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Disparities in Reproductive and Sexual Healthcare of Women with Disabilities

By Manasvini Pochimireddy.
Author’s Note
: I wrote this piece for a general academic audience of my peers. I specifically chose this topic because disabled women have been a historically marginalized group, with inadequate resources in the healthcare system to lead healthy lives. In terms of their reproductive and sexual healthcare, these women face a public stigma and are never made aware of any risks. While much more research is needed in order to implement lasting changes in the healthcare of this population, I wanted this paper to simply introduce people to this topic and raise awareness that this is a sector of healthcare requiring attention.

Abstract: 

Women with disabilities face many challenges in the healthcare system, as there has been a long-standing stigma around disabilities. Specifically, these women have been met with disregard and insensitivity, and sometimes they are even denied access to sexual and reproductive healthcare. Despite the large number of individuals with disabilities in the general population, there is a lack of research on the various issues faced specifically by women with disabilities. This review of literature will investigate the question: “What does current scholarship tell us about the disparities in reproductive and sexual healthcare faced by women with disabilities?” To provide a more complete understanding of why this disparity exists and how to effectively address it, more studies need to be conducted about changes that need to occur in this field.

Introduction: 

The term “disabilities” encompasses a variety of conditions that can result in lack of function, either physically (impairment in bodily activity) or cognitively (impairment in mental well-being) [1, 2]. Currently, individuals with some form of disability compose approximately 15% of the world population. However, when considering the amount of disabled individuals by gender, 19.2% of all women are affected globally, whereas only 12% of all men are affected [2]. This 7% difference would mean that there are approximately 250 million more women than men experiencing disability in our current global population [2].This has been especially prevalent for women, as their reproductive and sexual healthcare is not seen as a priority [3, 4]. Reproductive and sexual healthcare refers to treatment of women before and after conception, as well as gender specific care.  This review will focus on the disparities faced by disabled cis-gendered women in the United States, specifically in terms of their reproductive and sexual healthcare. Furthermore, when referring to “women” in this paper, it will be focusing on cis-gendered women. This is not to say transgender women do not face similar difficulties.

Women with disabilities face a multitude of challenges in the healthcare system, including a lack of proper health education, stigma concerning their reproductive health, and greater risk factors for specific ethnic groups [2, 3, 5-8]. In terms of education, women with disabilities are not provided with enough knowledge to make informed decisions regarding their well-being in terms of reproductive and sexual health [3, 7]. Healthcare practitioners and caretakers are equally uneducated on providing resources and knowledge to these women, leading to unanswered questions and uncomfortableness on both ends of these conversations [2].  This stems from lack of discussion in school systems regarding people with disabilities in the context of reproductive and sexual health [9].  Furthermore, many healthcare practitioners and family members hold a stigma against women with disabilities and their reproductive health, leading to poor quality of care in the few appointments that do occur [4, 8]. Many women with disabilities are further subjected to increased preconception risks (obesity, stress, medications) and marginalized because of their race [5, 6]. 

While we have made significant advances in many aspects of healthcare, resources to support these women have been at a standstill [3, 4]. The education about disabled women’s needs has also remained both inadequate and stagnant. While research has been done to establish that this is an issue, no further steps have been taken to improve the state of this problem. This review of literature will investigate the different factors that exacerbate the disparity in reproductive and sexual healthcare for women with disabilities. 

Reproductive and Sexual Health Education 

Inadequate education in terms of sexual health has remained a contributing factor to the lack of healthcare resources in preconception health for disabled women. Preconception health represents the general well-being of a woman during her reproductive/fertile years (between puberty and menopause) in terms of her overall health, including pre-existing conditions. Despite women with and without disabilities both having similar pregnancy rates, there was a significant lack of knowledge among disabled women regarding their own well-being and personal expectations for pregnancy [3, 7]. From 2018 to 2022, multiple independent studies confirmed there were higher rates of unplanned pregnancies reported amongst the disabled womens’ population when compared to women without disability [3, 7, 10]. For example, one study found among pregnancies in women with disabilities, 53% were unwanted vs. 36% being unwanted in non-disabled women [7]. Along with high rates of unplanned pregnancies, a similar trend exists in the use of birth control. A survey identifying rates of birth control use found 19.7% of sexually active disabled women among the ages of 15-24 were not using any method of birth control, compared to 10.6% of non-disabled women in the same age group [10]. This means that nearly double the amount of disabled women are at risk for unplanned pregnancies when compared to non-disabled women [10]. These higher rates of birth control usage and unplanned pregnancies in the disabled womens’ population stem from the lack of sexual and reproductive health education being taught during their formative years [3, 9, 10]. Current studies examine the lack of sexual health education for women with disabilities, but more studies should be conducted on how and when to provide this type of education to ensure that these women are informed about their health. Moreover, this discussion needs to be normalized to create amore inclusive environment when educating about disabilities in the context of reproductive and sexual health.

Not only is there a lack of sexual and reproductive health education for women with disabilities, but there is also a lack of this same education on the part of healthcare practitioners and caretakers in this field [1-3, 8]. It is vital for people in these positions to understand the needs of a woman with a disability in order to prepare them for what to expect, along with the fact that their needs may be separate from the needs of a woman without a disability [2, 3]. Kalpakijan et al. conducted a study among 81 self-reportededly disabled women who explained via group and individual interviews regarding their reproductive healthcare experiences. Kalpakijan et al. identified five major themes that informed a framework to be implemented across institutions. These themes were knowledge about reproductive health, communication about reproductive health, relationships, the reproductive health care environment, and self-advocacy/identity [11]. To provide adequate, quality care and be responsive to the questions of disabled women regarding their sexual health, changes need to be made to include sensitivity training, specifically in properly and respectfully communicating differences in needs for disabled women during pregnancy [2, 3, 8]. Further research needs to be conducted on how healthcare providers and caretakers can be further educated on the needs of disabled women in terms of sexual and reproductive health. 

Effects of Ethnicity on Healthcare Disparities of Disabled Women 

Ethnicity plays a role in exacerbating the differences in reproductive and sexual healthcare between disabled and non-disabled women. The systemic differences associated with different racial groups that result in unequal access to a variety of health resources extend to women with disabilities and their access to reproductive health resources as well [6]. There are much higher rates of reproductive-related complications, such as post-conception/postpartum complications, or issues during the pregnancy itself among disabled women when compared to non-disabled women. However, upon further examination, an unequal distribution of these complications across different ethnicities is found [5, 6].The combination of having a disability and being an ethnic minority seems to have an additive effect on the disparity in accessing adequate reproductive healthcare resources for women [5].  

There are certain preconception health risks (obesity, stress, medications) that are more severe in certain ethnic communities of disabled women, such as obesity in disabled black women [5]. There are also higher rates of gestational diabetes and gestational hypertension (preeclampsia) found among disabled women of Hispanic and African-American origin, with multiple possible causes, including high mental distress, lack of access to proper nutrition, and low levels of exercise [4, 5]. Most, if not all of these adverse preganancy conditions are rooted in structural racism resulting in restricted access to determinants of health [5].  Further studies should be done on how to lessen the impact of the combination of ethnicity and disability on access to healthcare, and to isolate why specific conditions and complications are more prevalent among specific ethnic communities of disabled women. 

Social Attitudes Towards Women with Disabilities 

Public stigma of women with disabilities severely limits their access to adequate resources in healthcare, specifically when concerning pregnancy and reproductive health. Firstly, women with disability are seen as less sexually active, despite many studies showing equal rates of sexual activity amongst women with disability and women without disability [9, 12, 13]. 

With these false expectations, many healthcare providers do not think to offer the same resources concerning reproductive and sexual healthcare to women with disabilities [3, 9]. Many disabled women are unaware of the fact that they could have children, due to the lack of information from their healthcare providers. As a result, they are often surprised by unforeseen pregnancies [3] In a survey from 2022 asking women about their healthcare provider visit, when disabled women opted to discuss their reproductive and sexual healthcare, they often felt insensitivity from the provider [3, 8]. They also felt uncomfortable asking further questions about their health [3, 8, 9] Not only did women feel this sense of embarrassment, their family members also felt this due to the public stigma of women with disabilities engaging in sexual activities [8].

This stigma resulted in a decrease in quality of care provided to women with disabilities [4]. When evaluating the number of visits by expectant mothers during pregnancy, it was found that there was a significantly lower number of overall visits amongst women with disabilities when compared to women without disabilities, especially in the first trimester [4]. Moreover, when comparing rates of miscarriage among women with disabilities vs without, it was found that disabled women experience miscarriages at a rate of 31.63 % versus women without disabilities experience miscarriages at a rate of 21.83% [14]. Many women also experience fear for their offspring inheriting their disability, even when there is no genetic link, due to the inadequate explanations provided by healthcare providers [2, 8]. These concerns should be properly addressed and answered without judgment, but instead are sidelined or in some cases, not even received [2]. The existing stigma can be combated through open communication between individuals with disabilities regarding their needs and people in positions who can implement changes to diminish the existing disparity. In addition, a more inclusive curriculum in sexual health should be implemented in primary school systems so that more individuals, as well as future healthcare professionals, can be exposed to this subject from an early age. This would allow for discussion about disabilities in context to reproductive health to increase, and to become more normalized in society. 

Conclusion: 

Overall, a variety of factors aggravate the disparity present in the reproductive and sexual healthcare of disabled women. The lack of sexual health education for disabled women remains, along with the lack of training and knowledge on the part of healthcare practitioners and caretakers attending to the needs of disabled women [1, 3, 7, 9]. This causes difficulties during family planning stages and during treatment, when these women haven’t been properly informed of the necessary measures [1, 15]. The current healthcare system has resources to support women without disabilities who face these issues, but when disabled women undergo similar circumstances, they find themselves with few places to turn to that can accommodate their needs [15]. Further studies also need to be conducted to find out why certain preconception health risks are more severe among certain ethnic groups, as there is evidence that specific medical conditions are more prevalent in specific communities [5, 10]. A systemic change to tackle the disparities faced by women with disabilities who are also ethnic minorities needs to be taken. To this day, disabled women who pursue reproductive health measures face negative attitudes from healthcare professionals [2, 11]. These attitudes can be dissipated through changes in the current sexual education curriculum, which would allow for both the disabled community and non-disabled community to learn about the needs of disabled women. Another vital part of reducing these disparities includes encouraging conversations about mental and physical differences that clearly exist and acknowledging them, so that more individuals are aware of the challenges faced by disabled women in the healthcare system. In the literature reviewed, there was a great discussion and evidence of the existence of this problem, but rarely were any solutions offered. There were a couple of suggested frameworks, but none that looked at the efficacy of its implementation. Moving forward, there need to be studies done regarding possible methods that can truly alleviate the disparity faced by disabled women.

References: 

  1. Crabb C, Owen R, Heller T. Female medicaid enrollees with disabilities and discussions with health care providers about contraception/family planning and sexually transmitted infections. Sex Disabil. 2019; 38: 299-312 doi: 10.1007/s11195-019-09599-y 
  2. Nguyen TV, King J, Edwards N, Dunne MP. “Nothing suitable for us”: Experiences of women with physical disabilities in accessing maternal healthcare services in northern Vietnam. Disability and Rehabilitation. 2020;44(4):573-581. doi:10.1080/09638288.2020.1773548
  3. O’Connor-Terry C, Harris, Pregnancy decision-making in women with physical disabilities. Disabil Health J. 2022;15(1): 1-5 doi: 10.1016/j.dhjo.2021.101176 7. 
  4. Horner-Johnson W, Biel FM, Caughey AB, Darney BG. Differences in prenatal care by presence and type of maternal disability. American Journal of Preventive Medicine. 2019;56(3):376-382. doi:10.1016/j.amepre.2018.10.021 
  5. Horner-Johnson W, Akobirshoev I, Amutah-Onukagha NN, Slaughter-Acey JC, Mitra M. Preconception health risks among U.S. women: Disparities at the intersection of disability and race or ethnicity. Womens Health Issues. 2021;31(1):65-74 doi:10.1016/j.whi.2020.10.001 
  6. Alhusen JL, Bloom T, Laughon K, Behan L, Hughes RB. Perceptions of barriers to effective family planning services among women with disabilities. Disability and Health Journal. 2021;14(3):1-6. doi:10.1016/j.dhjo.2020.101055 
  7. Horner‐Johnson W, Dissanayake M, Wu JP, Caughey AB, Darney BG. Pregnancy intendedness by maternal disability status and type in the United States. Perspectives on Sexual and Reproductive Health. 2020;52(1):31-38. doi:10.1363/psrh.12130 
  8. Nguyen TV, King J, Edwards N, Pham CT, Dunne M. Maternal healthcare experiences of and challenges for women with physical disabilities in low and middle-income countries: A review of qualitative evidence. Sexuality and Disability. 2019;37(2):175-201. doi:10.1007/s11195-019-09564-9
  9. Namkung EH, Valentine A, Warner L, Mitra M. Contraceptive use at first sexual intercourse among adolescent and young adult women with disabilities: The role of formal sex education. Contraception. 2021;103(3): 178-184. doi:10.1016/j.contraception.2020.12.007 
  10. Mosher W, Hughes RB, Bloom T, Horton L, Mojtabai R, Alhusen JL. Contraceptive use by disability status: New National Estimates from the National Survey of Family Growth. Contraception. 2018;97(6):552-558. doi:10.1016/j.contraception.2018.03.031 
  11. Kalpakjian CZ, Kreshcmer JM, Slavin MD, Kisala PA, Quint E, Chiaravalloti ND, Jenkins N, Bushnik T, Amtmann D, Tulsky DS, Madrid R, Parten R, Evitts M, Grawi CL. Reproductive health in women with physical disability: A conceptual framework for the development of new patient-reported outcome measures. J Womens Health. 2020;29(11):1427-1436 doi:10.1089/jwh.2019.8174 
  12. Shandra C. L. & Chowdhury A. R. “The First Sexual Experience Among Adolescent Girls With and Without Disabilities.” 2012. Journal of Youth and Adolescence. 41:515–532 https://doi.org/10.1007/s10964-011-9668-0 
  13. Kah, N.F. & Halpern, C.T. Experiences of Vaginal, Oral, and Anal Sex From Adolescence to Early Adulthood in Populations With Physical Disabilities. 2018. Journal of Adolescent Health. 62(3):294-302. https://doi.org/10.1016/j.jadohealth.2017.08.003 
  14. Dissanayake, M. V., Darney, B. G., Caughey, A. B., & Horner-Johnson, W. (2020). Miscarriage Occurrence and Prevention Efforts by Disability Status and Type in the United States. Journal of women’s health (2002), 29(3), 345–352. doi: /10.1089/jwh.2019.7880
  15. Collins B, Hall J, Hundley V, Ireland J. Effective communication: Core to promoting respectful maternity care for disabled women. Midwifery. 2022:1-27. doi:10.1016/j.midw.2022.103525

Most Endangered Whale on Earth is America’s–and you’ve never heard of it

By David Kwon.
In 2021, a joint team of researchers led by the National Marine Fisheries Service (NMFS) revealed the discovery of a new species of baleen whale: the Rice’s whale. Baleen whales (mysticetes) are whales that don’t have teeth. Instead, they have bristle-like structures called
baleen that are perfected for filter-feeding. Unlike most new species, which are often small critters hidden in corners seldom disturbed by humans, this cetacean was hiding in plain sight all along. Long as a school bus, it inhabits the northern Gulf of Mexico (GOMx), not far from United States shores [1]. In fact, if you hitch a seaplane in Pensacola, Florida and fly a 40-minute trip about 60 miles south) to the offshore De Soto Canyon (roughly the distance from Davis to Berkeley), you’ll have reached the area these whales call home. Perhaps you’ll even spot a surfacing individual! But alongside the distinction as its own species, this baleen whale had eluded another, more dire secret–it’s on the very brink of extinction with only about 51 whales remaining [2]. It is already the second most endangered marine mammal in the world.

 

A new species is, whale, very hard to name

Figure 1. Maximum size of a Rice’s whale scaled to a human and a school bus with the whale’s diagnostic features labeled

 

How have we missed a giant whale swimming along our doorstep? Actually, we have known a population of baleen whales has existed in the GOMx since at least 1965 [3], and historical records suggest that local whalers attempted to hunt them since at least the late 1700s [4]. However, scientists initially believed that they were members of another wide-ranging tropical species called the Bryde’s whale, which frequents the neighboring Atlantic Ocean and Caribbean Sea. This is easily forgivable, as the outward appearance of these GOMx whales are virtually indistinguishable. Both have essentially the same streamlined, sleek bodies of uniform dark charcoal gray or brown coloration on top, and a mix of pale and pink underneath. A large, hook-shaped dorsal fin is placed around two-thirds down from the tip of the snout. The snouts themselves are spear-shaped with three distinct prominent ridges on top (a thick central one extending from snout end to blowhole, and two slightly smaller ones flanking both sides) (Figure 1) [1]. It was not until the 1990s [3] when scientists realized that the GOMx whales inhabits an extremely narrow and isolated area. Nearly all reside within the scientist-dubbed “core habitat”—a thin deep-water stretch off the western coastlines of Florida with seafloors between 150-410 meters deep—while a few exist in even narrower secondary habitats of similar seafloor depths extending to Texas (Figure 2) [1]. This hinted that they may be set apart from the Atlantic Bryde’s whales.

Figure 2. Map of the Rice’s Whale habitat within the GOMx

 

The possibility that populations thought to be an existing known species are actually new species is nothing new with cetaceans. Mobile marine mammals that seek refuge below the surface can be difficult to study, and granting any divergent population its own scientific name requires (1) substantial morphological and genetic evidence from bone and tissue samples to prove it’s not simply a variant of an existing species, and (2) a skull to serve as a defining specimen, or holotype. In other words, we need good DNA and dead whales. As a result, many potential species are left undescribed as scientists wait for a beached individual to obtain a cetacean cadaver without needing to harm the same whales they seek to study and save [1].

 

This was the case for the GOMx whales when Rosel & Wilcox (2014), two NMFS geneticists, compared the genetic sequences of the mitochondrial DNA control region (mtDNA CR) collected from beachings and biopsies with other Bryde’s whales. The mtDNA CR is often used by geneticists to study recent evolutionary histories due to its exceptionally fast mutation rate, capturing even the most subtle of population diversity [5][6]. The geneticists found that the GOMx whales were actually most closely related to a similar Asian species called the Eden’s whale–also previously thought to be a Bryde’s whale–with a ~10% net nucleotide divergence. This was far above the 2% divergence threshold for a distinct species, establishing that a new species likely exists [7]. A multi-year hunt for a holotype followed. First, the NMFS visited museums that held skeletons of GOMx Bryde’s whales, but none had a complete skull. Then, they attempted to recover the skeleton of a whale that washed up in Tampa Bay, Florida after colliding with a ship in 2009 and was subsequently buried in a nearby park [1] as standard disposal practice to prevent spreading infectious diseases or attracting scavengers [8]. Unfortunately, upon excavation in 2018, they found that seeping tides had damaged much of the specimen over its years of burial. Finally, a stroke of luck occurred when in 2019 another individual washed up in Everglades National Park, which had bled to death due to a laceration in its stomach caused by a tiny piece of plastic it swallowed. The NMFS and National Park Service quickly genetically sampled and buried the whale in a more secure location, exhumed the skeleton, and safely transported it to the Smithsonian’s Whale Collections. There, Rosel et al. (2021) had the holotype and morphological evidence, in the form of a unique cranial and nasal structure, needed to formally describe a new species, giving it the scientific name Balaenoptera ricei [1].

 

Second most endangered in the world

 

Though identical in external appearance, the Rice’s and Bryde’s whales are otherwise very different. A molecular clock shows that they diverged at least 4-8 million years ago [1, 9], and the few hints we have so far suggest a unique biology for the former. But as further study of the new species unfolds, understanding how exactly it stands apart continues to develop [1, 2, 10, 11]. We know that it’s the only baleen whale native to the GOMx. While the basin receives occasional fin, blue, sei, minke, and right whale visitors, they never stay for long and have no influence on the local ecology [1, 12]. Rice’s whales are also entirely resident, meaning the species stays in the same area year-round and doesn’t migrate. This is the only instance we know of that an entire species of mysticete is tied to a tiny piece of the ocean. While other baleen whales hold populations and subspecies that have settled into areas of reliable year-round productivity, such as the Arabian Sea humpback whales [13] and Gulf of California fin whales [14], their species still include wide-wandering members that will endure when one population tragically dies out. To lose the Rice’s whales is to lose a special diversity, endemism, and ecological role of an entire classification of animals in the GOMx.

 

This newest species of marine mammal is, ironically, also one of the closest to extinction. The most recent population study from a 2017-2018 survey within US waters numbers 51 individuals left in existence [2], with only 26 of them being mature individuals capable of reproduction [15]. This makes it the second most endangered marine mammal species and arguably the fourth most endangered mammal species in the world. Only the Sumatran rhinoceros, with a slightly lower population of 34-47 individuals [16], Hanian gibbon, with at least 35 individuals [17], and vaquita, with merely 10 individuals remaining [18], inch closer to extinction. As is often the consequence of such a low population, the Rice’s whale also suffers from extremely low genetic diversity. Only two haplotypes, inherited chromosomal DNA variants, were identified from a sample of 36 individuals. Tests for Hardy-Weinberg equilibrium yielded a mean observed heterozygosity frequency of 0.256, meaning that on average, over 74% of the samples’ gene pool were homozygous genotypes that carried only one allele each. Previous studies have shown that healthy Bryde’s whale populations can display an average of 3.6 to 9.3 alleles per loci, or different genes within fixed positions on chromosomes. But examination of 42 loci within the Rice’s whale population showed an average of 2.5 alleles per locus. This lack of diversity underlines the genetic threat Rice’s whales face in restoring populations [5]. With less available alleles, a population has less variety of traits that support adaptability. In addition, increased homozygosity decreases the ability to suppress recessive genes that are deleterious, or cause genetic diseases. Such a low genetic diversity further puts the Rice’s whale at risk of inbreeding depression, which can cause the accumulation of deleterious genes that will further weaken the population [1, 5, 12]. At worst, pessimistic ecologists expect the species to be the first great whale to go extinct in over 300 years and largest victim of the Anthropocene extinction to date [19, 20].

 

Things look grim for the Rice’s whale, but there is hope: rebounding from the spiral toward extinction is possible. For this, ecologists recommend the 50/500 rule, which postulates that a minimum of 50 viable individuals are required to escape inbreeding depression and 500 individuals to reduce harmful genetic drift [12]. It has been projected that a population of 35 Rice’s whales could achieve the 500 threshold within 68 years if conservation efforts can successfully sustain a recovery trend [12, 21].

 

Demystifying Gulf of Mexico’s only native mysticete

 

Setting the stage for this recovery requires better understanding of the ecological dynamics of the Rice’s whale and how it intersects with potential environmental threats. Although the existence of its population was acknowledged for decades, they remained unstudied [4] until the mid 2010s, meaning research of the whale is novel. To unravel the secrets mystifying a new mysticete, scientists face the challenge of finding a starting point to begin at. For the Rice’s whale, this was identification. Because Bryde’s whales were never known in the GOMx, one could infer that any similar baleen whale spotted in the area is likely a Rice’s whale. But since the two can’t be visually distinguished, this geographic inference isn’t an objectively rigorous method. Genetically testing biopsy samples, while conclusive, isn’t feasible for every encounter. Instead, scientists are adopting acoustic measurements as a method of differentiation that is both efficient and readily available [2, 22, 23]. By sticking microphones underwater during ship expeditions, in a procedure called passive acoustic monitoring (PAM), scientists can collect a soundscape of the surrounding ocean environment. While the soundscape will contain ambient noises of both random water sounds and the ship’s own propeller, it may also pick up vocalizations of marine animals that are stereotyped, or unique to them. By identifying these stereotypes from ambient noise, scientists can identify the animal producing them. The possibility of identifying Rice’s whales through their vocalizations was recognized in literature as early as 2014 [22, 23], but it took years of PAMs, survey expeditions, and painstaking data analysis to connect beyond reasonable doubt each potential whale vocalization to the species. It was eventually concluded by 2022 that Rice’s whales have a vocal repertoire of at least three stereotyped call types, the most common and diagnostic being dubbed the long-moans. Sounding like a faraway airplane’s takeoff but slowed-down and muffled, this call was especially easy to identify for its unusually long duration of about 22 seconds on average [2].

 

Scientists then studied the whale’s feeding behavior. In 2015 and 2018, scientists tagged two Rice’s whales. The suction-cup tags, which contained kinematic recorders, collectively provided nearly 90 hours of data of the individuals’ exact positions and orientations in a 3D space. This revealed their quarter-week routines. With a big gulp of air, the whales descended to the twilight zone and foraged near the seafloor for up to 10 minutes at a time. There, the whales swam large circles around their prey before capturing them with a powerful lunge or two. They spent the entire day cycling between entering deep water to feed (up to 271 meters below the surface) and surfacing to breathe. At nightfall, the whales ascended and hung around the surface, spending 85% of the night within 15 meters of the surface, and descended again at daybreak. [2, 11, 24] This pattern of oscillating between deep and shallow water through day and night is a typical example of diel vertical diving [10]. If the two samples are representative for the Rice’s whale, it’s an unusual strategy, as most baleen whales like the Bryde’s whale will typically feed at the surface or within the sunlight zone [25].

 

A 2023 study investigated the deep-water diet behind this peculiar behavior using the emerging techniques of stable isotope models. Each animal carries a distinctive signature of stable isotope ratios that broadly reflect that animal’s ecology, most significantly its diet. True to the phrase “you are what you eat,” when a predator eats another animal, the prey’s isotope signatures are integrated into the predator’s tissue. How the predator’s resulting signature is made up depends on what prey it ate and how much of it, creating a sort of chemical food diary. By comparing the stable isotope ratios of tissue samples of the predator and suspected prey and using a set of probabilistic models that addresses the abundance and biomass of suspected prey relative to its ecosystem, one can reconstruct and quantify the entire food web of the predator, including what it specifically targets as its favorite food. This is all without cutting open a single stomach [26, 27]. The scientists measured the stable isotope ratios of carbon (δ13C) and nitrogen (δ15N), the most informative in revealing diet, in skin and blubber biopsy samples of Rice’s whales collected during survey expeditions. They then compared with the ratios found in potential prey species caught during a July 2019 trawling survey in the core habitat, whose relative abundances and biomasses were also determined. The resulting analysis found that the Rice’s whales are picky eaters. Their diet is overwhelmingly composed of a single prey–a stumpy sardine-like schooling fish called the silver-rag driftfish (Ariomma bondi)–which made up over two-thirds of Rice’s whale diet. Interestingly, Rice’s whales do not appear to target the extremely common Atlantic pearlside (Maurolicus weitzmani), a similar schooling fish that made up over 88% of the core habitat’s ecological community by abundance. By contrast, the silver-rag only comprised 1.21% of community abundance. Why bother the effort to seek out a far rarer species? It turns out that the energy content of silver-rags surpasses all other prey by a wide margin. Every pound in wet weight of silver-rag contains on average over 36% more calories than the next animal on the menu. Rice’s whales seem to actively select their prey based on nutritional quality rather than abundance, singling out the silver-rag as the best bang for buck [26].

 

These feeding preferences also demonstrate an ecological importance of Rice’s whales: as ecosystem engineers. Whales feeding at the seafloor consume nutrients essential for photosynthesis, like iron and phosphorus, and then release them at the surface in massive fecal plumes. Through their diel vertical behavior, Rice’s whales are essentially pumps, cycling nutrients tucked away hundreds of meters deep up into sunlight-rich waters where they stimulate primary productivity. The amount of biomass this can produce is immense; one 2023 study suggests that a population of 2,500 minke whales, the smallest of the baleen whales, can cycle enough phosphorus to support over 70 metric tons of carbon biomass per day [28]. If Rice’s whales achieved a similar population in the past, they would have been no different.

 

Collision course with an industrialized Gulf

 

We do not yet know how the Rice’s whales came to be so endangered. Although historical records suggest attempted hunting during the 1700s and 1800s, the NMFS ruled out historical whaling as a likely factor for population decline. None of these records included successful kills, and the population evidently never experienced the dramatic rebound characteristic of other whales hunted to near-extinction in the past once overhunting by humans stopped [29]. But we know what threatens the species today is industrialization. Both the core habitat and secondary western habitats of the Rice’s whale are situated right within the intersection of the most commercially and industrially active waters in North America [10, 12, 29]. This is a place home to ten of the fifteen largest ports in the US and holds vast networks of shipping lanes with hundreds to thousands of giant commercial ships that carry nearly half America’s sea cargo by weight per year [12]. This places Rice’s whales at high risk of a literal collision course with vessel strikes that are prone to going unreported. Because of the species’ diel vertical behavior, risk of collision is especially high during nighttime, when the whales reside at the surface while visibility is reduced [10]. At least two instances of vessel strikes are already documented: the 2009 Tampa Bay beaching and a survivor left with a deformed spine [30]. Using a model for unreported collisions, the NMFS estimated that up to 20 ship strikes already occurred between 2002 and 2018. They further extrapolated that strikes may kill or seriously injure up to 17 Rice’s whales, over 30 percent of the current population, in the next 50 years without increased vessel restrictions [31]. Ships that don’t run over whales still produce voluminous quantities of underwater noise that muffle out vocal communication between whales and cause heavy stress that adversely alter behavior [12, 29].

 

Figure 3. Diagram illustrating Rice’s whale foraging behavior and its risks by human activity

 

The northern GOMx is also one of the US’ most active sites for offshore oil exploitation. Since the first drillings in 1942, over 6,000 oil rigs have been installed, with 3,200 active rigs still extracting fossil fuel from the seafloor, and oil companies continuing to explore new marine reservoirs to tap [32]. Exploration involves the frequent use of powerful airguns to blast ground-penetrating sound waves with intensities of up to 260 dB, which easily rupture cetacean eardrums. These airguns fire every few seconds in many parts of the GOMx [12, 29]. But the greatest threat to the Rice’s whales is the oil itself. With so many active oil rigs, the GOMx is a site for frequent spills of this environmentally toxic substance, which ocean currents can carry eastward into the core habitat. While the majority of spills are rather small-scale [33], a combination of wavering environmental regulations and susceptibility of oil companies to skirt those regulations set the groundwork for a catastrophe. We know this because it has already happened. In 2010, an explosion of the BP-operated rig Deepwater Horizon off the coast of Louisiana leaked over 4 million barrels of oil into water. Federal litigation ruled that this would have been preventable if regulations were followed, but BP chose to ignore them [34]. Policy scholars also cited those regulations as too lax to enforce proper accountability anyways [35, 36]. The result was the worst environmental disaster in North American history. Caught in the center were the Rice’s whales. Their core habitat was near the oil rig, and as a result nearly half of this critical refuge was smothered in oil (Figure 2). The consequences on the population are staggering. A 2015 federal investigation found that the event directly killed 17 percent of the population and caused reproductive failure in 22 percent of the female population, in total single-handedly reducing the Rice’s whale population by 22 percent. Take a moment to let that sink in. One-fifth of an entire species was wiped out by a single company’s negligence. Even of the survivors, 18 percent will live on with potentially lifelong illnesses [21]. We were never able to clean up all of the oil, which still remains on the seafloor or as marine snow and other bioaccumulating derivatives that will continue to affect Rice’s whale health [37].

 

Road to recovery: disentangling environmental policy and politics

 

Despite the odds against the Rice’s whales, it’s not too late to bring them back from the brink. As emphasized in a 2022 open letter signed by over a hundred marine and wildlife scientists, Rice’s whales are still reproducing [38]. We can still secure a rebound through efforts to eliminate their threats. With 51 individuals balancing on a knife’s edge, the fate of this unique whale lies within the hands of our immediate collective action–or inaction. This is so delicate that there was even a debate over whether an alternate common name “Gulf of Mexico whale” is more effective in inspiring action [20]. Saving an endangered species is no cakewalk, but the road to recovery for Rice’s whales will be especially challenging. Its habitat lies at the intersection of powerful industries, bringing the financial interests of the energy, shipping, and resource sectors, and even the military’s defense interests to the forefront of conservation decisions. 

 

Rice’s whales are primarily protected under two major environmental laws. The Marine Mammal Protection Act (MMPA) bans any killing, capture, or harassment of a marine mammal. The latter refers to direct actions with the potential to injure or disrupt its behavior (i.e. causing stress). The NMFS bears responsibility of translating the MMPA into specific regulations [39] and has interpreted harassment as to include harmful activities within proximity of a whale. For example, one MMPA-justified policy requires oil exploration vessels to cease all airgun activities within 500 meters of a whale sighted by onboard protected species observers in GOMx waters east of Mobile, Alabama or within seafloors deeper than 200 meters [40].

 

The second law is the Endangered Species Act (ESA), of which the species was listed as “Endangered” as a then-unnamed Bryde’s whale subspecies in 2019. The listing was the fruit of years of fierce efforts, beginning with a petition by the non-governmental organization (NGO) Natural Resources Defense Council (NRDC) within two months of Rosel & Wilcox (2014)’s publication. The agency subsequently assembled a research team which published their concurring investigation in 2016. The final decision to list was made after additional years of deliberation despite opposition by industry interests and following a mandatory public notice and comment session that received nearly a thousand comments and letters with over 115,000 combined signatures [29].

 

The ESA mandates the federal government to (1) establish a “critical habitat” zone for a listed species, (2) form a recovery plan that includes a delisting criteria, and (3) execute the plan until the species is delisted [41]. These duties for Rice’s whales are delegated to the NMFS, which is awaiting public comments for a proposed critical habitat uniting the core and secondary habitats until September 2023 [42] and is working on the recovery plan. As they construct the plan, the agency must navigate through environmental and political webs to finalize something that is both effective and legally sound. In 2021, the NMFS hosted a workshop involving 45 scientists, environmental specialists, NGO leaders, and industry representatives to contextualize the focuses of the recovery plan. A Word Cloud illustrated in order the four greatest challenges to Rice’s whale recovery according to participants: small population, vessel strikes, energy exploitation, and insufficient regulation [43].

 

While the critical habitat remains in progress, measures are being taken to secure the core habitat as a surrogate. In a 2020 biological opinion regarding an expansion to leasing parts of the GOMx for oil and gas, the NMFS proposed a 10-knot daytime speed limit and entry ban during nighttime or low-visibility conditions within the area for oil and gas exploration vessels. Ships traveling at 10 knots or less were significantly less likely to hit large whales than faster speeds. When collisions do occur, the worst would be minor injuries [31]. These recommendations have since been adopted by the Bureau of Ocean Energy Management (BOEM), the agency managing offshore energy leases, as conditions for authorizing oil and gas activities [44]. However, Rice’s whales are still at risk of lethal high-speed collisions by unaffiliated vessels, such as cargo traffic from Florida’s western ports. Recognizing this, a team of six organizations led by the NRDC submitted a petition the following year to expand the NMFS’ proposal as legal policy for all vessels within the core habitat. They pointed out the successes of universal slow-zones for critically endangered North Atlantic Right whales [30], estimated to have reduced the risk of lethal strikes by up to 90 percent [45]. The proposal is not without stakeholder concerns: local fishing communities that rely on hotspots within the core habitat fear paralysis of their main sources of income [46], while the Florida Ports Council, an organization representing the state’s ports, argues it jeopardizes the western ports [467. Nevertheless, the NMFS is now considering the petition and requested public comments until July 2023 [30].

 

Another victory came in 2023 when the NMFS denied permission for the Florida-based Eglin Air Force Base to test weapons within the core habitat during an authorization renewal. The base frequently conducts tests in the northeastern GOMx with the potential to inflict considerable harm to nearby cetaceans [48]. The NMFS is mandated to review the military’s plans to ensure minimal damage to marine mammals without seriously hampering national defense capabilities. Sometimes accidental harm can’t be avoided, so the NMFS can invoke exemptions in the MMPA and ESA if necessary [39, 48]. By choosing to safeguard the Rice’s whales, the NMFS set an important precedent on how valuable protecting the endangered species is. But this is vulnerable to shifting political landscapes. Opposing the decision was far-right US congressman Matt Gaetz, who tried to see Rice’s whale protections rolled back. Claiming that 51 poorly-known whales should not stand in the way of conflict readiness [49], he went as far as to personally introduce legislation to exempt the species from the MMPA [50]. While Gaetz’s efforts ultimately failed, this demonstrates the political dangers entangling the Rice’s whales.

 

Towards a future for the whales and us

 

While successes occur in core habitat, none of these measures cover the western secondary habitats. The secondary isn’t as formally defined as the core yet, but another reason why the NMFS can act swiftly in the core habitat may be because the area sees comparatively little economic pursuits. This is in part due to a congressional moratorium on offshore drilling in the eastern GOMx recently extended by President Trump until 2032 [51]. On the other hand, the majority of oil rigs and vessel activity operate in the western and central GOMx (Figure 2). The Deepwater Horizon spill must remind us of the ease of spillovers into the core habitat. Additionally, whales that venture westward (as confirmed by an acoustic survey [52]) face the brunt of marine industrialization. Any resulting deaths are detrimental to the 51 remaining whales. Protecting these corridors are therefore as important as protecting the core habitat.

 

The unfortunate reality is that Americans still rely heavily on GOMx oil [53], so an immediate prohibition isn’t feasible. Instead, we must take steps to reduce the impact of existing oil activities while progressively phasing out the industry. In the short term, we ought to demand better government oversight on oil regulations to hold the accountability necessary to prevent negligent spills. In the meantime, the 2021 NMFS workshop also recommended a clean-up: decommissioning the over 14,000 defunct oil wells at risk of spills [43, 54]. While President Biden has since signed into law the bipartisan Infrastructure Investment and Jobs Act that funds such efforts, the $4.7 billion set aside [55] is a small fry to the estimated $30 billion needed to neutralize all disused GOMx wells [54]. Raising this requires joint political action and/or grassroots fundraising. In the long term, we must collectively discourage oil expansion by supporting renewable energy. This isn’t just innovation; it also means bottom-up environmental justice that opens accessibility to marginalized groups least likely to afford clean technologies. But as we develop renewables, the NMFS workshop emphasized mindfulness to prevent potential harms to the Rice’s whales: poorly-placed marine infrastructure can introduce debris hazards and exacerbate shipping traffic and underwater noise, avoidable through robust spatial planning [43].

 

Long-term change towards a green future also addresses another fundamental challenge to the Rice’s whales’ future: climate change. With their reliance on a single prey, Rice’s whales are especially vulnerable to the unraveling crisis. The core habitat’s location is no coincidence: it’s within one of the most silver-rag-abundant regions in the northern GOMx [56]. This is thanks to the area’s unique position between the fresh nutrient-rich Mississippi River Delta, the warm Loop Current, and upwelling from the De Soto Canyon, mixing the three waters to produce a highly productive environment [11, 57]. The Loop Current is part of the thermohaline circulation (THC), earth’s global ocean conveyor belt, powered by optimal water temperature and salinity. But as the planet warms, the THC weakens. This diminishes the Loop Current [58], threatening the water-mixing that enriches the core habitat and therefore the abundance of silver-rags that sustain the Rice’s whales. This isn’t an isolated relationship: countless animals globally rely on few resources that may be lost due to climate-induced habitat disruption [59]. By acting to protect and recover the Rice’s whales with a climate mindset addressing big oil and other industrializers of the Gulf, we are not just “saving the whales”: we are also setting a precedent for tackling the looming global catastrophe faced by everyone everywhere.

 

We have power in the word

 

A most important component to recovering the Rice’s whale–but one that lags behind–is public awareness. Many Americans remain unaware of the Rice’s whale’s existence. While much can be done through policymaking by the NMFS and other government agencies, their top-down authority alone can only go so far when fundamental long-term and climate-allied change is ultimately necessary to truly pull back the critically endangered species. Rice’s whales are under direct protection by some of the most powerful environmental laws in the world, but the effectiveness of this advantage depends on the willingness of the nation’s citizens to push for lasting change in the GOMx.

 

Public awareness positively shapes the collective perspective. It combats disinformation [60], such as the false narrative that the new species’ recognition was arbitrarily crafted by “some scientist” [47, 49] to push an agenda, and empowers stakeholders like local boaters to participate in policy-making. This removes barriers to the synthesis of valuable community experience with scientific knowledge into policies that both protects the Rice’s whale and respects community needs. When people learn about species on the brink, it builds sympathy and determination to do what can be done to save them, inspiring political willpower to influence both citizen and government decisions from the bottom-up [61].

 

Rice’s whales hold strength through their potential to be a charismatic species: their enormous size to man’s eyes captures the icon of a majestic gentle giant. Through its direct relationship with oil, the Rice’s whale can be a flagship for what is preserved–or destroyed–by our choice on climate. Finally, the Rice’s whale is all-American: no other nation can be responsible for its extinction; its fate is the reflection of how we as Americans treat the environment. It’s why senior marine mammalogist Peter Corkeron of the New England Aquarium, one of the leading figures in the species’ conservation effort, suggested Balaenoptera ricei is better called the “American whale” [62].

 

Informing the people about the Rice’s whale, what our industrial actions are doing to them, and piquing a vision of a brighter future that could be–a healthy Gulf of Mexico echoing with year-round songs of America’s baleen whale, teeming with fish, dolphins, birds, and sea turtles fated not to an oily death but flourishing at a diversity imperceivable today alongside the whale that helped engineer its possibility–is enough to inspire support for the cause.

 

The road ahead is hard, but there is power for wonderful change in you, the reader, through a simple action. Tell another around you. Let them know: a great American whale is on the brink of extinction. Spread the word.

References

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Lung Cancer Vaccines: An Investigation of Potential Targets for a Novel Immunotherapy

By Rhea Bains.

Abstract:

This review comprehensively synthesizes research published within the last five years about a novel immunotherapy for lung cancer, known as a cancer vaccine in situ or intratumoral vaccination. The treatment involves an injection administered directly to the site of the tumor to trigger an immune response in the body for cancer treatment, thereby having the potential to extend the efficacy of other commonly used immunotherapies for lung cancer. Current immunotherapies have been found to not work in all patients and, given that lung cancer is known for high mortality rates, this treatment could potentially save countless lives. The scope of the research reviewed is limited to the two primary subsets of lung cancer vaccines in situ: vaccines containing genetically modified whole cells and vaccines containing modified viruses. It was found that most whole-cell vaccines can be optimized with the concurrent use of existing immunotherapies, but these vaccines have not been proven to improve patient prognoses. This subsequently contributed to the rise of research in the area of virus-based vaccines, which may also require simultaneous use with current immunotherapies to prevent immune-related adverse events. Although each method explored shows promise respectively, it remains unclear which method would be most valuable to isolate as a potential future lung cancer treatment. Many of the trials that show promise were conducted on mouse models, so further human trials of both whole-cell and virus-based vaccines would be beneficial in the quest to expand upon the current capabilities of modern cancer treatment.

Introduction: 

Lung cancer is best known for its high rates of mortality, making up for 23% of cancer-related deaths in 2020 alone [1]. Lung cancer’s two main subsets include non-small cell lung cancer and small cell lung cancer, the latter being rarer (15% of all cases) than the former (85% of all cases) [2]. Studied intensively over the past several decades, lung cancer in both its forms has proven a difficult ailment to combat, but extensive progress in treatment has been made. Immunotherapy is considered to be a rising field in potential treatments for advanced cancers. Using the body’s own immune mechanisms to produce an antitumor response is an effective way to improve patients’ prognoses [3]. Leading research institutions work on innovative immunotherapy solutions in the hopes of extending the efficacy of current treatments, which include chemotherapy, radiation, and surgery. Ideally, a new cancer immunotherapy treatment, a vaccine, would help mitigate the common complications brought on by traditional therapies and minimize healthy tissue damage [4]. 

Recently, there has been a push for the implementation of a cancer vaccine as a vector for future immunotherapies. Because of cancer’s innate ability to evade immune system detection through downregulating antigen (binding molecules) presentation on its cells [5], scientists are looking into a variety of approaches to either mount an immune system response against the tumors actively, using added antigens, or passively, using a nonspecific reaction against the area the tumor cells are located [2-4, 6, 7-9]. Similar to how vaccines evoke a response from the body to fight off infectious diseases, a cancer vaccine, or an intratumoral immunotherapy can be administered at the tumor site to invoke immune mechanisms [10]. An ideal combination of chemical and biological compounds would be administered via an intratumoral immunotherapy injection delivered locally to the site of the tumor (“in situ”), eliciting an immune response. Two components being investigated now fall into the categories of genetically modified virus-based and cell-based vaccines both surmounting an immune response to the tumor [2-4, 6, 7-9]. This review will discuss current research being conducted to evaluate modified viruses and modified whole cells for use in intratumoral immunotherapy, a lung cancer vaccine in situ. Used prior to (neoadjuvant) or after (adjuvant) traditional therapies, advancements in the targets and components of this vaccine could revolutionize lung cancer immunotherapy treatments. 

Figure 1: Whole cell and oncolytic virus injections in-situ induce immune response to tumor cells.

Tumor Evasion of Immune System Responses and The Rise of the Cancer Vaccine: 

Checkpoint inhibition is a common immunotherapy where patients are administered a compound that commonly blocks interaction between receptors, or specific antigens that bind to the antigens of other cells, found on immune system-derived T-cells and tumor cells, such as the PD-1 and PD-L1 interaction [11]. Normal interaction between the PD-1 and PD-L1 receptors inhibits the T-cell killing of tumor cells in an immune response, which occurs by the interaction of a different pair of cell receptors. An inhibitor of the PD-1 and PD-L1 interaction is known to promote T-cell killing of tumor cells. However, this first-line therapy has been found to only produce a response rate in only 20% of patients [6, 7]. It is unclear why 80% of patients are unable to produce an efficient immune response, but it has been theorized by Lee et al. that these tumors experience under-expressed antigens which limit the response the immune system can produce. 

Figure 2: Mechanistic view of T-cell inhibition through PD-1 and PD-L1 interaction.

It is known that some tumors downregulate antigen processing because of low levels of mRNA genes that are essential to signaling the cell to express certain intracellular proteins as antigens. This lowers the amount of antigen expression on the surface of their cells [5]. The human body’s immune cells (including T-cells, dendritic cells, and others) require antigens to effectively recognize tumor cells to bind, and a lack of PD-L1 expression in particular can make tumor cells immune to traditional checkpoint inhibition therapy [6]. Restifo et al. note that while one way to combat this is through administering drugs such as interferon gamma to enhance expression of the low mRNA, this treatment may interfere with the proliferation of T-cells and other immune cells which would counteract effective immune response. Therefore, another method being researched to combat this is using intratumoral immunotherapy to create an immune response that enhances antigen presentation of tumors [4, 6, 9], recruits immune cells [3, 8], and/or induces an inflammatory immune response [7]. 

Using either cell-based vaccines or virus-based treatments, current research focuses on achieving one or more of the aforementioned results to effectively treat patients with advanced stages of lung cancer. Those who have developed resistance to prior immunotherapeutic treatments or do not initially respond stand to benefit most from vaccination in situ. In combination with other immunotherapies and conventional treatments, this therapy would reduce the recurrence of tumors by building a memory within the immune system. This would transcend the current abilities of treatments like chemotherapy, radiation, and surgery [2], which require multiple treatments in cases of tumor recurrence, each with its own undesirable side effects. 

Mechanisms of Modified Whole Cells in Intratumoral Immunotherapy: 

The use of modified whole cells in cancer vaccines can be further subdivided into immune cell, tumor cell, and bacterial cell vaccines. The dendritic cell studies mentioned here were conducted in humans while the tumoral and bacterial vaccine studies are mouse-model (murine) based. Each study demonstrated technical success, but there are limitations presented by each of the research groups. Using modified dendritic immune cells to produce an immune response can help improve patient survival rates through increasing antigen presentation for evoked immune responses [6]. Locally injecting a modified dendritic cell injection containing tumor antigens twice and then collecting a tumor biopsy after a seven-day period yielded raised T-cell counts in 8 of 16 patients, so future use of gene-modified dendritic cells along with PD-1 and PD-L1 inhibition could be a promising avenue of therapy. Lee et al. state that tumor cells exhibit low antigen expression, corroborated by Restifo et al., which is why this treatment in concurrence with checkpoint inhibition is ideal to ensure that the best results are achieved. Increased antigen presentation from intratumoral therapy would be used for immune system response to the tumor, and any inhibitory antigens that present could be countered through checkpoint inhibition. Dendritic cells can also be modified to attract other immune cells. These administered whole cells combat cancer’s ability to suppress immune cell activity by recruiting the body’s T-cells to fight off malignancies. Shahrouki et al. conducted a feasibility study and found using dendritic cells in intratumoral immunotherapy to be potentially practical for widespread use, with technical success and minimal complications. However, Shahrouki et al. concurs with the assessment of Lee et al. that the best practice of intratumoral immunotherapy with modified dendritic cells is used in combination with checkpoint inhibitors. 

Inactivated whole tumor cells in an intratumoral vaccine can be used to increase antigen expression, primarily when exposed to radiation. Radiation was used in prior studies to inactivate the cells, but Luo et al. explore the possibility that irradiating tumor cells for use in cancer vaccines releases tumor antigens, allowing them to be more easily recognized by the immune cells of the body. The study yielded that irradiated tumor cells produced a substantial immune response in mice, but it is acknowledged that a human trial would be more telling of the efficacy of this treatment. 

Bacterial cells can also be used to stimulate an immune reaction, particularly modified E. coli. This bacterium produces a stimulator of interferon genes, which produce interferon gamma, through the STING pathway, activating a cascade of dendritic and T-cells through increased antigen presentation [5, 8]. However, again, this pathway works best when used in combination with a checkpoint inhibitor (atezolizumab), analogous to the findings of Lee et al. and Shahrouki et al, and only 2 of 23 patients experienced stable disease post-treatment. Thus, the markers of increased antigen presentation and immune response in each study are promising, but further human trials need to be conducted with each compound adjacent to checkpoint inhibition to fully understand the efficacy of the treatment. 

Mechanisms of Viruses in Intratumoral Immunotherapy: 

Discourse in the scientific community suggests that whole-cell vaccines have limited efficacy. Whole cells have shown some success in clinical trials, but further improvements need to be made to enhance it for use in patients [9], and many whole-cell vaccines do not improve overall survival in studies [2]. In fact, although Lee et al. found increased immune response in lung cancer patients, the median survival of the research participants was a mere 3.9 months. As a result of these challenges, some studies have pursued a different method entirely as a result, using select viruses that are injected into tumors via an intratumoral vaccination rather than whole cells. 

Using a strategy called gene-mediated cytotoxic immunotherapy (GMCI), a respiratory virus (adenovirus) is administered locally to a tumor site, prior to tumor resection surgery [7]. The oncolytic virus in the form of adenoviruses, herpes simplex viruses, and others only replicate within tumor cells, killing only the cancerous cells in the body [2]. Predina et al. Used an oncolytic virus to selectively infect and kill tumor cells when a secondary drug was added to activate the virus (valacyclovir). This trained the immune system to recognize and kill cancerous cells during a secondary immune response triggered by the inflammation the killing of the tumor cells induces, shrinking the tumor. Post cell death, the inflamed and infected area released tumor antigens that were targeted by the immune system. Predina et al. found that the method elicited increased T-cell activation and more surface antigens, but few patients showed evidence of antibody responses. They hypothesize that the antigen upregulation increased the expression of PD-L1, causing more inhibitory interactions between cancer and T-cells, which could reduce the efficacy of the treatment. Future studies might use this method with checkpoint inhibition to counter the uptake in PD-L1 expression that occurs from increased tumor antigen expression, just as Riese et al., Shahrouki et al., and Lee et al. found in whole-cell vaccine models. 

Wang et al. found that although the adenovirus method is effective, two viral injections achieved the best results in a mouse model, rather than just one. The virus would be injected in two parts: the first injection (not intratumoral) would hold whole inactivated tumor cells infected with a modified Newcastle virus, and the second injection would be an intratumoral injection holding just the virus. This virus not only killed tumor cells and upregulated T-cell activation but also increased inflammation and anti-inflammatory responses [9]. Again, this method shows promise but requires further human studies to confirm efficacy; however, Wang et al. provides a solid foundation for future studies on oncolytic viruses in potential intratumoral immunotherapies. 

Conclusion: 

Intratumoral immunotherapy is a rising field in potential treatment for advanced lung cancer, but there is a wide array of differing opinions about the best mechanism to use to target cancer. While modified cells and viruses have each shown some progress, there are still challenges to be overcome in both areas of research, and consensus has not yet been reached about which method holds the most merit. Both methods may require use with other immunotherapies to maximize success, so current therapies cannot be replaced entirely. There is an array of different types of both cells and viruses that have shown some potential in their own way, so no one method shows significant benefit over the other. In addition, Truong et al. suggest that both methodologies do not account for the typically lower immune system of older patients, who typically make up the demographic suffering from lung cancer. However, current research suggests that in patients with active immune systems (when used with checkpoint inhibitors) cell-based intratumoral vaccines and virus-based vaccines each have the potential to combat low antigen presentation by malignant cells and produce an autologous immune response in patients. With future efforts, perhaps one method of treatment can be isolated and then personalized for individual treatment.

Works Cited:

  1. Centers for Disease Control and Prevention. An Update on Cancer Deaths in the United States. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, Division of Cancer Prevention and Control; 2022. 
  2. https://www.cdc.gov/cancer/dcpc/research/update-on-cancer-deaths/index.htm. 
  3. Truong, Cao-Sang, and So Young Yoo. “Oncolytic Vaccinia Virus in Lung Cancer Vaccines.” Vaccines vol. 10,2 240. 4 Feb. 2022, https://doi.org/10.3390/vaccines10020240. 
  4. Shahrouki, Puja, et al. “Technical Feasibility and Safety of Repeated Computed Tomography–Guided Transthoracic Intratumoral Injection of Gene-Modified Cellular Immunotherapy in Metastatic NSCLC.” JTO Clinical and Research Reports, vol. 2, no. 11, 2021, pp. 100242–100242, https://doi.org/10.1016/j.jtocrr.2021.100242. 
  5. Luo, Lumeng, et al. “Irradiation Increases the Immunogenicity of Lung Cancer Cells and Irradiation-Based Tumor Cell Vaccine Elicits Tumor-Specific T Cell Responses in Vivo.” OncoTargets and Therapy, vol. 12, 2019, pp. 3805–15, 
  6. https://doi.org/10.2147/OTT.S197516.
  7. Restifo, N. P., et al. “Identification of Human Cancers Deficient in Antigen Processing.” The Journal of Experimental Medicine, vol. 177, no. 2, 1993, pp. 265–72, https://doi.org/10.1084/jem.177.2.265. 
  8. Lee, Jay M., et al. “Phase I Trial of Intratumoral Injection of CCL21 Gene-Modified Dendritic Cells in Lung Cancer Elicits Tumor-Specific Immune Responses and CD8 + T-Cell Infiltration.” Clinical Cancer Research, vol. 23, no. 16, 2017, pp. 4556–68, https://doi.org/10.1158/1078-0432.CCR-16-2821. 
  9. Predina, Jarrod D., et al. “Neoadjuvant Gene-Mediated Cytotoxic Immunotherapy for Non-Small-Cell Lung Cancer: Safety and Immunologic Activity.” Molecular Therapy, vol. 29, no. 2, 2021, pp. 658–70, https://doi.org/10.1016/j.ymthe.2020.11.001. 
  10. Riese, Richard, et al. “500 SYNB1891, a Bacterium Engineered to Produce a STING Agonist, Demonstrates Target Engagement in Humans Following Intratumoral Injection.” Journal for Immunotherapy of Cancer, vol. 9, no. Suppl 2, 2021, pp. A532–A532, https://doi.org/10.1136/jitc-2021-SITC2021.500. 
  11. Wang, Hui, et al. “Tumor Cell Vaccine Combined with Newcastle Disease Virus Promote Immunotherapy of Lung Cancer.” Journal of Medical Virology, 2023. https://doi.org/10.1002/jmv.28554.
  12. Hammerich, Linda, et al. “In situ vaccination: Cancer immunotherapy both personalized and off-the-shelf.” Molecular oncology vol. 9,10 (2015): 1966-81. 
  13. https://doi.org/10.1016/j.molonc.2015.10.016. 
  14. Li, Rui, et al. “Inhibition of Granulocytic Myeloid-Derived Suppressor Cells Overcomes Resistance to Immune Checkpoint Inhibition in LKB1-Deficient Non-Small Cell Lung Cancer.” Cancer Research (Chicago, Ill.), vol. 81, no. 12, 2021, pp. 3295–308, https://doi.org/10.1158/0008-5472.CAN-20-3564. 

Olive Oil Harvesting

By J Capone, Agriculture and Environmental Education, ’24

It was a warm Saturday morning in November when Sam rounded the corner and asked if I wanted to join the harvest. He looked like a laureate in the light, with a crown of olive branches placed upon his wide-brimmed field hat. We were taking Intro to Sustainable Agriculture together, and I had heard how he wanted to do a community olive harvest this weekend at the Student Farm, a 23 acre agriculture program at UC Davis. I was next door when I came across him and his friends talking around a field bin, strategizing the day forthcoming. Later, I would join him in the orchard, amazed at the crowd of people collected, the energy exuding from them as joyous as a traditional field harvest. 

“It’s crazy,” he told me “that they were just going to let the olives rot on the tree instead of doing something with them”. 

He had learned through a friend that the olive grove at the Student Farm would not be harvested this season. There was simply not enough manpower. Within a week, he had organized a team effort and convinced the head of the Student Farm to let him and his friends hand-pick as many olives as they could and bring them to a community milling project outside of Livermore, CA. One had a truck, another brought music and blankets, and yet another brought more friends until this manual labor event seemed more like a block party, with clean, empty, dark wine bottles collected to later fill up with the products of their harvest. 

Sam quickly gave me the safety rundown – and Tim gave me the waiver to sign, pinky promising to not sue if my head gets chopped off in the process. The ground under the grove was littered with ankle-splintering holes, dug by ground squirrels to nest close to a fallen food source. I carefully stepped my way to a tree, where a nice girl introduced herself and showed me the strategy for harvesting the olives – taking a big stick, usually with a rake attached to the end of it, and smacking the hell out of the branches, pushing and pulling to entice the tree to release some of her swollen fruit. Together we took turns bashing, raking, holding, and scrubbing until the tarp under us was littered with ripe, firm, green olives. We each grabbed two ends and brought our bounty over to the sorting groups, who cheered as we deposited our load into piles. 

I sat down in one of the circles, and a neighbor showed me exactly how they picked which olives were good and could be pressed and milled, and which were bad and would spoil the batch. Crouched on my feet, I scooped up a handful and admired the pale farina clouding the surface of the fruit. Slowly, I turned it around in my hand, looking for pits or worms or the dreaded Olive Fruit Fly, before tossing it in the “Good” basket. Around me, the fellow harvesters who had been doing this for hours already would scoop up a handful while chatting, roll it around in their palms as they scanned, and quickly made their selection of good and bad fruits, all while singing, chatting, and joking around while the music played. Clearly, there was a rhythm I had to learn. 

In case you were ever interested in the selection process for these olives, here’s what you looked for: a uniform color on a solid, firm skin, no holes or lesions, and especially no scales or larvae. Olives naturally had small pits and divots, but the key difference was the indication of something burrowing into or out of the flesh and skin of the fruit.  The Olive Fruit Fly, an invasive pest that destroys the olive crop in this way, would spoil the batch if too many were detected. Their life cycle depends on laying their eggs in forgotten, fallen crops, and we had to be careful to properly dispose of rejected fruits lest we exacerbate the problem in next year’s harvest.

If we hadn’t collected these olives – even though we left many on the trees – the ground would be littered with rotting olives, a useful food source for pesky pests and other critters on the student farm. It would also be a habitat for insects, like the Olive Fruit Fly, and could bolster their population the following year, even spreading to and worsening the situation on neighboring farms. We made sure all of the soft, scarred, and unsavory olives made their way into the compost pile, so they could be repurposed as agricultural waste into food for next season’s crops. 

As I got into the groove of things, another neighbor made a joke about working under the warm sun. “I can feel my Greek ancestors frowning at me, going ‘We left for America so you wouldn’t be doing farmwork!’” The group laughed at his joke, but it had me thinking about my own connections to the olives, how this group of harvesters made me feel more connected to my ancestors than any other part of modern life. 

Instead, olive tree growers in the south Mediterranean have their own pest problems to worry about. A new virus, called xyzella fastidiosa, has infected thousands of olive trees in Italy and has ravaged orchards [3]. With no natural defense against the introduced pathogen, farmers are having to pull every trick out of their toolbox to protect their trees before it totally destroys the industry, or spreads to any neighboring countries. An already parched basin, Italy and other olive-producing countries have faced drought and intense heat as climate change spreads, altering the global weather patterns. Coupled with these pre-existing climate troubles with the desertification of the Mediterranean, the olive industry, which has flourished for thousands of years in the fertile valleys of southern Europe, is on the ropes. 

As the day stretched on, we all grew hungry and tired under the warm sun, standing up to stretch and daring each other to eat the tempting fruit we were sorting under our fingers. Unfortunately, uncured olives like the ones we were handling taste extremely bitter, and the offensive taste tends to linger in one’s mouth. By the time the sun started setting, we had almost filled the entirety of the truck bed up with gorgeous, colorful olives, ranging from candy apple green to a wine-dark skin. We had only harvested from 6 of the 28 trees in the grove, with not enough people or time to attack the entire orchard in the limited sunlight. Sam and Tim rounded up the last buckets, as everyone helped fold up tarps, put away supplies, and swapped photos taken of the harvest. The next day, Sam and Tim would drive down to the Olivina, an olive orchard and mill in Livermore, that participated in a once-yearly Community Milling Day, where we could get our olives milled for free. In order to make the freshest extra virgin olive oil, we had to get these picked olives milled as quickly as possible, within 24 hours. Promises were made to meet back up in a week, where a taste-testing party with bread would be provided at the Domes. 

At the end of the day, I brought my hands up to my face and inhaled deeply at the fresh, earthy smell of olives still dusting my hands, the farina settled and coating the crevices of my hands and nail beds. Within a week, I was meeting up with Sam and Tim again, and finally getting my own bottle of this liquid gold. A total of 470 lbs of olives were harvested, resulting in 10 gallons of oil to distribute. Gathered around the tasting table, I nabbed some bread and took a dunk in the oil. Instead of a mellow flavor most grocery store oils held, this tasted like a kick in the teeth, the peppery notes coating my mouth and tingling on the way down. Paired with bread and balsamic, or added into a focaccia recipe, this hand-harvested olive oil tasted like satisfaction and a hard day’s sweat under the sun, with the benefit of caring for the land and next year’s crop.

The Use of Stem Cells to Treat Alzheimer’s Disease

By Tara Nguyen, Human Development, ’25

Alzheimer’s disease (AD) is a neurodegenerative disease that causes cognitive and motor functions to worsen over time, eventually leading to the loss of day-to-day function [1]. AD is the fifth leading cause of death in individuals aged 65 and older. Other causes of death within the top five, such as stroke and cardiac arrest, have decreased in numbers since 2000 while deaths from AD have increased by over 145% [2]. In 2022, an estimated $321 billion was spent on long-term and hospice care for AD patients older than 65 years, an increase from $234 billion as recently as 2019 [1-2]. This piece will cover the pathogenesis of AD and how stem cell research is contributing to finding a successful treatment for AD.

One of the foremost signs in the pathogenesis of AD is the accumulation of amyloid-beta (Aβ) peptides, 39-43 residue amino acids derived from the irregular activity of the amyloid-beta precursor protein (APP) [3-4]. The Aβ peptide forms plaque deposits in areas of the brain that control memory function such as the medial temporal lobe and the neocortical structures [4-5]. The impacts of plaque deposits in these areas of the brain include impaired memory, attention, thought, and perception.

The other most common sign in the development of AD is the occurrence of neurofibrillary tangles (NFTs), which occur due to the misfolding of tau proteins. Tau is an important microtubule protein that takes on six distinct isotypes, each with its own precise function. This protein is important in maintaining the stability of the microtubule system, which contributes majorly to axonal transport [6]. In axonal transport, motor proteins use microtubule systems to transport proteins between neurons. Without stable microtubule systems for this transport, the development, function, and survival of nerves are inhibited [7]. Hyperphosphorylation of the tau protein leads to its overexpression and aggregation, meaning that the microtubule system which tau maintains will no longer be stable. This means that nerve transport, development, function, and survival will be impacted, and NFTs will propagate in the neuronal space of patients with AD. Furthermore, the overexpression of hyperphosphorylated tau proteins can lead to the damage and loss of neurons [6]. 

Most cells in the human body are specialized cells, such as those that make up the nervous system or the cells that function in the liver. However, there are cells that have regenerative abilities and, unlike specialized cells, are not restricted to one specific function: stem cells. Stem cells provide opportunities for research into regenerative medicine due to their ability to specialize into different cells of various functions rather than only into one. Specifically, multipotent stem cells (MSCs) can specialize into cells from one particular organ or system. For example, neural stem cells (NSCs) are MSCs in the central nervous system that have the ability to differentiate into all nervous system cells. While these cells are indeed stem cells, they only have the potency to specialize into neural system and related cells. 

In 2009, a study focusing on NSCs was completed at the University of California, Irvine’s Department of Neurobiology and Behavior Institute for Memory Impairments and Neurological Disorders by Mathew Blurton-Jones et al. This study used transgenic mice models that expressed features of Alzheimer’s Disease, such as pathogenic forms of APP and phosphorylated tau proteins [8]. However, instead of targeting these pathogenic hallmarks of AD, researchers transplanted NSCs into the hippocampus of these mice [8].

Despite there being no change to the amounts of APP present or the tangles in phosphorylated tau proteins, this study found that cognitive function of these mice improved through brain-derived neurotrophic factor (BDNF), which mediates the survival and growth of neurons in the central nervous system [8]. While the hallmarks of AD were still present in these mice, they were able to regain some cognitive function.

Another study done by I.S. Kim et al, in cooperation with the Yonsei University College of Medicine in South Korea in 2015, used stem cells to investigate potential therapeutic effects in AD. Like the study by Blurton-Jones et al, this study utilized NSCs in a transgenic mouse model. The transgenic mouse model had a neuronal disease state that resembles that of Alzheimer’s Disease with features including damaged neurons, an excess of APP, and phosphorylated tau proteins [9].

This study found that non-engineered human NSCs, when inserted into this transgenic mouse model, inhibited the phosphorylation of tau in the model by interfering with the related signaling pathways [9]. As previously discussed, the overexpression of phosphorylated tau is one of the causes of damaged neurons, a primary cause of AD. The researchers hope that a similar effect may show in humans, since the insertion of human NSCs into the transgenic mouse model was able to limit one of the factors and indicators of the development of AD [9].

Further studies are needed to determine whether or not stem cells can prove truly useful in the treatment of AD. Studies that have been approved and published thus far have shown a hopeful light towards the usefulness of stem cells in the modeling and treatment of AD. The works of Matthew Blurton-Jones et al. and I.S. Kim et al. provide a stepping stone towards a working treatment to inhibit, or even reverse, the effects of AD. Some next steps may include researching a possible solution for Aβ plaques, or finding solutions to consider both NFTs and Aβ plaques, and these studies may, hopefully, help the process of developing a successful treatment for AD in humans.

References:

  1. “2019 Alzheimer’s Disease Facts and Figures.” Alzheimer’s & Dementia 15, no. 3 (2019): 321–87. https://doi.org/10.1016/j.jalz.2019.01.010. 
  2. 2022 alzheimer’s disease facts and figures. (2022). Alzheimer’s & Dementia, 18(4), 700–789. https://doi.org/10.1002/alz.12638 
  3. Breijyeh, Zeinab, and Rafik Karaman. 2020. “Comprehensive Review on Alzheimer’s Disease: Causes and Treatment” Molecules 25, no. 24: 5789. https://doi.org/10.3390/molecules25245789
  4. Danielle G. Smith, Roberto Cappai, Kevin J. Barnham, The redox chemistry of the Alzheimer’s disease amyloid β peptide, Biochimica et Biophysica Acta (BBA) – Biomembranes, Volume 1768, Issue 8, 2007, Pages 1976-1990,ISSN 0005-2736, https://doi.org/10.1016/j.bbamem.2007.02.002. (https://www.sciencedirect.com/science/article/pii/S0005273607000387)
  5. Rukmangadachar LA, Bollu PC. Amyloid Beta Peptide. [Updated 2022 Aug 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459119/
  6. Cheng Ying, Bai Feng, The Association of Tau With Mitochondrial Dysfunction in Alzheimer’s Disease. Frontiers in Neuroscience, Volume 12, 2018, https://www.frontiersin.org/articles/10.3389/fnins.2018.00163     https://doi.org/10.3389/fnins.2018.00163, ISSN 1662-453X 
  7. Sleigh, J.N., Rossor, A.M., Fellows, A.D. et al. Axonal transport and neurological disease. Nat Rev Neurol 15, 691–703 (2019). https://doi.org/10.1038/s41582-019-0257-2
  8. Blurton-Jones, M., Kitazawa, M., Martinez-Coria, H., Castello, N. A., Müller, F.-J., Loring, J. F., Yamasaki, T. R., Poon, W. W., Green, K. N., & LaFerla, F. M. (2009). Neural stem cells improve cognition via BDNF in a transgenic model of alzheimer disease. Proceedings of the National Academy of Sciences, 106(32), 13594–13599. https://doi.org/10.1073/pnas.0901402106 
  9. Lee, IS., Jung, K., Kim, IS. et al. Human neural stem cells alleviate Alzheimer-like pathology in a mouse model. Mol Neurodegeneration 10, 38 (2015). https://doi.org/10.1186/s13024-015-0035-6

Interview :

VP: You’ve been described as the most prolific science fiction writer living today. I really want to know how this became your niche.

KSR: I was reading fiction and Jules Verne fiction art adventures were exciting. At the end of my library’s section, I began to explore the top of my head: life is really whatever and written before all its history, and if I wanted to write about the present, California, where they were more realistic, then which hit me like the graphics, the numbers. That’s like getting creative and since then, I got married to a scientist and I’ve been able to watch a real scientist work. So that’s how once you publish it mostly to build up your getaway. It was a subculture that had a very particular audience and bookstores, in publishing

VP: It’s fascinating when you discuss the scientific community. I’ve noticed that many scientific works seem to have a left-leaning political theme. Do scientist-writers aim for objectivity? I remember during one of your talks, you mentioned that when people claim to be against scientists, they’re actually against the ownership of labor. Have you spoken to scientists or those in the science fiction community about this?

KSR: The political spectrum exists in all fields and communities, including science fiction and writing. From hardcore reactionary right-wingers and military science fiction libertarians to left liberals and the radical wing, the spectrum is vast. Personally, I align with the left, but I dislike the precise labeling that often happens, leading to internecine warfare and the narcissism of small differences. My characters express a range of opinions, and my own opinions are fluid. I was fortunate to be trained by Frederick Jamison, one of the most famous Marxist literary critics on Earth, and I still listen to his classes as podcasts. As a science fiction writer, I am interested in the birth and development of science, and how it works as a political force. I have explored this in my novels, including Shaman, which looked at the birth of science in the Paleolithic era, and in Galileo and the Years of Rising Salt, which imagined a scientific revolution occurring in a fictional culture where India, Islam, and China met. In my Washington DC trilogy, also known as Science in the Capitol or Green Earth, I examined how federal science works and its influence on policy. As a science fiction writer, I am always looking for new stories and exploring the role of science and scientists in society. The Mars trilogy was a turning point in my career, and science remains a prominent theme in all of my work

VP: You wrote a book called New York 2150 In which New York was completely submerged, with the sea level going up 50 feet from where it is today. I don’t know where the sea level is going to be by then, but what do you think about science fiction making predictions or  placing readers in fear to prevent those predictions.

KSR: One thing about the science fiction readership is that they are accustomed to playing the game of the genre, which means that this novel can be seen through two lenses. On the one hand, it is about the future, and on the other hand, it is about the present.. This novel is about our choices right now, and how we will cope with the future consequences.Some questions it answers are: How will humans cope?Specifically, how will they cope with the situation we would have left them with? They’ll say look, this is what we got. I’m going to try to find a partner, have a family, make some money, have some fun, all that will be on the minds of people.

VP: You know, I think it’s interesting that you mentioned things like humans coping with the future because I think you’ve been described as an optimist about the climate crisis. I personally can’t help but be a pessimist with regards to not only how we’re dealing with the climate crisis now, but also things like capitalism and the modern rise of global fascism. 

KSR: I often recommend just giving up on optimism or pessimism. It will be interesting for you during the course of your lifetime–you’re going to see lots of losses and inappropriate behaviors by people who are, in effect, trying to wreck the world, for motives that are opaque even to themselves. A lot of good things are already started. And it’s become a topic of interest. And I tell you, when I started writing science in the capital, it was just a science fiction story. It made a difference when Al Gore did the movie, An Inconvenient Truth, but it was an outlier opinion. Now it’s the central story of history. And I’m seeing private capital realizing that they can’t make a profit if the world has gone crashing. So now private capital is interested. Could we still make a buck doing green work? That’s a big jump. And it may or may not be true because the inherent rules of capitalism are unjust, they’re extractive, and this is all very straightforward leftism. They’re made for the rich: the rich extract value and ruin people’s lives. They misery people and scare them so that the people will take any job they can stay alive, while the rich live off of an obscene amount of wealth. 

And we can beat these guys, because a lot of them are older, they’re my generation, a lot of them will die out and there will be a new structure of feeling. And this is another leftist concept and it has to do with the general intellect or what is common sense, what everybody just thinks of as normal. And by the time your generation takes over power, then saving the biosphere is going to be seen as normal. It won’t be as contested as now because there’ll be that many disasters and there’ll be that many solutions. 

It does seem to represent to me a full employment program. Young people, especially young intellectuals, but in fact all young people, they’re going to have jobs. People are going to be begging them, because you got to take care of the old people. You got to green the world. And you’ve got to grow the food and make the machinery there’s more work to be done, then there’s going to be humans after the baby boomer pulse dies out. 

It won’t just be flipping burgers or doing Starbucks; that’ll be necessary but that will probably be even those jobs. They’re going to have to be offered an adequate living wage or else nominal take that job because they can take care of old people or they can go out and work in some kind of green industry. The clean transition already needs more. We need more electricians and more engineers than we have right now. And it goes on and on like that. 

And now I’m talking about ministry for the future. I’m talking to all these power centers, and they are almost all being run by people 20 or 30 years younger than me. They’re smart,well educated, and determined to do good and are in positions of power.. So the baby boomers of my generation, accomplish a lot, fail a lot, but are becoming irrelevant. They’re saying things like, “ I’m going to become a technocrat, I’m going to work for the government”, or “I’m going to work in the international diplomatic world. And I’m going to try to make changes.” “ I’m going to make a billion and then I’m going to throw that billion into good causes.” This kind of affective Altruism, which is interesting and kind of bogus. But on the other hand, I have seen many billionaires and Silicon Valley who love science fiction. I met a lot of these people, and they are actually very smart and they want to make sure that the biosphere survives. They have justice as a goal.

Dr. Robinson then delved into various ideas pitched to him by said “technocrats,” each with their fair shares of upsides and downsides. Some of the topics included pumping water from Antarctica, utilizing an industrial process to mechanically drive Carbon back into soil, and other potential agricultural techniques.

KSR: This is a great opportunity for for UC Davis for Regenerative AG. I mean that I think is the project for your generation is and then as I always say the economics, you know, you’ve got to be able to make a living doing that you don’t want to make everybody say to everybody, oh, you need to go bankrupt or you need to do this as charity on the margin. You have to be able to make your living at it. And that this is where looking at that IRA bill is simply saying, Look, we’ll give you money if you do the right thing. And if that was expanded out as a general principle then you get to the carbon coin, et cetera, and then you can make your living doing green things. It’s there it’s on the table. It’s just incoherent and it’s got enemies that would like to kill it in the cradle for reasons that are a little bit ugly.

Our discussion then went to places outside of UC Davis. Dr. Robinson mentioned the International “4 per 1000” Initiative, launched by France in 2015, signifying a goal to increase carbon fixation in soil by .4% every year. The world’s soils contain 2 to 3 times more carbon than the atmosphere, so increasing fixation every year should significantly reduce the Carbon Dioxide in the atmosphere.

VP: I also kind of want to give us give some space for you to just talk about “the new Green Revolution” as you’ve called it. How can readers of the Aggie Transcript and UC Davis students be a part of it?

KSR: Here’s where I gotta say, I am a student trying to learn. Your readers will after a couple classes know more about it than I do. I think I mean, there’s things about it that immediately make me wonder, can this work? Like no till agriculture. So you then suddenly you don’t plow the soil anymore, and you begin to work in perennials rather than annuals and the carbon needs to be sequestered in part by not disturbing the soil. That strikes me as an awesome ask but are there other ways to sequester carbon in soil? We got nitrogen fixers are all around us right now are there carbon fixers Well, there are but can we eat them etc. I’m not well versed in this and I don’t know if there’s a good tutorial on it that I’ve missed. Or if it doesn’t exist, and it’s still a project to be theorized. But the people I keep asking, this village itself is filled with people from UC Davis agriculture who live here. I keep asking them, What do you think about this and they’re like, work in progress, or it’s some or it’s some think tanks idea that it’s actually harder than hell in practice, which may be true. That’s part of my research right now: trying to find out more about what regenerative agriculture would imply.

A Warmer World Leading to a Health Decline

By Abigail Lin, Biological Sciences.

INTRODUCTION

Rising temperatures due to global climate change cause several detrimental impacts on the world around us. This paper will analyze the consequences of climate change, specifically temperature changes, within California. Livelihoods of farmers and fishermen, distribution of disease, and fire intensity are examples of how California is affected by this crisis. Climate change in California is especially visible because California dominates the nation’s fruit and nut production, two water-intensive crops. The state’s reliance on large quantities of water to fuel its agricultural system makes it particularly susceptible to drought. Proliferation of detrimental disease vectors, loss of beneficial crops, and elevated levels of dryness imply a complex interaction between California ecosystems and climate change. 

Crops

There are many farmers and agricultural workers in California impacted by changing climates, as the state is a major agricultural hotspot. Two-thirds of the nation’s fruits and over one-third of the nation’s vegetables are produced in California [1]. Crops such as apricots, peaches, plums, and walnuts are projected to be unable to grow in 90% or more of the Central Valley by the end of the century because of the increase of disease, pests, and weeds that accompany rising temperatures [1]. 

Figure 1. Projection of crop failure by the end of the century. Heat increases diseases, pests, and weeds. Plum, apricot, peach and walnut crops will be unable to grow in 90% of Central Valley as a result.

Crop yields significantly decrease when heat sensitive plants are not grown in cool enough conditions. Fruits and nuts require chill hours, when the temperature is between 32 and 45 degrees Fahrenheit, to ensure adequate reproduction and development [2]. However, with increasing temperatures, crops are receiving less chill hours during the winter. California grows 98% of the country’s pistachios, but changes in chill hours have affected fertilization [3]. A study found that pistachios need 700 chill hours each winter, yet there have been less than 500 chill hours over the past four years combined [1]. As a result, in 2015, 70% of pistachio shells were missing the kernel (the edible part of the nut) that should have been inside [3]. 

Repeated crop failures have also left farmers mentally taxed. Evidence suggests that suicide rates for farmers are already rising in response to farm debt that accumulates in response to poor crop yields [4]. Not only is people’s financial well-being threatened by climate change, but so is their mental health. Mental stress threatens to rise as climates warm around the world, causing economic loss and upheaving agricultural careers. 

Crab Fisheries

Crab fisheries and fishers in California are also negatively impacted by the rise in temperatures. Warming oceans have led to an uncontrollable growth of algal blooms, which contaminates crab meat with domoic acid, a potent neurotoxin that causes seizures and memory loss [5]. The spread of this toxin has forced many fisheries to close. California fishers lost over half the crabs they regularly catch per season, and qualified for more than 25 million dollars of federal disaster relief, during 2015 to 2016 [5]. In response to financial loss, fishers adapted by catching seafood species other than crab, moved to locations where algal blooms have not contaminated their catch, or in the worst case, stopped fishing altogether [5]. California crab fishers’ careers have already been dramatically altered by global warming, and the amount of algal blooms will only continue to increase if warming continues. 

Disease

Temperature plays a major role in the prevalence of infectious diseases because it increases the activity, growth, development, and reproduction of disease vectors, living organisms that carry infectious agents and transmit them to other organisms. It is predicted that warm, humid climates will allow bacteria and viruses, mosquitoes, flies, and rats (all common disease vectors) to thrive [6]. Most animal disease vectors are r-selected, meaning they put little parental investment into individual offspring, but produce many. Warm temperatures allow r-selected species to grow quickly and reproduce often. However, warm temperatures speed up biochemical reactions and are very energy demanding on organism metabolism [7]. In response, disease vector ectotherms, organisms requiring external sources of heat for controlling body temperature, have successfully adapted to changing temperatures. These organisms thermoregulate, or carry out actions that maintain body temperature [7]. Behavioral thermoregulation has shifted the geographical distribution of infectious diseases as disease vectors move to the warm environments that they favor [7]. 

Initial models about the distribution and prevalence of disease suggested a net increase of the geographical range of diseases, while more recent models suggest a shift in disease distribution [7]. Recent models recognize that vector species have upper and lower temperature limits that affect disease distribution [7]. It is estimated that by 2050, there will be 23 million more cases of malaria at higher latitudes, where previously infections were nonexistent, but 25 million less cases of malaria at lower latitudes, where previously malaria proliferated rapidly through populations, because the conditions necessary for malaria transmission will shift [7]. 

Figure 2. Shift of malaria disease distribution by 2050. Higher latitudes will have 23 million more cases of malaria while lower latitudes will have 25 million less cases. Although habitat suitability changed, there is little net change in malaria cases. 

Cases of Coccidioidomycosis (Valley fever), an infectious disease spread from inhaling Coccidioides fungal spores, have recently reached record highs in California [8]. Valley fever is especially prevalent in areas experiencing fluctuating climates, vacillating between extreme drought and high precipitation [8]. After studying 81,000 cases collected over 20 years, researchers identified that major droughts have a causal relationship with increasing Coccidioidomycosis transmission rates [8]. Initially, drought will suppress disease transmission because it prevents proliferation of the Coccidioides fungi. However, transmission rebounds in the years following drought because competing bacteria die off in high heat [8]. Fungi have a number of traits that make them more tolerable to drought compared to bacteria including osmolytes for maintaining cell volume, thick cell walls to mitigate water loss, melanin which aids in thermoregulation, and hyphae that extend throughout the soil to forage for water [9]. Disease spikes are seen after drought, such as the wet season between 2016 and 2017, which had about 2,500 more cases of Valley fever in comparison to the previous year. [8]. 

The role of rising temperatures in increasing Valley fever cases is evident in Kern County, one of the hottest and driest regions of California. Kern Country has the highest Valley fever incident rates in California; 3,390 cases occurred in a 47-month drought from 2012 to 2016 [8]. Kern County has many cases of Valley fever because of its drought-like conditions. As climate change pushes areas throughout California that are usually cool and wet year-round into alternating dry and wet weather conditions, Valley fever cases are projected to increase. 

Fires

Climate change is also associated with an increase in fire season intensity. The Western United States experienced three years of massive wildfires from 2020 to 2022, with each year burning more than 1.2 million acres [10]. The ongoing drought has led to an accumulation of dry trees, shrubs, and grasses [10]. A 2016 study found that this increase of dry organic plant material has more than doubled the number of large fires in the Western United States since 1984 [10]. One of the ways that dry matter may ignite is by lightning. Projections show that by 2060, there will be a 30% increase of area burned by lightning-ignited wildfires compared to 2011 [10]. 

Residents in California are in danger of losing their lives and property to fire damage. A single fire can lead to massive destruction. In 2018, the Woolsey Fire burned 96,949 acres and hundreds of homes, and killed three people [11]. Over one million buildings in California are within high-risk fire zones, and this number is projected to increase as temperatures continue to rise [10]. With the amount of dry organic matter increasing and wildfire incidence surging, there will be more cases of property damage and loss of life in California. High temperatures and extreme weather events make it more likely that people will fall victim to these life-threatening disasters. 

CONCLUSION

Increases in global temperature have a negative effect on human physical health and mental wellbeing. Climate change is making it more difficult to secure a livelihood, changing the spread of disease, and destroying lives and property. However, projections about rising temperatures allow farmers the chance to make informed decisions about which crops to grow, fishermen to relocate to areas that are less impacted by algal blooms, health experts to predict when and where outbreaks of certain diseases might occur, and fire protection services to increase their presence in high-risk areas. Projections help people predict where and when a climate change associated event is likely to occur, so that they may hopefully respond quicker and more efficiently. Consequences of climate change can be mitigated by using models as a guide for what to expect in California’s future. 

REFERENCES

  1. James I. 2018. California agriculture faces serious threats from climate change, study finds. The Desert Sun. Accessed January 31, 2023. Available from www.desertsun.com/story/news/environment/2018/02/27/california-agriculture-faces-serious-threats-climate-change-study-finds/377289002/
  2. U.S. Department of Agriculture. Climate Change and WINTER CHILL. Accessed December 23, 2023. Available from www.climatehubs.usda.gov/sites/default/files/Chill%20Hours%20Ag%20FS%20_%20120620.pdf
  3. Zhang S. 2015. Time to Add Pistachios to California’s List of Woes. WIRED. Accessed February 15, 2023. Available from www.wired.com/2015/09/time-add-pistachios-californias-list-problems/
  4. Semuels A. 2019. ‘They’re Trying to Wipe Us Off the Map.’ Small American Farmers Are Nearing Extinction. TIME. Accessed January 31, 2023. Available from time.com/5736789/small-american-farmers-debt-crisis-extinction/
  5. Gross L. 2021. As Warming Oceans Bring Tough Times to California Crab Fishers, Scientists Say Diversifying is Key to Survival. Inside Climate News. Accessed January 31, 2023. Available from insideclimatenews.org/news/01022021/california-agriculture-crab-fishermen-climate-change/
  6. Martens P. 1999. How Will Climate Change Affect Human Health? The question poses a huge challenge to scientists. Yet the consequences of global warming of public health remain largely unexplored. Am Scien. 87(6):534–541. 
  7. Lafferty KD. 2009. The ecology of climate change and infectious diseases. Ecol Soc Amer. 90(4):888-900. 
  8. Hanson N. 2022. Climate change drives another outbreak: In California, it’s a spike in Valley fever cases. Courthouse News Service. Accessed March 8, 2023. Available from www.courthousenews.com/climate-change-drives-another-outbreak-in-california-its-a-spike-in-valley-fever-cases/
  9. Treseder KK, Berlemont R, Allison SD, & Martiny AC. 2018. Drought increases the frequencies of fungal functional genes related to carbon and nitrogen acquisition. PLoS ONE [Internet]. 13(11):e0206441. doi.org/10.1371/journal.pone.0206441
  10. National Oceanic and Atmospheric Administration. 2022. Wildfire climate connection. Accessed January 31, 2023. Available from www.noaa.gov/noaa-wildfire/wildfire-climate-connection#:~:text=Research%20shows%20that%20changes%20in,fuels%20during%20the%20fire%20season
  11. Lucas S. 2019. Los Angeles is the Face of Climate Change. OneZero. Accessed January 31, 2023. Available from onezero.medium.com/los-angeles-is-burning-f9fab1c212cb

Sex on a spectrum: biological perspectives of intersexuality and transexuality

By Vishwanath Prathikanti, Anthropology ’23

Author’s note: This past quarter I took ANT158, Evolution of Sex: A Biological Perspective. I had falsely believed prior that most of our understanding of sex and sexuality was from a psychological perspective resulting from differences in hormonal cascades that occurred before birth. It was enlightening to learn about evolutionary theories behind sexuality, the relatively high frequency of intersexed individuals, and how different cultures are shaped because of it. For this paper, I wanted to focus on two groups I was previously unaware had so many biological basises; intersexed individuals and trans individuals. I hope to help someone correct misconceptions such as the fallacy that according to biology, there are only two genders.

 

Many understand the difference in sexes as a difference in gonads, or reproductive parts. Males have testes and females have ovaries, with the growth of each determined by hormonal cascades. However, many do not understand that even sex exists on a spectrum; if a gene is not expressed or a hormone is not released, there may be a mismatch between the genetic code and the expression of that code for the individual. Such individuals fit the intersexed definition, though an exact definition of what an intersexed individual is has been a subject of controversy in the scientific community.

Perhaps one of the most important contributors to the acceptance of intersex individuals as something more than fringe cases was Dr. Anne Fausto-Sterling, who published a number of books and papers on intersex individuals. In a literature review summarizing research from the 1950’s to 2000, Fausto-Sterling and colleagues first presented the notion that the percentage of intersex individuals in the population may be as high as 2% [1]. In this paper, they defined intersex as any individual that deviates from the idea that there are only two sexes via a wide variety of biomarkers. These deviations can present themselves in chromosomal, gonadal, or hormonal levels in individuals. In other words, the key difference between transsexuals and intersexed individuals is that intersexed individuals always have some kind of observable biological element, and there are a wide array of markers. Transsexuals simply have to identify as something besides their gender assigned at birth, and some may have biological markers associated with the opposite sex and others may not. A famous example of a biological marker in transsexuals, the BSTc region of the brain, is discussed further.

In her 2012 book, Sex/Gender: Biology in a Social World, Fausto-Sterling expands more towards brain-sex and the potential mismatch between physical characteristics and their gender identity. A misunderstanding of what brain-sex is may be a contributing factor to the perpetuation of gender being the only thing on a spectrum. Brain-sex refers to the complicated ways in which hormones, gene expression and genetic imprinting by the father and/or mother affects the child and the way their brain works. It is not limited to how a person perceives their sex, and this myth may contribute to the idea that gender and sex are completely different and one (sex) refers to biology and the other (gender) to the brain’s perception of identity. In reality, both are linked to biology [2].

Despite these efforts, sex existing on a spectrum is still challenged. In 2002 for example, Leonard Sax posited that the rate of intersexed individuals was much lower—around 0.018% [3]. However, Sax came to this number through a strangely strict definition of intersex; Sax posits that if an individual had an XXY chromosome and had some cells with XX and others with XY configuration, this person would not be intersexed, as their cells technically match their chromosomes. To be intersexed according to Sax, someone must have a mismatch between phenotypic sex and genotypic sex. For example, a person under Sax’s definition would be intersex if they had Complete Androgen Insensitivity Syndrome, if they had XY chromosomes but they never developed male genitalia due to a defect in androgen receptors [3]. 

Such a definition, however, is comparatively much less valuable than what Fausto-Sterling tells us. Her definition of intersex is simply being somewhere in between a man and a woman, and her definition seeks to dismantle the myth that there are only two sexes. While detractors claim that they seek a more clinically rigorous definition, like Sax, it is possible that it furthers the myth that intersex individuals are simply outliers in society, and sex exists in a binary system.

Similarly, if we understand that we can exist on a sexual spectrum, it becomes understandable why transgender individuals, or people that want to switch the gender imposed on them due to their genitalia, exist in society. In addition to the research conducted by Fausto-Sterling indicating a disconnect between external genitalia and internal genes and hormones, there is other clear evidence showing a biological basis for transgendered individuals. Specifically, a study conducted by Zhou and colleagues examined the volume of the central subdivision of the bed nucleus of the stria terminalis (BSTc), a white matter band that acts as a relay site during a stress response. The BSTc is essential for sexual behavior due to multiple reasons, but perhaps most importantly, it is the major center of the aromatization process essential in converting testosterone to estrogen, the two most common male and female growth hormones [4]. It also forms unique connections with the amygdala and hypothalamus, making it highly influential in growth and development. Uniquely, the BSTc region is much larger in males than females, and is directly related to the testosterone and/or estrogen it helps create and regulate. Zhou and colleagues found that the BSTc region among transgendered women and non-transgendered women, where neither groups were on any kind of hormonal therapy that would affect the size of their BSTc, were similar in size. This female brain structure in a genetically male individual supports the notion that gender identity develops as a result of the developing brain [4].

While the research base for transgendered and intersexed individuals is very strong, cultural pushback is rooted in either misinformation or a sense of feeling threatened transgendered individuals. One prominent example of this can be seen in their participation in sports. Over the years, the regulation of trans peoples’ participation in sports has led to absurd levels of regulation, notably for people that do not identify as trans. Most famously are the numerous cases against Caster Semenya, multi-gold winning olympic track athlete, on the basis of testosterone, a shaky metric. The International Association of Athletics Federations (IAAF) currently states that to compete in the olympics, a woman should have testosterone levels below 5 nmol/L. Otherwise, they must compete as a male or receive testosterone blockers to compete as a female. However, in a review of nearly 700 elite athletes, Healy and colleagues found that 16.5% of men had testosterone levels below the 5 nmol/L limit and 13.7% women had testosterone levels above the limit [5]. The IAAF conducted their own study that upheld their regulations, but importantly, they opted to exclude outliers that they deemed having “differences of sexual development,” something they have been criticized for but have not rectified as of the publishing of this paper [6]. These discriminatory practices perhaps further fuel ignorance on the subject of intersexed individuals, and do not properly tackle biology in sexuality. 

The reality is that human beings are more complicated than we’d like to admit. “Bodies are not bounded,” Fausto-Sterling emphasizes in the conclusion to her book. “We will learn a lot about the science of sex and gender in the years to come. But to the extent that our social settings and thus experiences change, at least some of the subtleties of sex and gender will remain a moving target” [2].

REFERENCES

  1. Blackless, M., Charuvastra, A., Derryck, A., Fausto-Sterling, A., Lauzanne, K., & Lee, E. (2000). How sexually dimorphic are we? Review and synthesis. American Journal of Human Biology, 12(2), 151–166. https://doi.org/10.1002/(SICI)1520-6300(200003/04)12:2<151::AID-AJHB1>3.0.CO;2-F
  2. Fausto-Sterling, A. (2012). Sex/Gender: Biology in a Social World. Routledge. https://doi.org/10.4324/978020312797
  3. Sax, L. (2002). How common is intersex? A response to Anne Fausto-Sterling. Journal of Sex Research, 39(3), 174–178. https://doi.org/10.1080/00224490209552139
  4. Zhou, J.-N., Hofman, M. A., Gooren, L. J. G., & Swaab, D. F. (1995). A sex difference in the human brain and its relation to transsexuality. Nature, 378(6552), Article 6552. https://doi.org/10.1038/378068a0
  5. Healy, M. L., Gibney, J., Pentecost, C., Wheeler, M. J., & Sonksen, P. H. (2014). Endocrine profiles in 693 elite athletes in the postcompetition setting. Clinical Endocrinology, 81(2), 294–305. https://doi.org/10.1111/cen.12445
  6. Pielke Sr, R., Tucker, R., & Boye, E. (2019). Scientific integrity and the IAAF testosterone regulations. The International Sports Law Journal, 19. https://doi.org/10.1007/s40318-019-00143-w

 

Precise Genome Editing by a Single Stranded Break

By Saloni Dhopte, Genetics and Genomics, ’23

Author’s note: Do you think CRISPR-Cas9 genome editing is amazing? Well, let me tell you about another technique that has been proven to be more accurate and efficient than CRISPR systems. It’s prime editing – a method of genome editing that utilizes a single stranded nick to edit DNA! I first learnt about prime editing from my then graduate student mentor, Dr. Peter Lynagh, while I was working in the Comai Lab at UC Davis. I remember scouring the internet for papers and looking up applications of this revolutionary technology, as it fascinated me beyond measure. So naturally, when we were tasked with writing a scientific review for my UWP 102B class, I had to write about this! Prime editing is an up-and-coming tool in gene editing, and I hope through my review, readers with basic to intermediate understanding of molecular genetics are able to share my amazement and admiration for prime editing!

 

Abstract

Current methods of genome editing involve a double stranded break on the DNA molecule, thus involving high frequency of unwanted base pair insertion/deletions (indels) and off-target effects in the repair process. Some are relatively limited in scope in terms of the length of the edit and specific type of base pair substitution. Recently, a new technique called prime editing has been developed which creates a single stranded break and shows high accuracy and editing proficiency along with minimal off-target effects in the genome. The molecular machinery of prime editing is very accurate; it recognizes the region of interest in the genome and is precisely able to insert an edited DNA sequence. In this review we discuss the mechanics of prime editing, compare it to other methods of genome editing, and investigate its applications as well as limitations in the health field. Numerous papers from the PubMed database point towards the potential of prime editing in repairing disease-causing mutations in humans. However, researchers are not using it for in vivo experiments (experiments that take place in a whole living organism) just yet, as they believe we need to learn a lot more about safe methods of delivery to human cell lines, side effects of the treatment, and overall efficiency of editing. Regardless, a lot of progress is consistently being made, including optimization of the prime editing machinery, online search databases, and ex-vivo applications. With the current pace of scientific discovery, the goal of using prime editing to its full potential will become reality soon enough. 

Keywords: single-stranded break, genome editing, CRISPR-Cas9, guideRNA, disease-causing mutation repair. 

 

Introduction

In 2019, Dr. David Liu published a paper introducing a new method of genome editing called prime editing (PE). The method is novel in its approach since it surpasses a majority of the drawbacks of pre-existing methods of genome engineering such as base editing (BE) and Clusters of Regularly Interspaced Palindromic Repeats (CRISPR)-CRISPR associated protein (Cas9), a method of genome editing adapted from the bacterial immune system’s defense mechanism. The main reason why PE is able to overcome these drawbacks is because it involves a single stranded break on the DNA molecule, as opposed to CRISPR-Cas9 which involves a double-stranded break (DSB), thus significantly reducing unwanted indels in the genome [1]. So far, a lot of studies have compared the efficiencies of PE with BE and CRISPR-Cas9. PE has been put to use in modeling diseases in organoids (tissue cultures that mimic in vivo organs) and researchers are developing ways of correcting the mutations that cause these diseases. In theory, PE could correct 90% of all disease-causing mutations in humans [2]. However, the unanimous opinion remains: a lot of work needs to be done in the field before PE can be used to correct mutations in a safe manner in vivo [1], [3], [4].

In this review I will investigate the mechanism and scope of prime editing and see how it can be used to study disease-causing mutations. By analyzing the technique and comparing it against the existing and well researched types of genome-editing, I will investigate PE’s effectiveness in repairing these mutations and see how the mechanism can be optimized. 

How does Prime Editing work? 

Mechanism

The prime editing system is based off of the CRISPR-Cas9 genome editing system. In CRISPR-Cas9, there is a single-stranded, guide RNA molecule (sgRNA) that is complementary to a specific region of the DNA and it is associated with a DNA endonuclease enzyme, Cas9. The sgRNA searches for and binds to the sequence homologies within the genome. Directed by the sgRNA to this complementary region of interest, the Cas9 protein then cuts the DNA, creating a DSB[2]. This DSB can then be repaired by double-strand break repair processes of varying levels of efficiency. In the case of prime editing, we still have the guide RNA, but it is modified such that it includes the sequence of our desired edit (referred to as prime editing guide RNA or pegRNA). Further, the Cas9 protein is partially inactivated (referred to as Cas9-nickase) such that it only cuts the 3’ strand of the complementary region on the DNA- creating a single stranded break [5]. And this makes all the difference.  Since PE involves a single stranded break, the machinery doesn’t rely on the inefficient and unpredictable DSB repair mechanisms. 

The single stranded break caused by Cas9 nickase leads to the formation of a 3’ DNA flap. This flap binds to a sequence on the pegRNA called the primer binding site (PBS). The reverse transcriptase enzyme, which is fused to Cas9 nickase, elongates the DNA using the 3’ flap as a primer, thus synthesizing a new “edited” DNA strand. The newly edited strand can then be incorporated into the original DNA molecule through a number of ways. The various approaches through which this resolution happens makes up the different kinds of prime editing. 

Reproducible Graphic : The mechanics of prime editing

https://www.synthego.com/guide/crispr-methods/prime-editing

 

Types of Prime Editing 

The mechanism PE1 relies on an endogenous endonuclease – FEN1, which cuts the 5’ end of our unedited DNA so that it doesn’t come in the way of our edited strand. With this cut, our edited DNA is thermodynamically favored to bind to the original DNA molecule. For PE2, the Liu group modified the sequence of RT to increase its thermostability, binding to DNA template and enzyme processivity. To take the mechanism to the next level, Anzalone et al. developed PE3 where they introduced a second guide RNA (gRNA) molecule that creates a 5’ nick on the non-edited strand, which allows for the edited DNA strand to be used as a template to complete the process. Finally, we have PE3b in which the gRNA is programmed such that it creates the 5’ nick only after the edited strand has been completely formed [5]. This approach led to reduced indel formation and improved editing. According to Anzalone et al., PE3 is 1.5 to 4.2-fold more efficient than PE2. PE3b, while not showing a significantly higher editing efficiency, has a 13-fold reduction in indel formation [2].

To summarize, the way PE works is by utilizing a special RNA molecule called pegRNA that encodes our desired DNA edit and targets the exact region of DNA where the edit has to be incorporated. Along with the Cas-9 nickase, it accurately creates a single stranded break, synthesizes the edited DNA, and finally incorporates the edit through various mechanisms – PE1, PE2, PE3 and PE3b.

Why is Prime Editing the best genome editing method we know?

Prime Editing versus CRISPR-Cas9

There are multiple characteristics of PE that make it better than our pre-existing methods of genome editing. 

First, PE involves a single stranded break in the DNA as opposed to CRISPR-Cas9 editing which involves a double stranded break (DSB). A DSB can be repaired in one of two ways – via homology directed repair (HDR) or non-homologous end joining (NHEJ). The latter leads to a lot of indels. Thus, the editing efficiency of genome editing methods employing DSB’s is low. In contrast, PE doesn’t involve a DSB to begin with, thus the process of repairing the break doesn’t rely on the generation of random indels. Chemello et. al showed how the mutations causing Duchenne Muscular Dystrophy (DMD) are corrected with less unwanted effects via PE as opposed to CRISPR-Cas9 [4].They used prime editing to correct one of the most common mutations of DMD – the deletion of exon 51. Chemello et al. first attempted to restore the correct open reading frame (ORF) by inducing exon skipping. They used CRISPR Cas9 to systematically make two cuts such that exon 52 would be skipped, and the ORF would be restored. However they were unsuccessful due to the high rate of indels and off-target effects of CRISPR-Cas9. On the other hand, with PE, they were able to reframe the exon and precisely inserted two nucleotides into exon 52, thus bypassing the need for exon skipping entirely. This demonstrates the ability of PE to specifically target and edit DNA sequences in order to correct disease-causing mutations without the unwanted effects of double-stranded break repair pathways.

Further, since PE requires 3 separate hybridization events (pegRNA spacer to target DNA for Cas9 binding, pegRNA PBS to target DNA, and target DNA 3’  flap to RT product) to occur, it has significantly less off-target effects in the genome. In CRISPR-Cas9,  the guide RNA, as it is searching DNA for complementarity, can bind to other regions of the genome with similar sequences, leading to DSB’s in places that were not targeted [2]. Kim et al. were unsuccessful in trying to correct DMD using CRISPR-Cas9, due to these off-target effects. However, they found no significant unwanted indels in the genome of mice hepatocytes that were prime edited to correct for HT1 [6]. Similarly, Geurts et al. performed whole genome sequence analysis on prime edited five colon organoids and reported no mutational differences among the edited organoid sequences [3]. These findings establish the safety of PE as compared to CRISPR-Cas9.

Prime Editing versus base editing 

 PE’s battle with base editing is not as one-sided as it is with CRISPR Cas9. Base editing performs rather well in most experiments. 

 There are two kinds of base editing – adenine base editing that can change a nucleotide from A to G or G to A, and cytosine base editing, which changes C to T or T to C. The mechanism involves an inactive Cas9 protein (dCas9) fused to a deaminase molecule which makes the respective base change possible [1]. Base editing doesn’t involve a break on the DNA molecule at all.  It also doesn’t rely on the generation of random indels for editing. Hence, it is not surprising that the efficiency of this method surpasses that of PE. Geurts et al. reported that base editing induced correct mutations in 50% of the colonic organoids whereas prime editing was only able to reach 22% [3]. Similarly, Schene et al. found that using PE for the correction of mutations in liver organoids was less effective than using base editing. In this way, both papers report the same finding – when working with a mutation that can be corrected by base editing, it outperforms PE. 

But here is the catch. First, base editing can make only four of the twelve possible base pair changes. If the disease of interest requires an adenine to be corrected into a cytosine, base editing doesn’t even come into the picture– that substitution is beyond its capability. This severely limits the scope of genome editing. The second drawback deals with the size of the edit. Some diseases require a stretch of nucleotides to be corrected– not just a single nucleotide. If the editing window for BE is increased to more than one nucleotide, especially if the edit includes more A or C bases, a lot of by-stander edits are observed. This is because the Cas9-deaminase complex makes all base substitutions in its range, including those we don’t want [2]. This problem doesn’t arise in PE because the pegRNA encodes highly specific DNA insertions up to 80 base pairs in length. Because 98-99% of insertions, deletions and duplications in the pathogenic human genetic variants are smaller than 30 base pairs, researchers have claimed that with PE, we will be able to correct 90% of disease-causing mutations in humans [1].

What has been accomplished so far using Prime Editing?

One of the most sought-after goals of genome editing is to be able to correct diseases-causing mutations. While PE is being used increasingly for its precision in editing DNA, it is a relatively new technique and so all of the research takes place in vitro ( in an artificial environment simulated to mimic the human body). In the hopes of eventually overcoming this gap and moving on to in vivo studies, scientists are also working on optimizing PE to have even less off-target effects. They have varied the molecular machinery, model organoids that mimic in vivo organ systems, and target mutations in different combinations, to find an approach with the best results. Optimization of the prime editing machinery is a well-established path to achieving the goal of using this technique in therapeutic applications. 

Repair and modeling of disease-causing variants 

 Prime editing has been successfully used to model several diseases in human organoids. Broadly speaking, there are two main goals of these particular studies. First, to study the efficiency of PE, and working on ways of improving the mechanism. Geurts et al. utilized PE to model the mutation causing cystic fibrosis in human adult derived colonic organoids and then used PE to correct the mutation. Scientists employed both PE and BE for these steps and found that BE was more efficient in inducing intended mutations as compared to PE, but again, it remains limited to 4 of the 12 base pair substitutions. They acknowledged that if edits need to be made outside of this window, PE is the best approach [3].

The second kind of PE editing studies investigate the ways in which disease-causing mutations can be corrected. Schene et al. modeled mutations in liver organoids to mimic the development of liver cancer, then used PE [1]. Schene et al. and Guerts et al. both confirmed that PE is the better choice only for the subset of mutations not applicable for correction using BE [3]. 

With that, it is quite clear that we need to work a lot more on PE to further increase its efficiency. To do this, multiple researchers are focusing their efforts on optimization of PE. 

Optimization of pegRNA’s 

The prime editing machinery is highly advanced in structure. Compared to CRISPR-Cas9, there are fewer elements involved and thus less unwanted indels. The key player making this possible is the prime editing guide RNA (pegRNA). Researchers have worked extensively on optimizing the performance of the pegRNA through a variety of approaches. Lin et al. identified two main factors that have shown increased efficiency of editing: first, designing primer binding sites (PBS) on the pegRNA with melting temperature less than 30 degrees Celsius, and second: using not one, but twopegRNA’s encoding the same edit [7]. Together, these boost the editing efficiency 17.4-fold. 

Moreover, there is an increase in resources and tools for pegRNA optimization. PegFinder is an online software that allows scientists to program the specific pegRNA to fit their experiment [3]. More recently, Lin et al describe the construction of their own web application called PlantPegDesigner. They claim that their tool is more user-friendly than PegFinder, as the latter necessitates experimental testing of pegRNA’s. PlantPegDesigner only requires a single DNA sequence as an input and provides a variety of parameters to be optimized by the user – an ideal candidate pegRNA [7]. This technology has the potential to greatly simplify prime editing experiments with plants, which in turn might lead to quickly reducing the knowledge gap in the field. Another similar web application is PrimeDesign – a tool that not only provides the user with an ideal pegRNA but visualizes the entire prime editing event. It allows users to rank pegRNA’s based on efficiency and includes extensive annotations. Additionally, Hsu et al. created a database called PrimeVar using all of these results, which can be used to search for pegRNA’s correcting ~70,000 pathogenic human genetic variants [8]. 

Conclusion

Prime editing is a novel breakthrough in the field of genome editing. It has been only three years since the publishing of Dr. David Liu’s original paper introducing the world to PE. PE is able to target and edit any region of the genome while avoiding drawbacks of current gene-editing methods, made possible by the induction of a single stranded break. Scientists have demonstrated the superiority of PE when compared to base editing and CRISPR-Cas9 editing. BE, although more accurate and known for less off-target effects than PE, can only correct a subset of base-pair substitutions. CRISPR-Cas9 involves a double stranded break on the DNA molecule, leading to high rates of unwanted insertions/deletions in the genome as compared to PE. Within a span of two years, four distinct types of PE have been developed – PE1, PE2, PE3 and PE4 – each more efficient than the last. The development of online tools such as PrimeDesign and PlantPegDesigner show the rate at which scientists are making progress with PE. However, we are far from the finish line. Most researchers still remain skeptical about the use of PE for in-vivo applications. While some say it is imperative to develop safe methods of delivery to human cell lines, others question the consequences of off-target effects in the genome. We don’t fully understand how PE might affect other cells of the subject [2]. Additionally, researchers aren’t certain about the longevity of prime edited disease corrections [4]. Most agree that in theory, prime editing will be revolutionary in terms of advancing human health, but given the relative recentness of the technology, there is still a lot of work to be done. Despite the gray area, PE certainly has a lot of potential and will be one of our strongest tools in improving human health in the future. 

 

References:

  1. I. F. Schene et al., “Prime editing for functional repair in patient-derived disease models,” Nat Commun, vol. 11, no. 1, p. 5352, Dec. 2020, doi: 10.1038/s41467-020-19136-7.
  2. A. V. Anzalone et al., “Search-and-replace genome editing without double-strand breaks or donor DNA,” Nature, vol. 576, no. 7785, pp. 149–157, Dec. 2019, doi: 10.1038/s41586-019-1711-4.
  3. M. H. Geurts et al., “Evaluating CRISPR-based prime editing for cancer modeling and CFTR repair in organoids,” Life Sci. Alliance, vol. 4, no. 10, p. e202000940, Oct. 2021, doi: 10.26508/lsa.202000940.
  4. F. Chemello et al., “Precise correction of Duchenne muscular dystrophy exon deletion mutations by base and prime editing,” Sci. Adv., vol. 7, no. 18, p. eabg4910, Apr. 2021, doi: 10.1126/sciadv.abg4910.
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Elizabethkingia anophelis: an Emerging, Opportunistic Pathogen

By Nelly Escalante, Molecular and Medical Microbiology, ’23

 

Overview

Elizabethkingia is a family of gram-positive, aerobic bacteria that includes the species Elizabethkingia meningoseptica, Elizabethkingia miricola, Elizabethkingia anophelis, Elizabethkingia bruuniana, Elizabethkingia ursingii, and Elizabethkingia occulta [1]. E. meningoseptica and E. anophelis are the only species within the genus that have been observed to cause disease in humans. While previous research has characterized E. meningoseptica’s predominant role in infection, emerging research has revealed that E. anophelis has been responsible for most of the recent Elizabethkingia case reports. 

Elizabethkingia anophelis is an emerging pathogen first discovered in 2011. It is a symbiotic bacterium that resides in the midgut of the mosquito Anopheles gambiae, which resides in the Gambia River region in central Africa [2]. While A. gambiae is endemic to that region, outbreaks have been observed in several Asian and African countries, with the biggest outbreak so far occurring in the United States. Most cases of E. anophelis are not due to direct contact with its host, A. gambiae, but rather are community-acquired in hospitals through a yet undescribed method of transmission.

Diagnosis

Clinical Presentation

Typical symptoms of E. anophelis infection include bacteremia and meningitis. Pyrexia, chills, and dyspnea have also been observed across several case reports. E. anophelis presents the greatest bacterial burden in the blood, causing bacteremia that can lead to further complications such as sepsis and septic shock. Removal of catheters or central lines may be a necessary approach to relieve bacteremia when E. anophelis is suspected [3]. 

Most of the information known about E. anophelis has come from case reports, as an animal model has not been developed yet to examine its pathogenesis in vivo. The first identified human case of E. anophelis infection was a case of neonatal meningitis in Africa. In this case, the 8-day-old patient experienced pyrexia, seizures, and apnea. Cerebrospinal fluid (CSF) analysis revealed hypoglycorrhachia [4]. In another case, a 7-month-old patient suffered from pyrexia, ecchymotic spots on the body, respiratory failure, and hemorrhaging [5]. These symptoms, however, are not considered to be within the standard clinical presentation of an E. anophelis infection and would only be seen with an especially acute bacterial burden. In both cases, the final diagnosis of E. anophelis infection was made after positive bacterial cultures were observed.

Diagnostic Criteria

Cultures are a powerful tool in the diagnosis of bacterial infection and are grown by sampling many bodily fluids, although blood and CSF are the most common. Once cultures are grown, they can be analyzed to identify the specific bacterium or bacteria causing the infection. Common methods used to identify the different Elizabethkingia species have been unable to differentiate between E. meningoseptica and E. anophelis with great accuracy. Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry, one of these common methods, utilizes a laser to ionize the bacterial sample and records the time it takes the ions to travel the length of a tube. Larger ions take a longer time, thus producing a mass spectrum that is known as a peptide mass fingerprint (PMF). The PMF of the sample is compared to the over 2,000 PMF of known bacteria species in the database [6].

MALDI-TOF mostly produces accurate identification of bacteria to the genus level. In combination with the lack of PMF samples of E. anophelis, this method has caused many cases of E. anophelis to be misidentified as E. meningoseptica. However, 16S ribosomal RNA gene sequencing has been successful in identifying E. anophelis as it directly uses genomic DNA to produce the 16s rRNA gene sequence and compare it to the more then 60,000 bacterial type strains in the database [7]. This analysis has shown that E. anophelis accounts for far more infections than E. meningoseptica.

Elizabethkingia anophelis culture taken from a patient and grown on 5% sheep blood agar

 

Treatment

Treatment regimens for E. anophelis infections have not yet been established because the range of antibiotic resistance of the bacterium has not been completely characterized. However, studies have shown that minocycline and levofloxacin are the most effective in treatment. Minocycline belongs to the class of tetracycline antibiotics that inhibit protein synthesis in both gram-positive and gram-negative bacteria and can be given orally. This medicine, however, cannot be given safely to children under the age of 8 [8]. Given that neonates are one of the most affected, other treatments are still being explored.

Levofloxacin, on the other hand, is part of a new group of fluoroquinolones that inhibits DNA gyrase and topoisomerase IV, enzymes that are essential to bacterial DNA replication. Levofloxacin is usually not administered to children except in life-threatening infections such as one by E. anophelis [9]. Moxifloxacin, a drug in the same class of antibiotics, was successful in the treatment of the first human case of E. anophelis infection.

E. anophelis has been classified as multi-drug resistant because it is not susceptible to common antibiotics such as β-lactams and β-lactam/lactamase inhibitors. Additionally, although many cases of E. anophelis have been misidentified as E. meningoseptica, they have distinct antimicrobial susceptibilities and require different treatments [10]. Many E. anophelis strains contain variants in the catB gene that confers antibiotic resistance to phenicol drugs and antibiotic inactivation enzymes [11].

The fatality of E. anophelis infection varies greatly across case reports, but in general has been estimated to be close to 30% [12]. Incorrect antimicrobial therapy regimens are a risk factor in the mortality of patients, which means deciding on the correct antibiotics is essential to ensuring a patient’s recovery and survival [13]. For example, antibiotics that are used to treat neonatal meningitis are ineffective against E. anophelis infection, further highlighting the importance of accurate diagnosis and treatment regimens.

Bacteriophages, also known as phages, are currently being investigated as an alternative to antibiotic treatment, given the multi-drug resistant nature of E. anophelis. In Taiwan, a phage named TCUEAP1 was isolated from the wastewater of a hospital. While there is no bacteriophage specific to E. anophelis, TCEUAP1 was able to infect three strains of the bacteria and reduce the number of colony-forming units (CFU). In a mouse model, the phage was able to decrease the bacterial load in their blood from 5×105 CFU/mL to 1×105 CFU/mL. In doing so, they were able to rescue 80% of the mice that would have otherwise died due to bacteremia [14]. Phages are a promising new therapy for treating multidrug resistant bacteria because they only attack their bacterial hosts and do so with a mechanism that is distinct from drugs. 

Prevention and Future Research

As a nosocomial infection, the best prevention is good hygiene practices. Frequent hand washing by medical personnel as well as routine, thorough disinfection of surfaces may help in reducing the spread. Person-to-person transmission, either through direct or close contact with an infected individual, remains a possible infection mechanism that has yet to be confirmed by in vitro models. It has been proposed that mothers are able to vertically transmit the infection to their child during birth. The exact mechanism of how a person becomes infected by E. anophelis is unknown, but many research efforts are underway to describe its pathogenesis and route of transmission.

Recent research has shown that the bacterium has been able to evade the immune system’s defenses. Macrophages are among the first cells of the immune system to respond to an infection. They have an antibacterial polarization state known as classically activated (M1) macrophages and are activated when a pathogen is detected. In this state, they change their morphology to engulf pathogens through phagocytosis to reduce the bacterial burden. E. anophelis evades this detection and prevents M1 macrophages from activating through a yet unknown mechanism. If activated M1 macrophages are present, the bacteria are also able to avoid being engulfed, which may be due to the bacterial capsule surrounding the bacterium. This type of phagocytosis evasion using a bacterial capsule has been observed by other bacteria such as Salmonella and Mycobacterium [15]. Considering that most patients who contracted an E. anophelis infection were elderly, newborn, or immunocompromised, this type of immune system evasion may be a contributing factor to the high mortality of the infection [5].

Image taken of E. anophelis using phase contrast microscopy. Bacteria are stained with Maneval’s solution with empty space around the bacteria showing the bacterial capsule.

 

Overall, there are many mechanistic mysteries to Elizabethkingia anophelis that have yet to be investigated, but are nonetheless pertinent to the prevention of further outbreaks and improved patient outcomes.

 

References:

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