Family First Prevention Services Act.” Accessed 4/12/2021. https://www.ncsl.org/research/human-services/family-first-prevention-services-act-ffpsa.aspx
- National Conference of State Legislatures. “Family First Legislation.” Accessed 4/12/2021. https://www.ncsl.org/research/human-services/family-first-updates-and-new-legislation.aspx
- Centers for Disease Control and Prevention. “Data Visualizations: Adverse Childhood Experiences (ACEs).” Accessed 5/18/21. https://www.cdc.gov/vitalsigns/aces/data-visualization.html#info2
It’s Not You, It’s Your Microbes: The Association Between Microbiota and Depressive Behavior in Mice
By Reshma Kolala, Medical & Molecular Microbiology ‘22
Author’s Note: A recent switch into the Microbiology major prompted me to explore recent developments in the field. I came across this study that examined the role of gut microbiota in brain function and mood regulation. With the globally rising prevalence of depression, this study provides some potential insight into the development of the disorder on a physiological level and provides a novel approach to anti-depression therapeutics.
Afflicting nearly 350 million individuals annually, depression is a leading cause of disability worldwide. Despite the widespread effort to uncover the environmental and genetic basis of the disorder, the pathophysiology of depression remains elusive. This is attributed to the fact that, similar to other mental disorders, depression is the result of a complex interplay between several biological and societal factors [1]. Several studies have found that the pathology of depression is influenced by dysfunction in neuromodulatory systems, such as the endocannabinoid system (ECS). The ECS is composed of endocannabinoids (eCB), lipid-based neurotransmitters that regulate mood, emotions, and stress responses [2,3]. Another physiological factor that contributes to depression is the impairment of the hippocampal region of the brain, specifically hippocampal impaired neurogenesis, which contributes to depressive-like behaviors in rodents [4]. This is due to the fact that adult hippocampal neurogenesis has been shown to help mediate stress responses and depressive behavior. The dysfunction of these critical processes has recently been investigated in relation to symbiotic microbiota.
It has been well established that the diversity of intestinal microbiota contributes to enhanced host function (particularly in immunity, metabolism, and the central nervous system) allowing an individual to better combat disease and regulate metabolic function [5,6,7]. Previous studies have demonstrated that dysbiosis, or altered intestinal microbial composition, has been found in depressed patients when compared to healthy controls [8]. It has also been observed that microbiota modulate anxiety symptoms in mice via the release of bacterial metabolites that may affect critical pathways in the brain [9]. Finally, colitis, a digestive disease characterized by inflammation in the colon, is influenced by gut microbiota and is commonly observed in depression patients [10]. Overall, these studies imply a potential association between intestinal microbial composition and depressive-like behaviors. The following study aims to examine the direct effect of gut microbiota on depressive behaviors in mice, allowing for a broader understanding of the physiological basis of depression and provide new avenues for therapeutics and potential treatment [11].
Researchers used unpredictable chronic mild stress (UCMS), a mouse model of stress-induced depression. To simulate stress, mice in the UCMS group were exposed to various stressors including cage tilting, altered cage bedding, foreign odor, and altered light/dark cycle. The mice in the UCMS group were exposed to two stressors a day for eight weeks. As expected, UCMS mice exhibited depressive-like behaviors such as decreased feeding and self-grooming behavior, consistent with apathetic behavior in those diagnosed with depression. UCMS mice also exhibited reduced hippocampal neurogenesis, confirming a previous study by Snyder et al. that noted this observation in rodents with depression [3].
Once depressive-like behaviors were established in UCMS mice, researchers conducted a fecal microbiota transplant (FMT) from mice exposed to stressors to mice that have not been exposed to any stressors. FMT’s are an innovative form of treatment in which a stool sample is collected from one individual and transplanted in the colon of another individual. This can be administered in various ways, such as a colonoscopy, oral capsules, or via a tube that stretches from the nose into the stomach or bowel [12]. In this study, mice received transplants via an oral gavage which involves the passage of a feeding needle down the esophagus. The purpose of an FMT is to populate the recipient intestine with diverse microorganisms that preferentially provide some benefit to the host. When the microbiota from the UCMS mice was transplanted into the healthy mice, the healthy mice exhibited decreased hippocampal neurogenesis and mimicked the depressive-like behaviors exhibited in the UCMS mice, although the healthy mice had not been exposed to any stressors.
The effect of the FMT on recipient mice illustrated the influence of intestinal microbial composition on the host. Researchers in this study hypothesized that this was due to alterations in the host’s metabolism. To investigate this further, the concentration of multiple small molecule metabolites in bodily fluids was measured. This revealed a significant decrease in levels of several short-chain fatty acids which may have resulted from dysbiosis-induced changes. As fat is primarily broken down in the small intestine via chemical and mechanical processes, an altered microbial composition in the intestinal tract would unsurprisingly influence fat breakdown. More specifically, there was a decrease in the concentration of an eCB precursor, fatty acids containing arachidonic acid (AA), in recipient mice. As dysregulation of the ECS has been studied in association with depression, this finding in recipient mice aligns with the typical model of depression. To further understand the role of impaired eCB signaling in the recipient mice, researchers observed whether enhancing eCB signaling via dietary supplementation could alleviate the depressive-like behaviors observed in the recipient mice. It was found that recipient mice that were orally administered AA had reversed the depressive-like behaviors indeed by UCMS microbiota. Additionally, AA supplementation aided hippocampal neurogenesis.
To determine how UCMS microbiota affected the microbial composition of recipient mice, fecal microbiota from UCMS mice was sequenced using 16s rRNA. As 16s rRNA is present in all bacteria, the 16s rRNA gene is highly conserved and therefore, a useful tool to identify microbes within complex biological mixtures. The analysis revealed increased levels of Ruminoccacaae and Porphyromonodaceae and a decrease in Lactobacillacae. This finding supports previous studies that report an association between decreased Lactobacillacae and stress in mice. The differences in the microbial composition of recipient mice and donor UCMS mice were maintained eight weeks after transplantation. To test the influence of decreased Lactobacillacae in recipient mice, Lactobacillacae was orally administered similarly to AA supplantation. Dietary complementation of Lactobacillacae had a similar effect as AA supplantation, where depressive-like behaviors and impaired hippocampal neurogenesis were reversed.
Using mice, researchers discovered that the onset of depressive-like behaviors is triggered by a reduction in lipid metabolites. These lipid metabolites, more specifically endocannabinoids, bind to receptors in regions of the brain that control emotion and memory. Surprisingly, the concentrations of endocannabinoids are biochemically influenced by the gut microbiota. Although the mechanism by which this occurs has yet to be understood, these studies have elucidated the impact of gut microbiota beyond digestive function, revealing the extensive scope of microbial composition on healthy host function. This study specifically illustrates the importance of balanced gut microbiota for healthy neural and metabolic function and supports the potential use of dietary or probiotic supplementation as a treatment option for those diagnosed with depression. However, it is important to note that this area of research is relatively new and further studies are required to determine the translational capacity of studies related to the gut-brain axis from mice to humans. With consideration of the limitations of this study, this finding does still provide an intriguing avenue of treatment for mood disorders by introducing a novel physiological approach to mediate depressive-like symptoms.
References
- Limbana, T., Khan, F., & Eskander, N. (2020). Gut Microbiome and Depression: How Microbes Affect the Way We Think. Cureus, 12(8). https://doi.org/10.7759/cureus.9966
- Hill, M. N., Hillard, C. J., Bambico, F. R., Patel, S., Gorzalka, B. B., & Gobbi, G. (2009). The therapeutic potential of the endocannabinoid system for the development of a novel class of antidepressants. Trends in pharmacological sciences, 30(9): 484–493. https://doi.org/10.1016/j.tips.2009.06.006
- Freitas, H. R., Ferreira, G., Trevenzoli, I. H., Oliveira, K. J., & de Melo Reis, R. A. (2017). Fatty Acids, Antioxidants and Physical Activity in Brain Aging. Nutrients, 9(11): 1263. https://doi.org/10.3390/nu9111263
- Snyder, J., Soumier, A., Brewer, M. et al. (2011) Adult hippocampal neurogenesis buffers stress responses and depressive behavior. Nature 476: 458–461. https://doi.org/10.1038/nature10287
- Belkaid, Y., & Hand, T. W. (2014). Role of the microbiota in immunity and inflammation. Cell, 157(1), 121–141. https://doi.org/10.1016/j.cell.2014.03.011
- Cani P. D. (2014). Metabolism in 2013: The gut microbiota manages host metabolism. Nature reviews. Endocrinology, 10(2): 74–76. https://doi.org/10.1038/nrendo.2013.240
- Sharon, G., Sampson, T. R., Geschwind, D. H., & Mazmanian, S. K. (2016). The Central Nervous System and the Gut Microbiome. Cell, 167(4): 915–932. https://doi.org/10.1016/j.cell.2016.10.027
- Jiang, H., Ling, Z., Zhang, Y., Mao, H., Ma, Z., Yin, Y., Wang, W., Tang, W., Tan, Z., Shi, J., Li, L., & Ruan, B. (2015). Altered fecal microbiota composition in patients with major depressive disorder. Brain, behavior, and immunity, 48: 186–194. https://doi.org/10.1016/j.bbi.2015.03.016
- Bercik, P., Denou, E., Collins, J., Jackson, W., Lu, J., Jury, J., Deng, Y., Blennerhassett, P., Macri, J., McCoy, K. D., Verdu, E. F., & Collins, S. M. (2011). The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology, 141(2): 599–609. https://doi.org/10.1053/j.gastro.2011.04.052
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- Chevalier, G., Siopi, E., Guenin-Macé, L. et al. (2020). Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system. Nat Commun 11: 6363. https://doi.org/10.1038/s41467-020-19931-2
- Gupta, S., Allen-Vercoe, E., & Petrof, E. O. (2016). Fecal microbiota transplantation: in perspective. Therapeutic advances in gastroenterology, 9(2): 229–239. https://doi.org/10.1177/1756283X15607414
A Conversation on Bioethics with Linda Sonntag, PhD
By Mari Hoffman, Genetics & Genomics ‘21
Author’s Note: I was interested in interviewing Dr. Linda Sonntag because of her time and dedication spent in the biotechnology field. She has been involved in multiple biotechnology companies as the Chief Executive Officer and participating as a board member. The multitude and diversity of her experiences with different companies and projects have encouraged her to get involved with bioethics. She has been a leader in bioethics and has started many of the bioethical conversations that are still being discussed today. In that capacity, she has formed multiple bioethics committees, including the very first. I was very honored to be able to interview Dr. Sonntag and ask her some of my own questions revolving around bioethics in the past and modern development of biotechnology.
This interview has been lightly edited for clarity and brevity.
Mari Hoffman: To start off, if you would like to give a brief introduction on who you are and your background.
Dr. Linda Sonntag: My name is Linda Sonntag, and I was born, raised, and educated in South Africa. I came to the United States in 1980 and completed my post-doctoral studies at UCSF with Herbert Boyer, the founder of Genentech. I quickly realized that I was not cut out for academia in this country. I come from being a very big fish in a very small pond and now I was a Mino in the ocean. I had to find a different way of using my education and I decided to go into industry, which was right at the beginning of the formation of biotechnology.
MH: Since you entered the field of biotechnology when it was still relatively new, when do you first remember a conversation on bioethics taking place and how has that conversation changed with the increasingly advancing technology and scientific capabilities that we have today?
LS: The very first conversation on bioethics took place before my involvement. I think it took place around 1976 at a seminar that was led by David Baltimore, after recombinant DNA and genetic engineering were first discovered. People were concerned about what could be done with biotechnology (a term only coined in the early 1980’s) and a public conversation on bioethics up until this point had not occurred. The technology was way ahead of any conversations or agreement on how to proceed to use it for the common good and not ill. To address the concerns on the ethical issues related to recombinant DNA, a conference was organized to discuss the ethics at Asilomar, in Northern California. A moratorium was placed on all genetic engineering for academic research until the scientist could agree on what was ethical or not. The moratorium lasted several years. During this time, a number of research areas were declared ethical and others not, and the organizers also played a significant role in establishing rules and regulations as well as the creation of multiple regulatory bodies to govern the use of recombinant DNA. At that time, the scientists were able to restart their research in a robust way.
MH: What was your first direct experience with starting a conversation on bioethics?
LS: The first company I worked with was called Agrigenetics and it was the very first agricultural biotechnology company. At the time, no regulations were in place by any federal agency to regulate genetically modified foods (GMA). The very first conversation that I had around bioethics was around whether or not the agricultural industry should be regulated. I was the lone voice who believed it should be regulated. I was very concerned that if there were no regulations, people would be very frightened by the products we wanted to commercialize if we were successful. They might view us as creating monsters that could escape into the environment. Although I had my concerns, for expediency’s sake, the industry leaders as a whole decided against being regulated because regulation adds significant costs and delays the time to reach the market.
The very first experiment that went into the field was in Davis, CA, associated with a company that was founded by academic scientists at UC Davis. It was for a strawberry plant that had been engineered to have an anti-freezing gene derived from fish inserted into its DNA so that strawberries would not freeze and the crop would not be destroyed when there was frost. When the GMO plants were planted, local citizens in the area protested and rioted by breaking down the greenhouses and destroying the crops. That product never reached the market.
Agricultural biotechnology eventually took off, but in a highly regulated way. You can still see the stigma today that GMO plants and seeds hold; people remain afraid of them and the business models around how they are sold.
MH: How did that experience lead to you making a change in a company’s regulations?
LS: My next involvement was a very interesting one. Around 1985, I joined a startup where we were the first to practice precision medicine and use it to create a preventive medicine program that was designed for a circumscribed group of individuals. Historically, prevention has always been in the domain of government and consequently had been very costly to implement since governments could not be seen to discriminate and therefore all newborns were being tested for those diseases that were preventable, whether they were at risk or not.
I went around the country and licensed many genes that had been identified in academic labs that were linked to preventable diseases. They had the potential to be powerful predictors to identify who was at risk for certain diseases. I eventually licensed about 50 different genetic markers that could be used to identify individuals’ predispositions for developing a disease that was preventable. I was only interested in licensing genetic markers for diseases that had an environmental and/or behavioral component to them and that a patient could do something to change the outcome of the disease. After licensing these technologies, we created the very first artificial intelligence system which allowed us to circumscribe who was at risk. To test out the system we were involved with a large telephone company in Washington, DC who opted to offer our test to their employees. It quickly became very evident that with no rules in place, individuals were not protected from being discriminated against by their employers or insurance companies because they had a genetic profile that identified them as being at risk of developing diseases that could result in considerable healthcare costs or disruption to an individual’s productivity. To think through and address these issues, I created the very first bioethics committee, dedicated exclusively to problem solve and develop systems to protect individuals from discrimination. To overcome these issues, we were successfully able to identify individuals, and only we held the key to their identity and were able to preserve the patient’s anonymity from their employers and insurers. They could now get access to educational programs and support without their identity being exposed. That was the very first time that a bioethics committee was created as an institutional entity that made decisions about how businesses would be run in a more mindful and ethical manner.
MH: That is very interesting. Would you say with ancestry tests like 23andMe where you are provided an option to give your name overrides the anonymity of genetic tests that you discussed?
LS: Absolutely. What we have discovered now is even if that data is anonymized, there are ways to deconstruct and identify individuals.
MH: It is very interesting that this conversation on data privacy that you started years ago is still a prevalent issue today. Are there any set laws that are currently in place today to provide protections?
LS: Laws do exist to protect genetic information from being used prejudicially, but if an individual gets refused insurance it is really hard to find out why they have been refused. If an employer has accessed that data and uses it prejudicially, for one to have any recourse, you have to prove that it was based on their knowledge of that genetic information, which is very difficult to prove.
The one law that is unfortunately currently at risk is the protections that come from the Affordable Care Act (ACA). The ACA forbids insurance companies from using pre-existing conditions to deny an individual any insurance. Due to COVID-19 and the Trump Administration’s attempt to end the ACA, a multitude of individuals who have lost their health insurance this past year due to the pandemic are now at risk of no longer being able to buy insurance that covers pre-existing conditions. All the sequelae and multitudes of long term health consequences of COVID-19 could be excluded from coverage by anyone who has lost their job as a consequence of this pandemic of epic proportions. A genetic predisposition might be included as a pre-existing condition, which might disqualify an individual for insurance. As long as the ACA is the law, nobody can be denied insurance for those reasons. Although there are these laws that exist, there are still issues around them and how to enforce them.
MH: Have there been any other experiences that you have that have led you to build a bioethics committee?
LS: The third time that I got involved in bioethics and formed a committee was when I was running a company called SyStemix, the very first stem cell company. We were using fetal tissue in our experiments which was a topic that has been controversial under Trump and prior to that during the George W. Bush administration. We were one of the first commercial companies that was openly admitting to using fetal tissue in our experiments. We knew that this might be highly controversial, so once again, I assembled a bioethics committee to opine on what we would face and how best to deal with the issues. Our committee actually included a Catholic Bishop to be a part of the conversation and eventually concluded that since we were not in any way women to choose abortion and since we were not paying for the tissue, the abortuses were simply being disposed of with no potential to benefit humankind. Even the Bishop agreed that using fetal tissue for the benefit of humankind was a worthwhile endeavor, as opposed to throwing the embryos away.
Just this last year, Trump dismantled every single research project funded by the United States government that used fetal tissue in any way, thereby squandering hundreds of millions, if not billions of dollars worth of experiments by having all that research come to a screeching halt.
Our company was founded on the use of a SCID-hu mouse model where any tissue from any organisms can be transplanted into the mouse since the mouse did not have an immune system of its own. It could not recognize the donor tissue as foreign and hence would not reject it. Few adult organs are capable of regeneration, whereas virtually every fetal tissue has applicability in these valuable experiments. This mouse model became the gold standard for all research on the etiology of human diseases and the potential ways to treat them.
In our case we were able to use it for AIDS and HIV research. It was the first time that we could actually create a fully functional human immune system in a mouse and infect it with HIV, to determine if different drugs could potentially cure HIV and AIDS. AZT, the very first approved HIV-antiviral drug was discovered to be effective in humans by using the SCID-hu mouse model around 1990. AZT is a pro-drug, and the only other organism that can convert it from a prodrug to an active drug is chimpanzees. By using this mouse model, it was no longer necessary to infect chimpanzees with HIV to study the disease. This year, unfortunately, for political reasons, all experiments that were using this gold standard mouse model for studying many human diseases came to a halt because President Trump decided that fetal tissue could not be used in any circumstance in any government funded research programs, for purely political reasons.
MH: What do you think are some of the most current pressing bioethical issues?
LS: The other discussion that is very current, but I have mixed feelings on is about vaccines for COVID-19. COVID-19 trials are blinded and are conducted by splitting cohorts of individuals in a control arm and a treatment group, without the researchers or participants knowing which group is receiving the vaccine. Now that the experiments are unblinded and we can see that the vaccine is highly efficacious, the question becomes whether or not people in the control arm should be vaccinated. If they get the vaccine, it truncates our ability to see for example the longevity of the protection provided by the vaccine or long-term side effects by no longer being able to track the control group. So, what to do? The way the health care community is leaning is that the control group has to get the vaccine to protect them and then we have to figure out other ways to understand the longevity and side effects of vaccination. This is an ongoing discussion at the FDA and the NIH in order to make these important decisions around how to continue the clinical trials. Also, once the first vaccine is approved, how do you get other vaccines tested if there is already a vaccine available? There are a lot of ethical questions to consider regarding these issues.
MH: There is a lot of stigma about taking vaccines, how do you think the implementation of distributing the vaccine and getting people to take it will play out?
LS: There are weekly conversations regarding how to distribute the vaccine and who should get it first. Clearly, they have to treat frontline workers first as they are the most at risk. Then the conversation is about who is most at risk for the virus aside from the frontline workers. People of color have a higher risk of getting sick from COVID-19 completely disproportionate to the population. The question raised asks if young children should be prioritized in getting the vaccine since they can be reservoirs of the virus and for their emotional and cognitive development must be allowed to return to school as soon as possible? There are still conversations going on around how to allocate the vaccine equally and I don’t think they have reached a complete conclusion other than the frontline workers will get it first. Who gets it next and how it rolls out is still under discussion.
MH: Is there worry that there will not be enough people willing to get the vaccine due to stigma?
LS: Yes, I think that is a very significant concern. I can personally tell you as a scientist that I think that vaccines and antibiotics have extended our lives dramatically. At the beginning of the 1900s, the average life span was about 40 years old due to people dying from common infectious diseases. The advantage of antibiotics and vaccines has extended our lifespan by double. I will not hesitate in getting a vaccine as soon as I can after it has been reviewed and approved by an independent, apolitical group of scientists.
MH: Are there any other major ethical topics that we missed that you would like to discuss?
LS: One critical vast ethical issue that we have not discussed is CRISPR technology. CRISPR technology is one of the most fraught technologies on the planet with the ability to do both good and bad. On the downside, scientists have found ways for example to change genes in entire populations of mice to render them infertile so that they cannot transmit Lyme disease or to eradicate entire populations of mosquitoes to prevent malaria or zika transmission or other mosquito borne diseases, of which there are many. What happens to the global ecosystem if these species are eradicated because they can no longer reproduce? The cat is out of the bag on this line of research, before a discussion on the ethics ever got started.
The first infants to have their genes in their germline modified have already been born in China. This means the germplasm (eggs and sperm) have been permanently altered and so these modifications will be transmittable to future generations. This is something that the scientific and civil community worldwide has historically completely forbidden. There are a lot more conversations surrounding ethics that need to take place in order for this technology to be broadly used. I’m afraid, it is already too late to regulate and control in a meaningful way from being used in ways that could be terribly detrimental to our planet and all its inhabitants, whether fauna, flora, microbes, or humans.
The Pursuit of a SARS-CoV-2 Vaccine: Lessons in Public Trust of Medical Institutions
By Jessica Lee, Biochemistry and Molecular Biology ‘21
Author’s Note: Alarmed by the fact that so many Americans are skeptical of receiving a COVID-19 vaccine, I wanted to write an article delving into the reasons why public trust in medical institutions has waned. I look to previous breaches of trust to propose public health messaging strategies for the rollout of the highly anticipated COVID-19 vaccine.
As of November 2020, approximately 63% of Americans say they would not be willing to immediately receive a COVID-19 vaccine—even if the vaccine was approved by the Food and Drug Administration (FDA) and free of cost [1]. Public willingness to receive a COVID-19 vaccine has rebounded since its all time low of 50% in September of 2020. The fluctuation in willingness to be vaccinated reflects how the public perceives undue influence on the vaccine development and regulation process. A successful vaccine distribution process will require broad public support to control the ongoing global pandemic.
[1]
The human and economic consequences of the COVID-19 pandemic are staggering: over 350,000 people in the U.S. have died from COVID-19 and the unemployment rate remains high at 6.7% as compared to 3.5% in February 2020 [2, 3]. Given the devastating impacts of COVID-19 on Americans’ health and well-being, why are so many Americans skeptical of a vaccine with the potential to restore normalcy?
The history of American public and private biomedical institutions may provide useful context for Americans’ skepticism of a potential COVID-19 vaccine. The anti-vaccination movements, opioid crisis, and bumpy introduction of COVID-19 therapeutics have all contributed to waning trust in public health institutions. With the approval of Pfizer/BioNTech and Moderna vaccine candidates for the prevention of COVID-19, the biomedical community needs to foster trust by delivering correct and consistent messaging to the public as vaccines become available to the American public.
Trust in Biomedical Institutions
The modern anti-vaccination, or “anti-vax,” movement in the U.S. was sparked by Andrew Wakefield’s infamous paper published in The Lancet and perpetuated by outspoken celebrities, politicians, and social media groups [4]. Even though Wakefield’s claims about a causal relationship between the childhood measles, mumps, and rubella (MMR) vaccine and autism have since been thoroughly debunked by a scientific majority, the damage caused by his falsified research is evident as measles outbreaks continue to impact the U.S. Characterized by fantastical and conspiratorial thinking, the modern anti-vax movement has evolved to include a range of beliefs about vaccines. On social media platforms, misinformation about vaccines can include false safety concerns to conspiracies about social control.
However, there are also legitimate reasons to be skeptical of the pharmaceutical industry and its regulators. Mistakes driven by commercial interests have resulted in horrific public health crises. Motivated by profit, pharmaceutical companies misled the public about the safety of opioids, such as oxycontin, resulting in the liberal prescription of highly addictive and dangerous drugs. Opioid overdose is now one of the most common causes of preventable death in the U.S. [5]. Financial incentives can corrupt the scientific process, even corrupting leading medical experts.
Dr. Russell Portenoy, a pain specialist, received millions of dollars from the manufacturers of opioids while assuring the public that addiction risks were low [5]. When the addictive nature of opioids became evident, Portenoy defended his actions.
“My viewpoint is that I can have these relationships [and] they would benefit my research mission and to some extent, they can benefit my own pocketbook, without producing in me any tendency to engage in undue influence or misinformation,” said Portenoy [5].
In light of the unethical—and often illegal—behavior of pharmaceutical companies, the reaction of the American public is not entirely unreasonable. However, the waning trust in biomedical institutions is nonetheless a public health problem with clear consequences. In 2019, there were several outbreaks of measles among communities with low vaccination rates [6]. Over 1,200 cases were reported by the Center for Disease Control (CDC), which is the highest number of measles cases since 1992 [6]. It is important to highlight that overall measles vaccination rates are high throughout the country. However, outbreaks of deadly diseases can still occur when vaccination rates within a community dip below those needed for herd immunity. To eradicate a disease, outreach to fringe communities is necessary to ensure they buy into the vaccination process. Furthermore, vaccines must be made accessible to traditionally underserved communities. Within the context of the COVID-19 pandemic, this means that public health officials must reach out to those with anti-vaccination tendencies, ethnic minorities, and immigrant populations. Furthermore, the vaccine must be made widely accessible for the poorest citizens of all countries. Only then can COVID-19 be completely eradicated.
Number of Measles cases reported by year
Data from CDC.gov as of October 15, 2020
[6]
The consequences of eroded trust in biomedical institutions are even more tangible as authorities in the U.S. attempt to control the COVID-19 pandemic. Confusing, conflicting messaging and policies on cloth mask usage has resulted in a partisan gap of 16 points between Republicans and Democrats on regular mask usage [7]. Even though current data and modeling demonstrate that masks reduce infections, some Americans continue to refuse to participate in this common-sense risk reduction practice [8].
The Credibility of the Food and Drug Administration (FDA)
There has also been widespread confusion on the development of COVID-19 therapeutics. The FDA has the authority to allow the use of unapproved drugs and medical products during national emergencies under an emergency use authorization (EUA). Many COVID-19 therapeutics such as Remdesivir, hydroxychloroquine, and convalescent plasma have been granted EUAs for use in specific populations, such as hospitalized patients [9]. Importantly, medical products that are granted EUAs are not granted full FDA approval. To obtain an EUA, it must be determined that the product meets three criteria: the product may be effective in diagnosing, treating, or preventing a serious disease or condition, the known and potential benefits outweigh the risks, and there are no available alternatives [9]. Many of the EUAs granted for COVID-19 treatment have stirred controversy within the biomedical community. For instance, the FDA’s decision to grant an EUA for the use of convalescent plasma in August resulted in dissent among biomedical institutions.
A National Institutes of Health (NIH) panel rebutted the FDA’s claims by issuing this statement: “There are insufficient data for the COVID-19 Treatment Guidelines Panel to recommend either for or against the use of COVID-19 convalescent plasma for the treatment of COVID-19” [10].
Other figures in the biomedical community such as Dr. Eric Topol, the director of the Scripps Research Translational Institute, criticized the head of the FDA, Dr. Stephen Hahn, for making hyperbolic statements on the safety and efficacy of convalescent plasma and for presenting misleading data to the public [11].
“So in order to get this straight, Dr. Hahn needs to also talk to the public and say that he erred and that there is no established evidence for survival advantage of convalescent plasma. That has to be determined through randomized trials that are ongoing,” said Topol on NPR’s All Things Considered [11].
The FDA also has played a controversial part in the development of hydroxychloroquine. The agency issued an EUA for hydroxychloroquine in March only to revoke the EUA in June after adverse cardiac events were reported [12]. Whether the FDA’s actions were influenced by political pressure, corporate pressure, or a desire to save lives, the controversy around COVID-19 therapeutics degrades public trust in the FDA as an institution.
Emergency Use Authorization for Vaccines to Prevent COVID-19
The discussion on therapeutic EUAs is important since the two currently approved COVID-19 vaccines were first approved through the intermediate step of an EUA. At time of publication, Moderna and Pfizer/BioNTech have successfully completed their phase three clinical trials for COVID-19 vaccines and received EUAs from the FDA [13]. Globally, approximately twenty other vaccine candidates are also in phase three clinical trials [13]. Each clinical trial has enrolled between 30,000 and 60,000 volunteers, half of which will receive the vaccine candidate and half of which will receive a placebo [13]. Approximately 160 infections of SARS-CoV-2 will be necessary to statistically determine the efficacy of each vaccine candidate. While only 160 infections might seem small in a clinical trial of 60,000, this number allows the FDA to determine if there is a statistical significance between the two arms of the clinical trial. Interim analyses may also be conducted at fewer infections by external data safety monitoring boards [14, 15]. Such data safety monitoring boards are independent of sponsors, regulators, and the scientists conducting the clinical trials. If the external board finds statistically significant results at an interim point, then the sponsors of the clinical trial may ask the FDA to review the vaccine for an EUA [14].
Published in a non-binding guidance document, the FDA outlines the criteria for potentially obtaining an EUA for a COVID-19 vaccine. Since this guidance document is non-binding, the FDA may modify the EUA process moving forward. If a sponsor seeks an EUA at an interim analysis of a phase three clinical trial, then they must demonstrate at least 50% efficacy, have a median follow-up duration of at least two months after the administration of the last dose, and safety data that would allow the FDA to make a favorable risk-benefit analysis [16]. Furthermore, the sponsor must provide sufficient data demonstrating the ability to consistently manufacture the vaccine [16]. If the FDA believes the criteria are met for an EUA, then the vaccine candidate may be administered to certain at-risk populations while the full-approval process continues. At the time of publication, both Pfizer and Moderna have produced data from their phase three clinical trials indicating their vaccines may be over 90% effective—far surpassing the 50% efficacy threshold set by the FDA [13].
Developing and Maintaining Public Trust
The COVID-19 vaccine trials are safeguarded in many ways. The scientists at the FDA have approved the phase three clinical trial protocols and monitored phase one and two clinical trials for safety and efficacy. The oversight safety boards have watched for unexplained adverse events and paused the AstraZeneca trial when unexplained neurological symptoms presented in one participant [14]. Peer reviewers have analyzed and criticized the data and conclusions generated from phase one and two clinical trials. Furthermore, influential members of the biomedical community have spoken out when they believe mistakes have been made. Evidently, there are safety measures in place to protect the public from a dangerous or ineffective vaccine. However, safety measures are not perfect. When the FDA allowed the use of hydroxychloroquine and then revoked its EUA, the FDA weakened its authority with the general public. Even the appearance of political and commercial influence on the scientific process may elicit skepticism from the public.
How can the biomedical community increase the public’s willingness to get the COVID-19 vaccine? Certainly, consistent messaging from figures of authority is important. Furthermore, the biomedical community must continue to hold regulatory agencies, corporations, and politicians responsible for their rhetoric. There must be political, legal, or economic consequences for misleading the public and degrading trust in medical institutions. Economic consequences—for example—might range from lawsuits to executives being debarred from working in the pharmaceutical industry.
Biomedical professionals have advocated for widespread outreach to many different types of communities [15]. Social media campaigns can be effective in rapidly disseminating information by engaging users to add their own input. However, social media may also hinder outreach as demonstrated by the uncontrolled spread of misinformation by anti-vaccination groups on platforms such as Facebook [17]. Viral posts containing misinformation can seed public distrust in medical institutions. Still, polling indicates that Americans overwhelmingly trust medical professionals over industry leaders or politicians for information about vaccines [18].
[18]
Utilizing this trust would mean elevating medical scientists as the voice communicating the state of a COVID-19 vaccine rather than relying on politicians, the news media, or industry leaders. However, it is important to communicate scientific consensus rather than relying on the voices of individual biomedical professionals. Individuals can make genuine mistakes, have differing opinions, or be corrupted; thus, it is essential that public health messaging is centered around scientific consensus.
The effectiveness of a COVID-19 vaccine on a population scale will depend on the percent of people willing to get the vaccine. To end the COVID-19 pandemic, it’s likely that most people will need to be vaccinated. To accomplish this, the biomedical community will need to work with the public to foster open and honest communication, understanding the public has relevant concerns about the influence of politics and commerce on the scientific process. By learning from previous anti-vax movements, public health professionals must counter the spread of misinformation with compelling, fact-based messaging. Ultimately, the public health community must regain the trust of the American public and appeal to Americans’ civic duty. The act of taking a vaccine is a social contract; as Dr. Topol says, “I take the vaccine to help you, not just me” [15]. The COVID-19 pandemic is one of the largest public health crises in modern times and it will require good science and good communication to solve.
References
[1] Brenan M. “Willingness to Get COVID-19 Vaccine Ticks Up to 63% in U.S.” Gallup, December, 2020.
[2] “CDC COVID Data Tracker.” Centers for Disease Control and Prevention, January 6, 2021.
[3] “Employment Situation Summary.” U.S. Bureau of Labor Statistics, December, 4, 2020.
[4] Hussain A, Ali S, Ahmed M, Hussain S. “The Anti-vaccination Movement: A Regression in Modern Medicine.” Cureus, July 2018. doi: 10.7759/cureus.2919.
[5] Gale AH. “Drug Company Compensated Physicians Role in Causing America’s Deadly Opioid Epidemic: When Will We Learn?” Mo Med, July 2016.
[6] “Measles Cases and Outbreaks.” Center for Disease Control, November 2020.
[7] Kramer S. “More Americans say they are regularly wearing masks in stores and other businesses.” Pew Research Center, August 2020.
[8] Zhang K, Vliches TN, Tariq M, Galvani AP, Moghadas SM. “The impact of mask-wearing and shelter-in-place on COVID-19 outbreaks in the United States.” International Journal of Infectious Diseases, December 2020. doi: 10.1016/j.ijid.2020.10.002.
[9] “Frequently Asked Questions for Veklury (remdesivir).” U.S. Food and Drug Administration, October 2020.
[10] COVID-19 Treatment Guidelines Panel. “Coronavirus Disease 2019 (COVID-19) Treatment Guidelines.” National Institutes of Health, Accessed November 2020.
[11] “Researcher Criticizes FDA’s Exaggeration Of Plasma’s Efficacy In COVID-19 Treatment.” All Things Considered. NPR, August 2020.
[12] “Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine.” U.S. Food and Drug Administration, June 2020.
[13] Corum J, Wee S, Zimmer C. “ Coronavirus Vaccine Tracker.” The New York Times, January 2021.
[14] Duke Science & Society. “Coronavirus Conversations: On the Ground – Inside the COVID-19 Vaccine Trials.” Online video clip. Youtube, 6 November 2020.
[15] Duke Science & Society. “Coronavirus Conversations: Emergency Use Authorizations, Public Trust, and Vaccines.” Online video clip. Youtube, 7 October 2020.
[16] “Emergency Use Authorization for Vaccines to Prevent COVID-19; Guidance for Industry.” U.S. Food and Drug Administration, October 2020.
[17] Johnson NF, Velásquez N, Restrepo NJ, Leahy R, Gabriel N, Oud SE, Zheng M, Manrique P, Wuchty S, Yonatan L. “The online competition between pro- and anti-vaccination views.” Nature, May 2020.
[18] Funk C, Kennedy B, Hefferon M. “Vast Majority of Americans Say Benefits of Childhood Vaccines Outweigh Risks.” Pew Research Center, February 2020.
The Mental Health Crisis of the COVID-19 Pandemic
By Aditi Venkatesh, Cognitive Science ‘21
Author’s Note: I wrote this piece for a UWP 104E assignment to explain the psychological consequences of the COVID-19 pandemic. I chose to focus on mental health because it holds personal value to me and addresses an often overlooked aspect of this pandemic. I support the creation of more accessible mental health services and hope to encourage people to reflect on their own mental well-being during these unprecedented times.
Recall your life just a few months ago. Hanging out with friends at a restaurant. Working in an office and chatting with coworkers. Sitting in a classroom with hundreds of classmates. Visiting family members. Buying groceries without worrying about wiping everything down. Going for a walk with neighbors.
Now, life looks a lot different. Zoom meetings all the time. FaceTime calls just to talk to friends and family. Paranoia about whether masks and gloves are covering your face and hands properly. Constantly checking social media for news. Using laptops every hour to communicate with classmates, coworkers, teachers, and pretty much anyone. The same routine repeated over and over again.
Undoubtedly, the COVID-19 pandemic has created a much different world. The consequences of this pandemic are primarily examined from a medical and economic perspective, but more attention needs to be brought to the psychological impacts of this pandemic. Mental health disorders have become increasingly prevalent in society; data from Active Minds, a mental health awareness organization, states that 50% of the United States population will experience a mental health condition at some point during their lifetime [1]. These statistics become even more concerning for young adults, with 75% of all cases of mental health issues beginning by the age of 24 [1]. With new layers of stress, anxiety, and isolation stemming from the pandemic, mental health issues are more widespread than before. Through the remainder of this piece, I will articulate outcomes of COVID-19 including the general effect of a pandemic on mental health, specifically focusing on younger populations at risk for anxiety and depression. I discuss alternative positive outcomes in people who normally thrive in times of limited social interaction and contrast this with the harmful impact of drastic isolation. I examine the benefits and consequences of increased technology use during COVID-19. Lastly, I have provided a few helpful mental health resources for students, and I urge everyone to assess their own mental health during these difficult times and advocate for better mental health services.
The coronavirus pandemic has created a mental health crisis across the world. Quarantining and shelter-in-place guidelines have isolated most people from family and friends, reduced social interactions drastically, and disrupted normal interpersonal interaction as shown in Figure 1 below, with data collected by the Kaiser Family Foundation towards the end of March 2020 [2]. People were already experiencing negative impacts on their mental health at the onset of the pandemic in early March, so undoubtedly, the duration of quarantine has exacerbated prior conditions. Individuals who are practicing shelter-in-place were more likely to report feeling mild or severe negative impacts on mental health than those who are not sheltering-in-place. Negative impacts include stress, anxiety, and general disruptions to life such as job loss, isolation, and income insecurity. These effects are particularly noticeable in individuals that were already at a higher risk for depression prior to the pandemic: younger adolescents, frontline healthcare workers, and individuals with chronic illnesses.
Figure 1:
Considering the isolation that comes with quarantining, we must recognize that levels of interpersonal dependence produce key vulnerabilities to depression and other comorbid mental health disorders. How much we depend on other relationships has strong implications on support systems, coping mechanisms to mental health issues, and willingness to seek treatment [3]. Prior research on psychosocial risk factors has shown that sociotropy and autonomy are two personality traits that predict depression. Sociotropy is the reliance on interpersonal relationships, while autonomy is related to independence and seeking self-control. A 2018 study conducted by Otani, et al. at the Yamagata School of Medicine in Japan found that sociotropy was associated with negative beliefs about oneself, but autonomy was associated with negative beliefs about others and short-lived positive beliefs about oneself [4]. These results highlight that dependence on others and an imbalance of self-esteem can be linked to depression. Since quarantining creates isolation, this isolation leads to an increased tendency to contemplate and overthink negative core beliefs about oneself, resulting in lower levels of confidence and self-esteem. We should be aware that certain personality traits are more vulnerable to depression during this pandemic and mental health needs to be prioritized more than ever before. However, one might wonder if autonomous individuals are thriving during this pandemic, since there is undoubtedly less social interaction than normal. For example, imagine a student that has mild social anxiety and does not enjoy their large classes in school. They might be relieved because they don’t have to have lengthy conversations with classmates and can independently complete their work. This very well may be the case for certain individuals. Previous studies have shown that autonomy can cultivate creativity, and introversion has been closely linked with autonomous tendencies [5]. Individuals that typically thrive in solitude and focus on hobbies, jobs, and other passions may find comfort in having more time to themselves due to COVID-19. Alternatively, extremely high levels of autonomy, such as complete disconnection from family and friends can be a factor that contributes to depression. This stresses the fact that a majority of individuals need some level of healthy social interaction to have a balanced life.
Despite the finding of a correlation between isolation and depression, since the onset of the pandemic, people are finding creative ways to socially interact and combat the loneliness COVID-19 has created. Many folks schedule weekly or monthly calls with family and friends to catch up. Organizations are holding virtual discussions about mental health and ways to practice self-care. Students across the world are creating online board games and holding virtual game nights.
However even with these alleviating factors, the magnitude and ongoing duration of the pandemic’s restrictions continue to foster unusually high levels of loneliness. Students who may have participated in many extracurricular activities (which are now canceled), can’t talk to their friends as much, feel out of the loop in their lives, and struggle to find ways to spend their free time. Loneliness is one feeling that can contribute to depression and anxiety. In Figure 2, among data collected by Healthline through a YouGov COVID-19 Tracker during April 2020, the age group most affected by depression and anxiety (33%) was adults younger than 35 years old [6]. Additionally, this younger population showed an increase of anxiety and depression over a two-week span from April 12th to April 26th. Lastly, 45% of the U.S. population tested showed anxiety and depression PHQ-4 values out of the normal range [6]. However, older populations reported a plateau or slight reduction, which may be due to less dramatic lifestyle changes or less technology use compared to younger generations. This is significant because it illustrates that younger adults, which includes most students, disproportionately face worsened mental health.
Figure 2:
At the same time in China, researchers found similar patterns of anxiety and depression and chose to analyze why this exacerbation was present in younger individuals. Many research studies in China, where the peak of COVID-19 has passed, are examining the psychological repercussions of the pandemic, with a focus on depression and anxiety. In a published study from April 2020, researchers in Wuhan, China measured that the prevalence of depression and anxiety in the general population was 35.1% and 20.1%, respectively [7]. Further analysis of the self-report questionnaire confirmed that individuals younger than 35 years old reported more severe symptoms of depression and anxiety. In fact, among the younger population, those that spent more than 3 hours per day thinking about the pandemic faced more severe anxiety than those that spent 0-2 hours. This result highlights that in addition to actual lifestyle changes, thoughts about COVID-19 induces anxiety in young populations. This begs the question, why are younger people thinking about COVID-19 more than older people?
The answer is technology. Even though everyone uses technology, younger ages rely on technology more, especially for school and interacting with friends. Of course, technology is not all bad. In fact, society is most likely only able to function during this pandemic due to advancements like video conferencing, telemedicine, and online social groups. However, another study conducted in Wuhan, China explored the use of social media during the recovery interventions placed after the peak of COVID-19 [8]. Researchers found that social media support groups slightly reduced depression. But more significantly, adults that spent more than 2 hours on COVID-19 news on social media had increased anxiety and depression. Another study in Chicago in May 2020 explored the role of mainstream media in coronavirus news and depression. Researchers found that greater exposure to COVID-19 news, through cable news channels like CNN, local news channels, and the New York Times, led to higher perceived vulnerability to COVID-19, and this was strongly correlated with depressive symptoms [9]. Social media and mainstream media sources can both produce an undue burden on individuals through a barrage of stressful information about COVID-19 and lead to greater anxiety and depression.
Another form of technology, while useful for work and school, has unintended negative consequences: video conferencing. People have started to refer to these downsides as “Zoom fatigue” [10]. Zoom fatigue is the phenomenon where people are more tired and stressed with online meetings compared to in-person ones. I am sure many readers have experienced the similar stresses of looking presentable, awkward silences when nobody is speaking, and simply, less fun meetings. During Zoom meetings, it is difficult to discern normal social cues, such as body language and eye contact, over a video. This nonverbal communication is crucial to making conversations run smoothly. Removal of many social cues makes video calls feel impersonal. It can make even a catch-up video call to your best friend seem stressful. Additionally, previous research has shown that when responding online, even delays of up to 1.2 seconds can make a person seem unfocused and unfriendly [10]. These slight technological delays can dramatically contribute to greater stress and anxiety. Zoom fatigue can be especially taxing on younger populations that are still in school and are constantly in and out of Zoom meetings for courses.
As the COVID-19 pandemic continues, society finds itself at crossroads. How do we balance the positive and negative impacts of the technology use? Obviously, we cannot simply get rid of Zoom meetings and online classes; however, this pandemic gives us a crucial opportunity to expand online mental health services. Past research on mental health effects during the 2003 SARS epidemic in China showed similar prevalence of worsened mental health, with 48% of the participants reporting deteriorated mental health because of the SARS epidemic through anxiety and depression; this is very similar to the 47% found in the 2020 KFF study [11, 2]. If mental health issues are just as exacerbated in our pandemic 15 years later even with greater technological advancements, it accentuates the disparities in accessible online mental health care. Increasing virtual therapy appointments, online support groups, and videos for stress-relieving techniques like meditation, breathing exercises, and self-reflection are some starting points.
A CDC study conducted in June 2020, several months following the onset of the pandemic, found that people aged 18-24 years still face the highest prevalence of mental health conditions [12]. However, 30.9% of all participants showed anxiety and depression symptoms above normal PHQ-4 measurements; this illustrates a reduction compared to the finding of 45% measured in the April 2020 Healthline survey [12, 6]. Most importantly, I hope this shows that things are getting better. I especially encourage all readers to reflect on how to better take care of their own mental health. It is so important to practice self-care, which can be different for everyone! This can be exercising, seeing a therapist, hanging out with friends, getting more sleep, or setting boundaries for your own capabilities. It’s okay to prioritize your mental health when things get overwhelming. Therapy can be helpful for some folks, so here are some resources to be aware of. Student Health and Counseling Services offers on-campus counseling appointments for students (call (530) 732-0871 or visit hem.ucdavis.edu to schedule). Free tele-mental health and online counseling appointments are offered through Therapy Assistance Online (visit taoconnect.org and sign up with your UC Davis email). Text RELATE to 741741 to chat live with a crisis counselor, available 24/7 through the Crisis Text Line. Lean on your support systems and know that you are not alone! Mental health is just as important as your physical health. I hope we can take this time to acknowledge the mental health crisis this pandemic has created by improving available mental health services and making mental healthcare more accessible for at-risk populations.
References
- Statistics. (2020, June 24). Retrieved August 07, 2020, from https://www.activeminds.org/about-mental-health/statistics/
- Panchal, N., Kamal, R., Orgera, K., Cox, C. F., Garfield, R., Hamel, L., Muñana, C., & Chidambaram, P. (2020, April 21). The Implications of COVID-19 for Mental Health and Substance Use. Retrieved from https://www.kff.org/coronavirus-covid-19/issue-brief/the-implications-of-covid-19-for-mental-health-and-substance-use/
- Meissner, B. L., & Bantjes, J. (2017). Disconnection, reconnection and autonomy: four young South African men’s experience of attempting suicide. Journal of Youth Studies, 20(7), 781–797. doi: 10.1080/13676261.2016.1273512
- Otani, K., Suzuki, A., Matsumoto, Y., & Shirata, T. (2018). Marked differences in core beliefs about self and others, between sociotropy and autonomy: Personality vulnerabilities in the cognitive model of depression. Neuropsychiatric Disease and Treatment, 14, 863–866. doi: 10.2147/ndt.s161541
- Runco, M. A., & Pritzker, S. R. (1999). Encyclopedia of creativity. San Diego, CA: Academic Press.
- Healthline Mental Health Index: Week of April 26 – U.S. Population. (2020, May 14). Retrieved from https://www.healthline.com/press/healthline-mental-health-index-week-of-april-26-u-s-population
- Huang, Y., & Zhao, N. (2020). Mental health burden for the public affected by the COVID-19 outbreak in China: Who will be the high-risk group? Psychology, Health & Medicine, 1-12. Advance online publication. doi: 10.1080/13548506.2020.1754438
- Ni, M. Y., Yang, L., Leung, C., Li, N., Yao, X. I., Wang, Y., Leung, G. M., Cowling, B. J., & Liao, Q. (2020). Mental Health, Risk Factors, and Social Media Use During the COVID-19 Epidemic and Cordon Sanitaire Among the Community and Health Professionals in Wuhan, China: Cross-Sectional Survey. JMIR Mental Health, 7(5). doi: 10.2196/19009
- Olagoke, A. A., Olagoke, O. O., & Hughes, A. M. (2020). Exposure to coronavirus news on mainstream media: The role of risk perceptions and depression. British Journal of Health Psychology. Advance online publication. doi: 10.1111/bjhp.12427
- Sander, L., & Bauman, O. (2020, May 22). Zoom fatigue is real – here’s why video calls are so draining. Retrieved from https://ideas.ted.com/zoom-fatigue-is-real-heres-why-video-calls-are-so-draining/
- Lau, J. T., Yang, X., Pang, E., Tsui, H. Y., Wong, E., & Wing, Y. K. (2005). SARS-related perceptions in Hong Kong. Emerging Infectious Diseases, 11(3), 417–424. doi: 0.3201/eid1103.040675
- Czeisler, M. É., Lane, R. I., Petrosky, E., Wiley, J. F., Christensen, A., Njai, R., Weaver, M. D., Robbins, R., Facer-Childs, E. R., Barger, L. K., Czeisler, C. A., Howard, M. E., & Rajaratnam, S. M.W. (2020, August 13). Mental Health, Substance Use, and Suicidal Ideation During the COVID-19 Pandemic — United States, June 24-30, 2020. Morbidity and Mortality Weekly Report 2020, 69, 1049–1057. doi: 10.15585/mmwr.mm6932a1
The History and Politics of Marijuana in the United States
By Vishwanath Prathikanti, Political Science, 23’
Author’s note: Marijuana today is a very controversial topic, with some arguing for a complete criminalization of it, others advocating for complete decriminalization of it, and many more in between. To understand marijuana today, and what it does to your body, we need to unravel its complex history and proven effects. Unfortunately, this is not always clear cut.
Marijuana, according to the National Institute on Drug Abuse (NIDA) is defined as “a greenish-gray mixture of the dried flowers of Cannabis sativa” and all other relatives, including Cannabis indica, Cannabis ruderalis, and hybrids [1]. The mind-altering effects of marijuana are mainly due to the chemical delta-9-tetrahydrocannabinol, commonly known as THC, and it is the active ingredient that makes marijuana so dangerous according to NIDA.
The reason for this mind-altering effect is due to the structural similarities between THC and anandamide, a naturally occurring cannabinoid that functions as a neurotransmitter. Anandamide is an agonist, meaning it is a chemical that binds to receptors in the human endocannabinoid system and causes a response. The endocannabinoid system is a network of receptors designed to maintain bodily homeostasis, or stable conditions for the body [13]. Anandamide activates receptors which send chemical messages between nerve cells throughout the nervous system, specifically to areas in the brain “that influence pleasure, memory, thinking, concentration, movement, coordination, and sensory and time perception” [1]. Mainly, the cerebellum, basal ganglia, and hippocampus areas are being activated the most. Due to the effects of pleasure, researchers have speculated that anandamide could be released in the early phases of brain development to strengthen positive reactions towards food consumption, essentially encouraging people to eat, although they cannot confirm it [2]. Regardless, due to its similarity to anandamide, THC is able to attach cannabinoid receptors on neurons in these brain areas and activate them. These receptors are usually activated by anandamide, but when they are activated by THC, various mental and physical functions become disrupted, such as cognitive function and balance, and various mental effects start to take place as well. These effects most commonly represent themselves as “pleasant euphoria” and other times “heightened sensory perception (e.g., brighter colors), laughter, altered perception of time, and increased appetite” [1].
Repeated interference of the endocannabinoid system due to THC can lead to various problems in areas of the brain that enable complex thinking, balance, and reaction time. THC has also been shown to have more permanent effects on developing brains, such as impairing specific learning and memory tasks, discussed in one study involving rats. Gleason et al. targeted cannabis receptor 1 (CB1), an endocannabinoid receptor that is prevalent “in the cortex, hippocampus and striatum” and is activated by THC in both mice and humans [3]. Gleason et al. administered a CB1 agonist during adolescence in one group, adulthood in another, and proceeded to observe brain development. They found that the adolescents developed long-term hippocampal learning and memory deficits, specifically manifesting in hippocampal long-term depression. Hippocampal depression is the process of reducing synaptic efficacy in the hippocampus due to a patterned behavior, in this case marijuana usage, resulting in the process of learning new information to become more difficult [17]. The adult rats in this study did not show signs of these changes. When it comes to humans though, studies show conflicting results.
Most of the consistently observed damage done to the human brain is within the prefrontal cortex area, due to the large volume of CB1 receptors. One study that observed adults who used marijuana four times per week compared to adults of a similar demographic that did not use marijuana found that the frequent use resulted in lower volumes of orbitofrontal cortex (OFC) gray matter [10]. The OFC is tied to various aspects of decision making and is widely believed to deal with emotional and sensory details linked to decisions. The study explains that the OFC “is enriched with CB1 receptors, and is highly implicated in addictive behaviors such as those related to disruptions in motivation” [10]. The consequences of losing gray matter are not only linked to suboptimal decision-making, but in order to compensate for the loss of volume, the brain builds more connections in the OFC. Due to the higher amount of connections, the brain requires more sustenance, particularly glucose, in order to function normally.
Despite the existence of marijuana in the world for centuries, marijuana research is still in its infancy. This is because the federal Drug Enforcement Agency (DEA) lists marijuana as a Schedule I drug, meaning “it has a high potential for abuse, no currently accepted medical use in treatment in the United States, and a lack of accepted safety for use under medical supervision” [5]. To put things into perspective, heroin, ecstasy and methamphetamine are also listed as Schedule I drugs. To study the effect on THC, researchers not only need a special permit, but they need to study individuals who are already consuming THC on a regular basis. This is a practice used for all Schedule I drugs; scientists are unable to administer heroin, methamphetamine or ecstasy to individuals in any research projects.
While THC has been shown to have various adverse effects on the brain, there is another component in marijuana that has resulted in various positive effects, cannabidiol (CBD). CBD is the second most prevalent ingredient in marijuana, and is an essential component in medical marijuana. While THC is the main psychoactive ingredient in cannabis, responsible for physical and mental disorientation, CBD is responsible for the sense of anxiety relief [4]. Until 2018, CBD was also considered a Schedule I drug, but it has since been removed due to its benignity, meaning anyone can legally buy and sell CBD in the US as long as it is derived from hemp [4]. Hemp is another plant in the cannabis family, but has different physical and chemical properties that separate it from marijuana. Hemp is typically characterized by its sturdy stalks used in textiles as well as a low concentration of THC [16]. In particular, CBD has been essential in treating “some of the cruelest childhood epilepsy syndromes, such as Dravet syndrome and Lennox-Gastaut syndrome (LGS), which typically don’t respond to antiseizure medications” [4]. There is evidence CBD helps with numerous mental disorders, including anxiety, insomnia and chronic pain, but further research investigating side effects is required.
Returning to the hippocampus region, Demirakca et al. observed hippocampal volume reductions in users who consumed cannabis that was higher in THC content than CBD content. They concluded that there was an inverse relationship between gray matter (GM) volume and THC/CBD ratio, meaning the more THC is in a product, the more likely it is that the user will have reduced GM volume [19]. However, study spanning three years conducted by Koenders et al. found that there was no relevant correlation between cannabis usage in young adults and reduced GM volumes in multiple regions of the brain, including the hippocampus [19].
CBD in particular, has been shown to have negative effects on the amygdala, whereas THC has not shown an effect. The amygdala is popularly known as being the collection of nuclei that control your sense of fear, linking it directly to a potential effect of THC usage, anxiety [18]. Surprisingly, a link between THC and the amygdala has been disproven by multiple papers. However, CBD does affect the amygdala. One study by Rocchetti et al. in 2013 and another by Pagliaccio et al. in 2015 disproved previously held beliefs linking marijuana and amygdala damage due to size. Rocchetti et al. conducted a smaller study and proved publication bias in the preceding amygdala research while Pagliaccio produced a wide study that found variation of amygdala size between marijuana users and nonusers fell within the range of normal variation [11, 14]. However, while amygdala size may not be affected, there is evidence that indicates its functionality is decreased. A study done by Fusar-Poli et al. in 2010 found that CBD actually negatively affects the amygdala due to its anti-anxiety effects. Fusar-Poli et al. found that CBD weakens signals sent from the amygdala during fear-inducing situations, meaning that CBD usage could prompt a delayed or subdued reaction compared to normal [15].
This begs the question, if further research is required to understand the full effects of THC and CBD, why is marijuana considered such a charged political topic today? To understand marijuana today, it is necessary to examine its history, often motivated for political reasons rather than scientific ones.
The history of regulation and fear associated with marijuana dates back to 1930 when Harry Anslinger was appointed as the first commissioner of the Federal Bureau of Narcotics (FBN). Due to the great depression, the federal government needed to cut funding for various agencies, and at the time, the FBN mainly combated heroin and cocaine, drugs used by a relatively small number of people. Anslinger needed to find a more widely used narcotic that would get him the necessary funds to continue his war on drugs [6].
Anslinger decided that the drug would be cannabis, and latched on to a story of a man named Victor Licata who killed his family with an Axe after consuming cannabis. While there was no evidence that he consumed marijuana before the killing, newspapers quickly sensationalized the story, and Anslinger went onto various radio shows claiming that the drug could cause insanity. The name “marijuana” was actually given by Anslinger to associate the drug with latinos, and used racial tensions to insinuate that the drug made black and latino americans “forget their place in the fabric of society” [6]. Anslinger’s actions culminated in his testifying before congress in hearings regarding the Marihuana Tax Act of 1937 which effectively banned sales.
Before it was categorized as a Schedule I drug however, there were numerous committees that ruled against the illegalization of marijuana. After the Marihuana Tax Act of 1937, New York City mayor Fiorello LaGuardia assembled a special committee with the New York Academy of Medicine “to make a thorough sociological and scientific investigation” on the effects of marijuana. The committee completely disproved Aslinger’s claims of insanity, saying “the basic personality structure of the individual does not change,” meaning after the “high” has passed, the user is unchanged personality-wise. They also stated that marijuana “does not evoke responses which would be totally alien [in an] undrugged state,” meaning the consumption of marijuana would not cause an individual to act out of character [7]. The information provided in the LaGuardia Report is quite consistent with research found today, and helped contribute to the supreme court overturning the Marihuana Tax Act in 1969 with Leary vs United States.
However, while the act was overturned, it was replaced soon after with the Controlled Substances Act 1971 under the Nixon presidency which established Marijuana as a schedule I drug. This act was another racially motivated law, with Nixon’s domestic Policy Advisor later admitting that “the Nixon White House had two enemies: the antiwar left and black people. We knew we couldn’t make it illegal to be either against the war or black, but by getting the public to associate the hippies with marijuana and blacks with heroin, and then criminalizing both heavily, we could disrupt those communities. We could arrest their leaders, raid their homes, break up their meetings, and vilify them night after night on the evening news. Did we know we were lying about the drugs? Of course we did” [8].
Nixon appointed a commission to investigate the effects of marijuana in 1972, and the report returned recommending the decriminalization of marijuana. The report argued that “Criminal law is too harsh a tool to apply to personal possession even in the effort to discourage use…It implies an overwhelming indictment of the behavior which we believe is not appropriate. The actual and potential harm of use of the drug is not great enough to justify intrusion by the criminal law into private behavior, a step which our society takes only with the greatest reluctance” [9]. In response to the report, Nixon not only refused to decriminalize marijuana, but created the DEA the next year, which would enforce the laws regarding marijuana as a Schedule I drug.
Because of the strict regulations on it today, marijuana research is still in its infancy. However, due to the aforementioned loosening of regulations on CBD research, marijuana is being pushed into the spotlight once again. This, coupled with marijuana’s past history and present realities of it being tied to members of the African American communities have made the marijuana debate into a hotbed for political discourse. Whether or not recreational marijuana becomes legal federally in the near future, it is clear that marijuana warrants further investigation in order to clear up the various inconsistencies surrounding its effects, both long-term and short-term, on the human body.
References
- National Institute on Drug Abuse research report series “Marijuana” https://www.drugabuse.gov/publications/research-reports/marijuana/what-marijuana
- Stephen V. Mahler, et. al “Endocannabinoid Hedonic Hotspot for Sensory Pleasure: Anandamide in Nucleus Accumbens Shell Enhances ‘Liking’ of a Sweet Reward.” Neuropsychopharmacology. 2007. https://www.nature.com/articles/1301376
- Kelly A. Gleason, et al. “Susceptibility of the adolescent brain to cannabinoids: long-term hippocampal effects and relevance to schizophrenia” Nature. 2012. https://www.nature.com/articles/tp2012122
- Peter Grinspoon, “Cannabidiol (CBD) — what we know and what we don’t” Harvard Health Blog, Harvard Health Publishing. August 24, 2018. https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-we-dont-2018082414476
- DEA “Drugs of Abuse (2017 edition)” 2017. https://www.dea.gov/sites/default/files/drug_of_abuse.pdf
- CBS News “The man behind the marijuana ban for all the wrong reasons” Nov. 17, 2016 https://www.cbsnews.com/news/harry-anslinger-the-man-behind-the-marijuana-ban/
- The LaGuardia Committee Report https://daggacouple.co.za/wp-content/uploads/1944/04/La-Guardia-report-1944.pdf
- Drug Policy Alliance “Top Adviser to Richard Nixon Admitted that ‘War on Drugs’ was Policy Tool to Go After Anti-War Protesters and Black People” http://www.drugpolicy.org/press-release/2016/03/top-adviser-richard-nixon-admitted-war-drugs-was-policy-tool-go-after-anti
- Schafer library of drug policy, “Marihuana: A Signal of Misunderstanding” http://www.druglibrary.org/schaffer/Library/studies/nc/ncmenu.htm
- Francesca M. Filbey, et al. “Long-term effects of marijuana use on the brain” PNAS. 2014. https://www.pnas.org/content/111/47/16913
- David Pagliaccio et al. “Shared Predisposition in the Association Between Cannabis Use and Subcortical Brain Structure” JAMA Psychiatry. October 2015. https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2429550
- Albert Batalla et al. “Structural and Functional Imaging Studies in Chronic Cannabis Users: A Systematic Review of Adolescent and Adult Findings” PLOS One. February 2013. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055821
- Cannabis research initiative “Human endocannabinoid system” UCLA Health. https://www.uclahealth.org/cannabis/human-endocannabinoid-system
- Matteo Rochetti et al. “Is cannabis neurotoxic for the healthy brain? A meta‐analytical review of structural brain alterations in non‐psychotic users” Psychiatry and Clinical Neurosciences. Sept. 2013. https://onlinelibrary.wiley.com/doi/epdf/10.1111/pcn.12085
- Paolo Fusar-Poli et al. “Modulation of effective connectivity during emotional processing by Δ9-tetrahydrocannabinol and cannabidiol” International Journal of Neuropsychopharmacology. May 2010. https://academic.oup.com/ijnp/article/13/4/421/712253
- NIDA Blog. “What is Hemp?” National institute on drug abuse for teens. November 2015. https://teens.drugabuse.gov/blog/post/what-is-hemp
- Peter Massey et al. “Long-term depression: multiple forms and implications for brain function” Cell. April 2007. https://www.cell.com/trends/neurosciences/fulltext/S0166-2236(07)00043-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0166223607000434%3Fshowall%3Dtrue
- Nicole Haloupek “What is the Amygdala?” Live Science. January 2020. https://www.livescience.com/amygdala.html
- Traute Demirakca et al. “Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol” April 2011. https://www.sciencedirect.com/science/article/pii/S0376871610003364?via%3Dihub
- Laura Koenders et al. “Grey Matter Changes Associated with Heavy Cannabis Use: A Longitudinal sMRI Study” May 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880314/
Stem Cells: Miracle Cure or Hoax? A Review of Present Application and Potential Uses of Stem Cells
By Vita Quintanilla, Genetics 23’
Author’s Note: My purpose in writing this piece is to educate the current safe applications of stem cell as misuse and damage due to the same is so prevalent in the US and abroad. While not detracting from the great advances being made in the field currently this piece is to take stock of the reality of this treatment.
Large segments of the American and world population living with medical conditions that cause significant loss of mobility and quality of life are searching for hope in Stem Cell therapy. The unfortunate reality is that many of these “therapies” are not only ineffective but potentially harmful and the clinics that distribute them are not always properly certified. While stem cell therapies are promising, run away hope for a miracle cure coupled with unethical advertising and untested procedures have caused patients in the United States and beyond to be harmed by a potentially life saving tool. Here we will examine the current state of stem cell investigation, treatment, US Regulation, prospects in the future of medicine, and information for consumers to consider in deciding to receive a stem cell treatment.
Stem cells are undifferentiated cells that are at the start of all cell lines. Embryonic stem cells come from the blastocyst, a small clump of cells that forms several days after conception, and are pluripotent, meaning that they can give rise to any cell type (except specific embryonic tissues not present out of utero). [1] While these are the most often referred to type of stem cells there are also multipotent stem cells that can only give rise to a specific kind of tissue and are present into adulthood. Somatic cells, or differentiated cells, can be reverted to a pluripotent state. Induced pluripotent stem cells (IPS) are a growing area of interest in the field as they carry with them the possibility of culturing tissues for transplant using the existing cells of a patient thus eliminating the possibility of rejection.[2]
IPS exemplify an unfortunate reality in the whole of stem cell research, that at present widespread stem cell therapies are not ready for the general public. While these cells have great potential, a major hurdle is the cost in both time and labor required to culture them in a safe and sterile environment. A single vial of research grade cells that will produce fewer than thirty colonies in five days under ideal circumstances can cost over 1,000 dollars. This does not include the cost of facilities, culture equipment, and labor making these therapies cost prohibitive as the resulting therapy can run as far as 10,000 dollars per treatment. [3&4] Furthermore, colonies of cells are far from fully developed tissues that could potentially be implanted. A patient in critical condition in need of a transplant likely cannot wait for the cells to grow into tissue in culture, even if they can afford it.
Difficulties in access however are not the greatest barrier to stem cell therapy, but rather the lack of widespread testing and approval for the treatment of the diverse conditions for which they are sometimes advertised. While these cells are promising for usage in widespread areas of medicine, at present they do not live up to the claims that many unscrupulous clinics make for them. US Stem Cell Clinic, with a sleek website, and moving testimonials, advertises the use of stem cells as a magical cure that make the old feel young again using stem cells to treat a host of orthopedic maladies. These claims are highly suspicious as the FDA website says, as of January 2019, that only stem cell therapies for blood disorders are approved. [5]
These cells have been proclaimed cure-alls and medical miracles by the mass media but the reality is that the research into the application of stem cells for diverse ailments in humans is not conclusive at the present moment. [5] The FDA only approves stem cell treatments for blood disorders using stem cells from umbilical cord blood or bone marrow, but many clinics are offering stem cell treatments for everything from vision problems to COPD. The FDA recently filed two complaints against US Stem Cell Clinic LLC in Florida and California Stem Cell Treatment Inc. for marketing stem cell products that do not have the proper approval and for having unsafe manufacturing conditions that compromised sterility and patient safety. Patients filed lawsuits against California based stem cell supplier Liveyon who sold umbilical cord stem cells contaminated with E. Coli that resulted in sepsis and several patient hospitalizations after the stem cells were used for unapproved treatments. [6] In a recent lawsuit Florida based US Stem Cell was ordered to cease and desist, destroy all stem cells in their possession and pay for twice annual facilities inspections after taking cells from fat and injecting them into the eyes of patients causing five women to be blinded. In a 2018 statement FDA Commissioner Scott Gottlieb, M.D. said “We support sound, scientific research and regulation of cell-based regenerative medicine, and the FDA has advanced a comprehensive policy framework to promote the approval of regenerative medicine products. But at the same time, the FDA will continue to take enforcement actions against clinics that abuse the trust of patients and endanger their health” [7] The FDA, has in the past been accused of slowing down progress with novel treatments, but in the case of stem cells it is apparent that their actions hold patient safety as first priority, protecting the public from doctors and companies that value monetization over public health.
Patients in the United States have been harmed by these clinics including adverse injection site reactions, migration of cells to the improper location, the failure of cells to work in the desired way, and even the growth of tumors. Clinics that operate these studies may even be operating criminally as the FDA has pressed charges against these clinics in the past in the form of permanent injunction, an order to cease and desist permanently. [7]
Patients are often motivated to take these risky treatments because there is no other hope for a cure, however, unapproved treatments can make the condition worse or even lead to death. The dangers of receiving unapproved therapies is illustrated in the case of a 38-year-old man, who developed a spinal tumor after a stem cell treatment in preformed in Portugal where doctors injected cells taken from his nose into his spine. The treatment was attempting to cure paralysis in his legs and arms. It had no effect on his paralysis, but twelve years later the tumor that formed further limited his mobility and quality of life as his bladder control and motor function in arms steadily declined. Complications have been even more dire as a thirteen-year-old male in Israel who was treated at a clinic in Moscow for Ataxia telangiectasia, which affects the nervous system, died of a tumor that arose from donor cells. These are not isolated instances of unsuccessful treatment in patients that were already ill, the stem cells themselves were directly the cause of degeneration in the patients, and more than 19 deaths confirmed by the National Institute of Health as of 2018. [8&9]
Predatory clinics that perform these unapproved procedures can be especially hard to identify. Many have sleek well-designed websites with official looking personnel and lofty claims of unrealistic success rates and propositions for stem cells as cures for many diverse and at times totally unrelated disorders. Many clinics are located in Florida and Southern California however there are hundreds of clinics across the United States. [10]*** Patients should be advised to do some research into these claims and check to see if the clinic in question as well as the treatment has FDA approval. A good strategy for determining the legitimacy of a clinic is to do research on the main doctors performing the procedure. If a clinic is claiming to be able to cure numerous unrelated and debilitating disorders, the doctors performing these procedures should be of high esteem in the community and have visible external measures to the importance of their work or the prestige of their practice. If this is not the case the patient should proceed with great caution.
The issue of deceptive stem cell clinics is not a mere issue of public health but an example of a greater problem, a break between scientific community and the public perpetuated by a few unscrupulous characters for the sake of profit. Stem cells have the potential to be life saving tools and usher in a whole new chapter of regenerative medicine, but if the reputation of this technology continues to be tarnished by clinics that do not abide by the laws and conventions put in place to keep consumers safe, this technology may never get an opportunity to reach its full potential.While stem cells have great potential for diverse treatments at some point in the future, at present their efficacy and safety for regenerative medicine has not been firmly established in the context of current technology. Not all stem cell treatments are to be feared, stem cell treatments for some blood disorders have been shown to be effective and safe. At some point in the future when culture and delivery techniques improve stem cells could revolutionize transplant and regenerative medicine. At present the best course of action for consumers in regard to these therapies is to partake only in treatments or clinical trials operating with the approval of the FDA, and keep up with developments in the field by reading peer reviewed papers published in reputable journals. Exercise great caution but do not lose hope for the future. Stay current with research and, considering the risks and benefits, consumers may choose to enroll in FDA supervised clinical trials that adhere to the three phase clinical trial process, but always be sure to exclusively receive treatment from FDA regulated and approved clinicians.
Sources
- Yu, Junying, and James Thomson. “Embryonic Stem Cells.”National Institutes of Health, U.S. Department of Health and Human Services, 2016, stemcells.nih.gov/info/Regenerative_Medicine/2006Chapter1.htm.
- “Home.” A Closer Look at Stem Cells, www.closerlookatstemcells.org/learn-about-stem-cells/types-of-stem-cells/.
- McCormack, Kevin. “Patients Beware: Warnings about Shady Clinics and Suspect Treatments.” The Stem Cellar, CRIM, 19 Jan. 2016, blog.cirm.ca.gov/2016/01/19/patients-beware-warnings-about-shady-clinics-and-suspect- treatments/.
- https://www.atcc.org/search?title=Human%20IPS%20(Pluripotent)#q=%40productline%3DL035&sort=relevancy&f:contentTypeFacetATCC=[Products]
- Office of the Commissioner. “Consumer Updates – FDA Warns About Stem Cell Therapies.” U S Food and DrugAdministration Home Page, Center for Drug Evaluation and Research, 16 Nov. 2016, www.fda.gov/ForConsumers/ConsumerUpdates/ucm286155.htm.
- William Wan, Laurie McGinley. “’Miraculous’ Stem Cell Therapy Has Sickened People in Five States.” The Washington Post, WP Company, 27 Feb. 2019, www.washingtonpost.com/national/health-science/miraculous-stem-cell-therapy-has-sickened-people-in-five-states/2019/02/26/c04b23a4-3539-11e9-854a-7a14d7fec96a_story.html.
- Commissioner, Office of the. “FDA Seeks Permanent Injunctions against Two Stem Cell Clinics.” U.S. Food and Drug Administration, FDA, 9 May 2018, www.fda.gov/news-events/press-announcements/fda-seeks-permanent-injunctions-against-two-stem-cell-clinics.
- Bauer, Gerhard, et al. “Concise Review: A Comprehensive Analysis of Reported Adverse Events in Patients Receiving Unproven Stem Cell-Based Interventions.” Stem Cells Translational Medicine, John Wiley & Sons, Inc., Sept. 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC6127222/#!po=19.4444.
- Flaherty, Brittany, et al. “Case Highlights the Risks of Experimental Stem Cell Therapy.” STAT, Staten News, 11 July 2019, www.statnews.com/2019/07/11/canada-case-long-term-risks-experimental-stem-cell-therapy/.
- https://usstemcellclinic.com/ [10]
- Commissioner, Office of the. “Step 3: Clinical Research.” U.S. Food and Drug Administration, FDA , 4 Jan. 2018, www.fda.gov/patients/drug-development-process/step-3-clinical-research.
- Hiltznik, Micheal. “Column: Judge Throws the Book at a Clinic Offering Unproven Stem Cell ‘Treatments’.” Los Angeles Times, Los Angeles Times, 26 June 2019, www.latimes.com/business/hiltzik/la-fi-hiltzik-stem-cell-injunction-20190626-story.html.
Potential Need for a New Mobile Medical Clinic to Provide ACE-Related Care to the Sacramento County for At-Risk Pediatric Populations
By Tara Allison, Biochemistry and Molecular Biology and Spanish ‘20
Author’s Note: I wrote this document as a UWP 102B assignment to evaluate the societal health care needs of Sacramento County, focusing on an upsetting mental health phenomenon, Adverse Childhood Events (ACEs). This review encompasses an in-depth analysis that illuminates the biological basis of ACEs and their connection to chronic health conditions in adulthood. This review further analyzes several Community Needs Assessments to ascertain that existing health care institutions do not, in fact, provide the proper focus or volume of mental health and ACE-related treatment needed for Sacramento County. The multidisciplinary nature of this paper connects scientific data that suggest a widespread health problem to an effective solution that UC Davis can adopt as a university. My on-campus organization R.I.V.E.R. (Recognizing Illnesses Very Early and Responding) is making progress towards development of this solution, a mobile pediatric ACE clinic.
1. Introduction
This review explores the potential benefits of developing a new mobile pediatric medical clinic that serves the northwest region of Sacramento County through Adverse Childhood Events (ACEs) related care. First, this review provides evidence of the community health needs in Sacramento County, discussed in three sections: what patients need, what currently exists for them, and what they need that is not currently offered. Second, this review examines the correlation between ACEs and future chronic health issues. And finally, this review proposes a solution based on successful existing mobile clinic models and associated limitations. For the studies included in this review, various criteria and characteristics were considered or excluded to achieve an accurate assessment of the ACE-related risk experienced by individuals in Sacramento and Palo Alto. Individuals not primarily living in these specified regions were excluded from these studies.
2. Community Health Needs In Sacramento County
2.a. What Patients Need
The northwest region of Sacramento specifically needs health care services for ACEs and primary care needs despite location and public transportation barriers and access to medical care regardless of insurance status. According to Table 5 of the 2019 Community Health Needs Assessment of Sacramento County, the northwest region of Sacramento lacks many types of health care services. Specifically, this area needs additional mental and behavioral health care services, access to quality primary care, and resources for active living and healthy eating. Additional factors contributing to an underwhelming health care sufficiency are lack of safe and violence-free environments, deficiency of functional mechanisms such as public transportation, reduced services for injury and disease prevention management, and shortage of overall cultural competency [1]. This table also explicitly highlights that youth populations need more mental health and ACE services. For the remainder of this piece, ACE-care can be considered a “mental, behavioral, and substance-abuse” service as indicated by the table.
According to Table 20 of the 2019 Community Health Needs Assessment of Sacramento County, Sacramento County has higher rates of children in poverty and children with single parents than the California averages. The median household income is comparatively lower than the California average, and there is a higher rate of violent crimes and homicides in Sacramento than in California as well [1].
The 2016 Sacramento County Community Needs Assessment establishes that medically underserved areas are localized around several different zip codes in the Sacramento area. Within these regions, pediatric emergency department admission rates are 50 percent higher than county rates due to substance abuse, mental health issues, and asthma [2]. Among the zip codes listed, 95815 and 95841 appear again in the 2019 UCD Community Needs Health Assessment, indicating that from 2016 to 2019 the same regions were consistently in need of improved health care services. This suggests that existing health care organizations are not sufficiently serving these communities.
Table 19 of the 2019 UCD Community Needs Health Assessment indicates varying amounts of clinical care providers in Sacramento County compared to the California average. It reports that portions of Sacramento are in a health professional shortage area (HPSA) for primary care and are generally considered medically underserved. However, the number of mental health providers, psychiatry providers, and primary care physicians is above the ratio for California overall. This may suggest that the location of these providers is potentially inequitable, creating a disparity across various regions of Sacramento by unevenly distributing providers. This disparity is demonstrated by the northwest Sacramento region, which lacks adequate mental health and primary care provisions.
2.b. What Exists Currently
Interestingly, although Sacramento does not lack health care professionals for mental health services compared to the average California benchmark, quality of life indicates that Sacramento residents experience poorer mental and physical health than the average California resident. This suggests that distribution of such health care professionals is inadequate and that care is not being provided to enough regions. The 2019 UCD Community Needs Health Assessment demonstrates this very clearly with data describing existing health organizations. Sacramento County contains 281 existing health care organizations that provide a variety of services. Out of those 281 organizations, only 96 institutions, or 34 percent of them, provide access to mental, behavioral, or substance abuse services. Only 73 of 281 institutions, or 26 percent, provide access to quality primary care services. And only 81 of 281 institutions, or 29 percent, provide access to active living and healthy eating resources [1]. These institutions are distributed across all of Sacramento County, so the actual health care accessibility of specific communities varies. Thus, even though existing organizations are present in Sacramento to provide these services, they are not equitably distributed across the county or provided in a high enough volume to meet expansive geographical demands.
As indicated by Table 5 of the 2019 Community Health Needs Assessment of Sacramento County, additional factors such as quality of public transportation and safety of neighborhoods may also influence patient accessibility to health care [1]. Poorly developed public transportation and frequent crimes may create an environment that encourages potential patients to stay at home, even if they reside nearby a clinic or hospital. Thus, violent environments and reduced transportation combined with inequitably-distributed health care services equate to unmet health care demands. This data indicates that Sacramento may not be well-equipped to address its various medical needs across the county.
It might make sense to conclude that any region containing a higher concentration of health care institutions for mental health should have adequate health care coverage in this category. However, this is not a completely valid assumption. The 2019 UCD Community Needs Health Assessment reports surprising contrasts within particular zip codes. It demonstrates that some areas contain plenty of clinics that provide mental health, behavioral, and substance abuse services, yet these areas are still indicated as regions that are in significant need of those services. For example, within the zip code 95823, 8 of 21 health care institutions provide mental health services in that area. However, according to the 2019 UCD Community Needs Health Assessment, the zip code 95823 resides in a region that still lacks adequate mental health services [1]. Despite that almost half of the health care organizations within 95823 provide mental health services, there is still a demonstrated need for higher volume of service or improved focus on mental health care within community clinics. This data further demonstrates that existing health care organizations are not meeting patients’ needs and could suggest that existing clinics do not provide the correct types of services or adequate volume of care required for the community.
2.c. What is Lacking
There are three primary issues that the northwest region of Sacramento is experiencing. These include health care insurance denial from current providers, location and public transportation barriers to attain proper health care, and lack of primary care access and ACE-related care.
Despite the various health organizations available, the northwest portion of Sacramento still has three unaddressed significant health care needs. In order to address all three issues, a proposal to develop a new pediatric mobile clinic should be considered. To address insurance barriers, the new clinic will provide free services to all patients regardless of insurance status. To address location challenges, the clinic will function in a large mobile vehicle equipped for medical care providers. Not only can new patient locations be reached, but multiple regions can be served by this clinic. And finally, the mobile clinic will provide services to address primary care and ACE-related care needs.
3. Correlation Between Adverse Childhood Events and Chronic Mental, Behavioral, and Physical Health Issues
The Center for Disease Control and Prevention defines ACEs as mentally and emotionally traumatic experiences that affect adolescents before the age of 18. These traumatic experiences can exist in many forms. Some examples include growing up in a household with family members who abuse substances, have mental health problems, are incarcerated, or divorced. Such experiences can undermine children’s sense of stability and safety while simultaneously interfering with their ability to bond with family or friends [3]. Many years of seminal research in this topic demonstrate a myriad of connections between ACEs and chronic health conditions, unsafe health behaviors, and premature death. This discussion will utilize research older than two years ago that is foundational to these health correlations.
3.a. Chronic Health Issues
Chronic health conditions such as autoimmune disease, cancer, chronic obstructive pulmonary disease (COPD), frequent headaches, ischemic heart disease (IHD), prescription drug usage, and liver disease have been proven to result from individuals plagued by ACE-related trauma [4, 5, 6, 7, 8, 9]. Dube and colleagues demonstrate that traumatic events during adolescence correlate with an increased probability of autoimmune disease hospitalization during adulthood [4]. In addition, Ports et al. establish a strong correlation between ACEs and exposure to modifiable cancer risks such as alcohol, chronic inflammation, obesity, UV radiation, and environmental carcinogens. Additionally, this study suggests that addressing ACEs may induce early cancer prevention [5]. Cunningham and colleagues study the correlation between COPD and ACEs such as verbal and sexual abuse, parental separation or divorce, observation of substance-abusing family members, and domestic violence. Their results indicated a higher chance of developing COPD if one or more of these ACEs were experienced in women specifically [6]. Another study by Anda and colleagues studied the relationship between the prevalence of headaches and migraines and the presence of ACEs. The results indicated that, in adulthood, there was a higher frequency of headaches or migraines if the subject had a higher ACE risk score. Subjects with lower or nonexistent ACE risk scores experienced far fewer headaches [7]. Additionally, a study completed by Dong and colleagues illuminates the connection between several types of ACEs and development of IHD. Their results demonstrate a 1.3 to 1.7 fold increase in the chance of developing IHD for patients experiencing more ACEs in comparison to those with a low ACE risk score [8]. In a different study, Dong and colleagues examine correlation of ACEs to risky behaviors that manifest later in life as liver disease. ACEs increased the likelihood of liver disease development by 1.2 to 1.6 times [9]. Beyond chronic health issues, ACEs have been shown to be related to other problems in adulthood such as unsafe health behaviors.
3.b. Unsafe Health Behaviors
Unsafe health behaviors such as alcohol abuse, drug use, obesity, sexual risk behavior, and smoking are health outcomes of ACEs as well [10, 11, 12, 13, 14]. Strine et al. establishes direct correlations between alcohol abuse and ACE-related experiences such as sexual abuse, childhood neglect and emotional abuse, family drug abuse or mental illnesses, and parental divorce. They claim that psychological distress associated with ACEs results in alcohol abuse later in life [10]. Furthermore, Anda and colleagues discovered a 40 percent increase in prescription drug usage in patients with non-zero ACE scores and a positive correlation between a higher ACE risk score and prescriptions across all age groups (18-44, 45-64, and 65-89 years of age) [11]. In another study, Williamson and colleagues identified a correlation between physical and verbal abuse and increased body weight and obesity measurements. Participants that experienced “being hit” were 4.0 kg heavier on average than participants that did not report physical abuse [12]. Additionally, Hillis et al. evaluated the connection between sexual risk behavior and ACE events and discovered a positive correlation between the two as well [13]. Strine and colleagues, in a different study, observed increased risk of smoking habits in women when ACE risk scores are present as well [14]. ACEs have been shown to relate to reduced lifespans as well.
3.c. Premature Death
ACEs correlate with suicide and depression in adulthood, leading to premature death in adulthood [15, 16]. According to Dube and colleagues, suicide rates increased two to five fold in adulthood due to connections regarding ACEs. Factors such as alcoholism and illicit drug use had close ties to the presence of ACEs and path to suicide attempt [15]. Additionally, Chapman et al. established a connection between a higher number of ACE-related events and a greater chance of developing a depressive disorder. The study also suggests that early recognition of childhood trauma may prevent future depression diagnosis [16]. This extensive, yet not exhaustive, collection of studies indicates that ACEs have a very real impact on pediatric mental health and adult health status later in life. In order to address the lack of mental health provision in Sacramento, the proposal to develop a new pediatric mobile clinic specializing in ACE-care and primary care services should be considered.
4. Proposed Solution and Limitations
The northwest region of Sacramento has three primary concerns: health care insurance denial from current providers, location and public transportation barriers to attain proper health care, and lack of primary care access and ACE-related care. In order to address these issues, this paper proposes the implementation of a new mobile medical pediatric clinic. The clinic will provide ACE-related care and primary care services for chronic and acute illnesses. It will mitigate health care insurance barriers by serving uninsured and partially insured residents of Sacramento County as well. Furthermore, the clinic will serve patients in a 26-foot vehicle equipped with two medical examination rooms and ample supplies. In this way, residents can access medical care despite any location or public transportation challenges. As a vehicular clinic, mobility ensures access to multiple communities in Sacramento.
The primary barriers to implementing this mobile clinic include shortage of staffing availability along with annual financial demands. These are not issues unique to a mobile or pediatric ACE-care clinic, so our proposal can model existing clinics to realistically overcome these barriers. First, UC Davis student-run clinics are excellent models to consider. Financially, a volunteer-based operations system will ensure low-cost annual expenditures. Furthermore, grant writing, fundraising, and donor support are effective funding methods these successful clinics utilize as well. Staffing availability can be mitigated by way of a reduced, yet consistent, weekend operations schedule. As physicians may not be available during weekdays due to employment commitments, weekends are an ideal time to volunteer.
We can observe many similarities between this mobile, ACE-care, pediatric clinic proposal and other vehicular clinic models. Existing mobile medical clinics provide similar services in other cities and provide excellent examples to base this proposal on. One especially successful case is the Stanford Teen Van, a mobile medical clinic that primarily serves youth in the Bay Area. The table below from the 2019 Stanford Community Health Needs Assessment indicates that this clinic provides ACE-related care in the form of mental health services in addition to primary care. Furthermore, this establishment has successfully provided improved access for 2,892 individuals that otherwise would experience location-based barriers [17].
The Stanford Teen Van also provides its services and medications for free, thus eliminating any insurance-based discrimination. This model is an excellent comparison to study because this clinic provides identical services to a similarly underserved population in the Bay Area. The Stanford Teen Van, alongside the UC Davis student-run clinics, are phenomenal infrastructures to learn from by way of mobility, service provision, and volunteerism. By analyzing successful practices, this proposal overcomes limitations and provides effective solutions based on existing infrastructures, resulting in a refined and well-rounded project concept.
5. Conclusion
This review discussed the potential benefits of developing a new mobile pediatric medical clinic that would serve the northwest region of Sacramento County. First, this review demonstrated extensive evidence of the community health needs in Sacramento. Second, this review examined the correlation between ACEs and future chronic health issues. Finally, this review discussed a proposed solution following successful existing mobile clinic models and associated limitations. When considering the data holistically, it is clear that a new pediatric mobile clinic would significantly benefit deserving patients in Sacramento. Furthermore, despite the fact that this mobile clinic proposal is built on well-established practices and successful existing infrastructure, this specific combination of ideas has not yet been implemented in Sacramento. While maintaining its merit and validity, this innovative project challenges the existing medical culture of Sacramento by introducing ACE awareness and the expansive versatility of a mobile clinic vehicle.
References
- Ainsworth D, Diaz H, Schmidtlein M, Van T, 2019 Community Health Needs Assessment. 2019 CHNA of Sacramento County 2019. 2019; 1-116.
- Wagner J, Rosenbaum A, Schmidtlein M, Underwood S. Sacramento County Community Health Needs Assessment. Sacramento County CHNA. 2016; 1-40.
- Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, Koss MP, Marks JS. Relationship of Childhood Abuse and Household Dysfunction to Many of the Leading Causes of Death in Adults. American Journal of Preventive Medicine. 1998; Vol 14, Issue 4, 245-258.
- Dube SR, Fairweather D, Pearson WS, Felitti VJ, Anda RF, Croft JB. Cumulative childhood stress and autoimmune disease. Psychol Med. 2009; 71:243–250.
- Ports KA, Holman DM, Guinn A, Pampati S, Dyer K, Merrick MT, Buchanan N, & Metzler M. Association between Adverse Childhood Experiences and Leading Risk Factors for Cancer in Adulthood. Journal of Pediatric Nursing. 2019; 44, 81-96.
- Cunningham TJ, Ford ES, Croft JB, Merrick MT, Rolle IV, Giles WH. Sex-specific relationships between adverse childhood experiences and chronic obstructive pulmonary disease in five states. 2014; 9:1033-42.
- Anda R, Tietjen G, Schulman E, Felitti V, Croft J. Adverse childhood experiences and frequent headaches in adults. Headache. 2010; 50(9):1473-81.
- Dong M, Giles WH, Felitti VJ, Dube, SR, Williams JE, Chapman DP, Anda RF. Insights into causal pathways for ischemic heart disease: adverse childhood experiences study. Circulation. 2004; 110:1761–1766.
- Dong M, Anda RF, Dube SR, Felitti VJ, Giles WH. Adverse childhood experiences and self-reported liver disease: new insights into a causal pathway. Arch Intern Med. 2003; 163:1949–1956.
- Strine TW, Dube SR, Edwards VJ, Prehn AW, Rasmussen S, Wagenfeld M, Dhingra S, Croft JB. Associations between adverse childhood experiences, psychological distress, and adult alcohol problems. Am J Health Behav. 2012; 36(3):408-23.
- Anda RF, Brown DW, Felitti VJ, Dube SR, Giles WH. Adverse childhood experiences and prescription drug use in a cohort study of adult HMO patients. BMC Public Health. 2008; 4; 8:198.
- Williamson DF, Thompson, TJ, Anda, RF, Dietz WH, Felitti VJ. Body weight, obesity, and self-reported abuse in childhood. International Journal of Obesity. 2002; 26:1075–1082.
- Hillis SD, Anda RF, Felitti VJ, Marchbanks PA. Adverse childhood experiences and sexual risk behaviors in women: a retrospective cohort study. Fam Plann Perspect. 2001; 33:206–211.
- Strine TW, Edwards VK, Dube SR, Wagenfeld M, Dhingra S, Prehn AW, Rasmussen S, Mcknight-Eily L, Croft JB. The mediating sex-specific effect of psychological distress on the relationship between adverse childhood experiences and current smoking among adults. Subst Abuse Treat Prev Policy. 2012; 7:30.
- Dube SR, Anda RF, Felitti VJ, Chapman D, Williamson DF, Giles WH. Childhood abuse, household dysfunction and the risk of attempted suicide throughout thelife span: Findings from Adverse Childhood Experiences Study. JAMA. 2001; 286:3089–3096.
- Chapman DP, Anda RF, Felitti VJ, Dube SR, Edwards VJ, Whitfield CL. Adverse childhood experiences and the risk of depressive disorders in adulthood. J Affect Disord. 2004; 82:217–225.
- Espino M, Stelle J. 2019 Community Health Needs Assessment. 2019 Stanford Community Health Needs Assessment. 2019; 1-52.
A History of Vaccines and How they Combat Disease
By Vishwanath Prathikanti, Political Science ‘23
Author’s note: The anti-vaccination movement has recently gained traction with many families across the nation and I wanted to tackle the idea of anti-vaccination and where it came from. I also wanted to see if there was any credit due to the anti-vaccinators and see if there was any truth to the idea that more vaccinations might be bad.
In April 2019, public health officials declared a measles outbreak in Los Angeles. To many, this sounded almost absurd; measles was eradicated in the United States in 2000 [4]. The outbreak highlighted the severity of a movement that many had declared irrelevant: the anti-vaccination movement. In light of this event, many had to question: what is the anti-vaccination movement? When did it begin? Is there any truth to the movement?
To understand the anti-vaccination movement, one must first understand vaccines and their history. Centers for Disease Control and Prevention (CDC) defines a vaccination as, “a product that stimulates a person’s immune system to produce immunity to a specific disease, protecting the person from that disease.” [1]. The human immune system uses white blood cells to fight infections in the body; specifically, there are three types of white blood cells that work together to fight infections: macrophages, B-lymphocytes and T-lymphocytes [2]. When a cell becomes infected or dies, it releases a chemical that attracts macrophages, which will engulf and degrade the cell. If the cell was damaged or died due to a virus or bacteria, the macrophage will leave behind antigens, which are recognized by the immune system as harmful [10]. When the immune system recognizes the antigens, B-lymphocytes will produce antibodies to attack the antigens and T-lymphocytes will attack cells in the body that have been infected by the identified antigen. After the infection is dealt with, the immune system will create memory cells that act immediately if the body encounters the same germ again. Vaccines work by imitating an infection; they do not cause illness but they will stimulate the production of T-lymphocytes, B-lymphocytes and memory cells to fight the disease in the future. Most vaccines require multiple doses to ensure full immunity, and how frequent these dosages are required depends on the vaccine [2].
Our knowledge of vaccines has not always been as vast as it is today. Evidence suggests that the earliest form of inoculation was in China during the late 1600s when emperor K’ang Hsi had his children inoculated after surviving smallpox (the process involved grinding smallpox scabs and inhaling them) [5]. The practice of vaccination has grown considerably since then, becoming vastly popular in the West by the 17th century. In 1853, Britain passed a law that made it mandatory for citizens to receive a smallpox vaccination and in 1855, Massachusetts passed the first U.S. law mandating vaccination for smallpox, allowing vaccinations to grow and develop.
In the late 20th century, research on the negative effects of vaccines started to emerge. A 1995 study published in The Lancet linked the measles-mumps-rubella (MMR) vaccine with bowel disease. Wakefield, a gastroenterologist and researcher in the study, went on to further speculate that persistent infection with the vaccine caused disruption of the intestinal tissue that could lead to autism. This led to the study that would capture the attention of parents for decades to come. In 1998, Wakefield and his colleagues published a case series study in which, out of 12 children who had recently been administered their MMR vaccine, eight had the measles virus in their digestive system and were demonstrating symptoms for autism. Wakefield then went on to claim that the combined vaccination led to this, and advocated instead to adopt single-antigen vaccinations as opposed to combined MMR vaccines [3]. He did not, however, list how he came to this conclusion, saying “the combined measles, mumps, and rubella vaccine (rather than monovalent measles vaccine) has been implicated” [3].
The link between autism and the MMR vaccination was studied intensively over the next few years, and no reputable study ever found a similar link. Additionally, a study published in The Journal of Pediatrics, while acknowledging a slightly lower than average antibody count when the combined vaccination was employed, stated that there was no significant reason why single antigen vaccinations should be favored over combined vaccinations. The lower antibody count was deemed irrelevant in light of the fact that failure of the vaccine was extremely rare in fully immunized children [7]. In 2010, The Lancet formally retracted the paper, and three months later, Britain’s General Medical Council banned Wakefield from practicing medicine in Britain. Finally, in 2011, it was revealed that Wakefield had falsified most of his data; in his study, he reported eight children developed symptoms of autism when in reality, there were at most two cases. In addition, two of the children had developmental delays that were not mentioned in the final published work [3].
Despite the study being completely discredited by the scientific community, the damage to society had been done; after the Wakefield paper was published, vaccination rates dropped below 50 percent in some parts of London. Luckily, immunization rates drastically rose since then, with over 90 percent in the UK vaccinated in 2013, with BBC declaring a “universal recovery” [8]. Although vaccination rates are high, the US still faces about 60 cases of the measles every year, caused by international travelers who carry the disease [9]. While the spread of misinformation due to the Wakefield paper has mostly subsided, its legacy continues keeping a minority of children in the US unvaccinated and susceptible to antiquated and preventable diseases.
References
- Centers for Disease Control and Prevention “Immunization: the basics” https://www.cdc.gov/vaccines/vac-gen/imz-basics.htm
- Centers for Disease Control and Prevention “Understanding how vaccines work” https://www.cdc.gov/vaccines/hcp/conversations/downloads/vacsafe-understand-color-office.pdf
- History of Vaccines “Do vaccines cause autism?” https://www.historyofvaccines.org/content/articles/do-vaccines-cause-autism
- Centers for Disease Control and Prevention “History of measles” https://www.cdc.gov/measles/about/history.html
- History of Vaccines “All timelines overview” https://www.historyofvaccines.org/timeline#EVT_1
- Wakefield A, et al. RETRACTED:—Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 1998; 351(9103): 637-641. https://www.thelancet.com/action/showPdf?pii=S0140-6736%2897%2911096-0
- Heinz J. Schmitt, et al. “Primary vaccination of infants with diphtheria-tetanus-acellular pertussis–hepatitis B virus– inactivated polio virus and Haemophilus influenzae type b vaccines given as either separate or mixed injections.” The Journal of Pediatrics. 1999. https://www.sciencedirect.com/science/article/pii/S0022347600260885
- BBC “Measles outbreak in maps and graphics” 2013. https://www.bbc.com/news/health-22277186
- NPR “Fifteen Years After A Vaccine Scare, A Measles Epidemic” 2013. https://www.npr.org/sections/health-shots/2013/05/21/185801259/fifteen-years-after-a-vaccine-scare-a-measles-epidemic
- Arizona State University “Macrophages” https://askabiologist.asu.edu/macrophage