Human Genome Editing: Ethical Considerations

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Rapid advances in genome editing technology following the development of CRISPR have led to almost miraculous progress toward the treatment of some diseases, such as sickle cell disease, beta thalassemia, and congenital blindness. These treatments induce somatic gene edits, meaning they are not passed on to offspring, and as such, there is widespread consensus that they should be administered to patients and researched further. Much more controversial is the use of germline editing, in which edits are made to an early-stage human embryo in vitro that is brought to term such that all the baby’s cells, and those of its future descendants, have the edited gene. The greatest concern surrounding this technology is that, once our understanding of the genetics of complex traits like intelligence and personality advance, prospective parents will be able to select which traits their child will inherit, resulting in the normalization of “designer babies.” Given the technology’s enormous potential toward both good and harm, ethical considerations for the young field of human genome editing are a major area of discussion.

While this reality is currently far beyond our technical capabilities, very real fears were realized in 2018 when Chinese scientist He Jiankui violated current regulations and ethics protocols by mutating a cell receptor for HIV from embryos in order to confer HIV resistance before implanting the embryos to be brought to term.1 In the aftermath of this bombshell announcement, discussions about the ethics of germline editing came to the fore of the scientific community. Many human genome editing researchers called on nations to enact a moratorium on germline editing until “broad societal consensus” on the ethical considerations of germline editing could be reached.2 Others have argued that, while caution must certainly be exercised, trials for germline editing should proceed, as it is unethical not to pursue treatments for genetic conditions that cause profound suffering when the technology exists.3

Much of the conversation on the ethics of germline editing centers on the circumstances in which it should or should not be employed. Many have embraced the argument that germline editing should only be used as a “treatment,” implying the existence of a disease or disability that the genome editing addresses, as opposed to as an “enhancement,” where there is no underlying medical need.4 Allowing germline editing in the latter case, according to many, would lead humanity down the slippery slope to eugenics. However, deciding what constitutes a disease or disability is not straightforward. Many forms of deafness, for example, are congenital, and are potential targets for germline editing. But plenty of deaf people lead long and fulfilling lives and feel they’ve gained from being deaf.5 Even sickle cell disease has advantages: carriers for the disease have increased resistance to malaria.6 Due to the complexity of these cases and others like them, there may not always be a consensus on whether it is ethical to edit the genes we perceive as causing disability out of the human genome.

Another ethical issue posed by human genome editing is that of inequality. When germline editing technologies eventually become mainstream, they will almost certainly be prohibitively expensive, at least at the outset. This may “exacerbate inequality and even permanently encode it into our species.”7

This scenario will not be a possibility for some time, due to our current technical capabilities and the strict regulations enacted by rich nations. All but 5 of 96 developed countries in one analysis prohibit germline editing for reproduction without exception,8 and the World Health Organization recently released a series of recommendations for nations to further ensure that gene editing technologies are not misused.9 Gene editing has the power to change the future of our species, and as our abilities to use it improve rapidly, it is critical that nations, institutions, and individual scientists give ethical considerations of genome editing the highest priority.

 

References

 

1 Cyranoski, D. “What CRISPR-Baby Prison Sentences Mean for Research.” Nature News, Nature Publishing Group, 3 Jan. 2020, www.nature.com/articles/d41586-020-00001-y.

2 Lander, E., et al. “Adopt a Moratorium on Heritable Genome Editing.” Nature News, Nature Publishing Group, 13 Mar. 2019, www.nature.com/articles/d41586-019-00726-5.

3 Ayanoglu, F. B. et al. “Bioethical Issues in Genome Editing by CRISPR-Cas9 Technology.” Turkish Journal of Biology, vol. 44, no. 2, 2020, pp. 110–120., doi:10.3906/biy-1912-52.

Human Genome Editing: Status

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The field of human genome editing has exploded in the past 10 years, thanks to the revolutionary gene editing technology known as CRISPR. In 2012, Jennifer Doudna and Emmanuelle Charpentier elucidated the mechanism of the CRISPR-Cas9 system, an ancient defense system evolved in bacteria to detect and cut the DNA of invading viruses, and showed that it could be leveraged for targeted genome editing in vitro.[i] Feng Zhang and his team at the Broad Institute subsequently showed that CRISPR-Cas9 could successfully modify target genes in mammalian cells.[ii] These two discoveries led to the implementation of CRISPR in many facets of basic research, the formation of new biotechnology companies dedicated to using CRISPR for a variety of purposes,[iii] and the successful use of CRISPR gene therapies in patients with genetic diseases. In recognition of CRISPR’s extraordinary potential, the Royal Swedish Academy of Sciences – which normally bestows Nobel Prizes several decades after a scientific discovery – awarded the 2020 Nobel Prize in Chemistry to Doudna and Charpentier, a mere eight years after their seminal paper, for discovering the genetic tools that “have taken the life sciences into a new epoch.”[iv]

When used for human genome editing, the CRISPR system only consists of three components: a Cas (CRISPR-associated) enzyme, which is likened to “molecular scissors,” a “guide RNA,” a piece of RNA complementary to the target DNA sequence, and a repair template, the desired sequence of DNA. The guide RNA binds to the desired stretch of DNA, allowed Cas to make a double-stranded break in the DNA. The repair template then becomes incorporated into the cell’s genome as it repairs the break. [v]

This basic approach has already been used to effectively treat several genetic conditions. Over the course of the past two years, patients with sickle cell disease and beta thalassemia, monogenic diseases characterized by defective hemoglobin, had stem cells from their bone marrow removed and edited with CRISPR so that they would begin expressing fetal hemoglobin (which normally is turned off shortly after birth), after which they received infusions of these cells.[vi] More than a year after treatment, the patients presented high levels of blood hemoglobin and a drastic reduction in painful symptoms.[vii] Trials are currently underway to treat genetic forms of blindness in vivo by injecting a harmless virus containing the CRISPR machinery into the back of the eye.[viii] A June 2021 study in which researchers eliminated the production of a defective liver protein that can cause fatal side effects showed that CRISPR can be safe and effective when injected directly into the bloodstream, likely an important step for the future of CRISPR therapeutics.[ix]

Congenital diseases represent a significant portion of health conditions faced globally, and many cause serious pain, disability, morbidity, or early mortality. The development of CRISPR technology has resulted in rapid increases in funding, research, and potential ability to treat such diseases via human genome editing. Results so far are promising, and it is likely that further research will improve the accessibility of this technology.

 

References

1 Jinek, M., et al. “A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity.” Science, vol. 337, no. 6096, 2012, pp. 816–821., doi:10.1126/science.1225829.

2 Ran, F. A., et al. “Genome Engineering Using the Crispr-cas9 System.” Nature Protocols, vol. 8, no. 11, 2013, pp. 2281–2308., doi:10.1038/nprot.2013.143.

2 Shaffer, C. “CRISPR Startups Give Genome Editing Several New Twists.” Genetic Engineering & Biotechnology News, 4 Aug. 2020, www.genengnews.com/insights/crispr-startups-give-genome-editing-several-new-twists/.

4 “The Nobel Prize in Chemistry 2020.” NobelPrize.org, 7 Oct. 2020, www.nobelprize.org/prizes/chemistry/2020/press-release/.

5 Pak, E. “CRISPR: A Game-Changing Genetic Engineering Technique.” Science in the News, The Graduate School of Arts and Sciences at Harvard University, 31 July 2014, sitn.hms.harvard.edu/flash/2014/crispr-a-game-changing-genetic-engineering-technique/.

6 Stein, R. “1st Patients to Get CRISPR Gene-Editing Treatment Continue to Thrive.” NPR, 15 Dec. 2020, www.npr.org/sections/health-shots/2020/12/15/944184405/1st-patients-to-get-crispr-gene-editing-treatment-continue-to-thrive.

7 Frangoul, H., et al. “CRISPR-Cas9 Gene Editing for Sickle Cell Disease AND Β-THALASSEMIA.” New England Journal of Medicine, vol. 384, no. 3, 2021, pp. 252–260., doi:10.1056/nejmoa2031054.

8 Stein, R. “In a 1st, Scientists Use Revolutionary Gene-Editing Tool to Edit Inside a Patient.” NPR, NPR, 4 Mar. 2020, www.npr.org/sections/health-shots/2020/03/04/811461486/in-a-1st-scientists-use-revolutionary-gene-editing-tool-to-edit-inside-a-patient.

9 Ledford, H. “Landmark CRISPR Trial Shows Promise against Deadly Disease.” Nature News, Nature Publishing Group, 29 June 2021, www.nature.com/articles/d41586-021-01776-4.

COVID-19 Transmission by Children

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Babies and toddlers may be more likely to transmit the virus that causes COVID-19 to others in their households compared to teenagers, a new study has found (Paul et al., 2021). Since early 2020, the coronavirus pandemic has overwhelmed countries all around the world. In the United States, the number of deaths from coronavirus is nearing 642,000, with an increase in cases, hospitalizations, and deaths in recent weeks (CDC). This study, which was published last month in JAMA Pediatrics, does not resolve the ongoing debate over whether infected children are as contagious as infected adults, nor does it suggest children are drivers of the pandemic. The study does, however, demonstrate that very young children can play a role in the transmission of COVID-19.

Researchers at Public Health Ontario, a Canadian public health agency, analyzed Ontarian health records from June 1 to December 31, 2020, and identified 6,280 households in which a child (0-18 years old) was the “index case” – the first person to develop COVID-19 symptoms or test positive for the virus. Then they looked for “secondary cases,” others in the household who got sick in the two weeks after the first child became ill (Paul et al., 2021). In most cases, the chain of transmission stopped with the infected child, but in 27.3% of households, children transmitted the virus to at least one other household member (Anthes, 2021). Another takeaway was that adolescents were most likely to bring the virus into the home, with 14–17-year-olds making up 38% of index cases (Paul et al., 2021). The study’s key finding, however, was that the odds of household transmission of COVID-19 were roughly 40% higher for infections in children 3 or younger compared to children between 14 and 17 (Paul et al., 2021). Behavioral differences might explain this finding, as babies and toddlers often require close contact and hands-on care. “The 0-to-3-year-old child is held differently, is cuddled,” offered Dr. Paul Offit, professor of pediatrics in the Division of Infectious Diseases at Children’s Hospital of Philadelphia (Salzman et al., 2021). And when young children are sick, for example, they cannot be isolated.

This study updates experts’ understanding of COVID-19 transmission risk. Earlier in the pandemic, some scientists suggested the risk of COVID-19 transmission declined with younger age, though this assumption was likely biased by the fact that lockdowns and social distancing limited  social encounters for young children (Choi, 2021). These new findings suggest the opposite, and Dr. Edith Bracho Sanchez, a primary care pediatrician and assistant professor of pediatrics at Columbia University Irving Medical Center, said that the study “just shows how humble we have to be when it comes to children and this virus. We always knew children could get it, could transmit it, and could get sick with COVID,” she continued (Salzman et al., 2021). “I think we’re learning more and more just how much.”

The study was conducted in 2020, before the delta variant emerged, so further research is necessary to understand transmission risk in the context of the variant and other potential variants. The study also took place before vaccines were available, so all household members were unvaccinated (Paul et al., 2021). Still, its findings reinforce the importance of implementing and maintaining mitigation strategies at schools and childcare facilities, especially as a new school year begins and more children are returning to school in-person. Strategies such as frequent cleaning, good ventilation, distancing, and masking when possible are essential. The study also reaffirms the importance of vaccination for all eligible people over 12, especially those that spend time with children (Salzman et al., 2021).

 

References

 

Anthes E. (2021, August 16). Babies and Toddlers Spread Virus in Homes More Easily Than Teens, Study Finds. New York Times. https://www.nytimes.com/2021/08/16/health/covid-kids-toddlers-transmission.html.

 

Centers for Disease Control (CDC). COVID Data Tracker, Updated Daily. U.S. Department of Health and Human Services. https://covid.cdc.gov/covid-data-tracker/#datatracker-home.

 

Choi J. (2021, August 19). Younger children more likely to spread COVID-19 to households than older kids. The Hill. https://thehill.com/policy/healthcare/568627-younger-children-more-likely-to-spread-covid-19-than-households-with-older.

 

Paul LA, Daneman N, Schwartz KL, et al. Association of Age and Pediatric Household Transmission of SARS-CoV-2 Infection. JAMA Pediatr. Published online August 16, 2021. doi:10.1001/jamapediatrics.2021.2770

Salzman S., Richter Lauren R. (2021, August 16). Younger children more likely to spread COVID-19, study finds. ABC News. https://abcnews.go.com/Health/younger-children-spread-covid-19-study-finds/story?id=79480836.

Returning to In-Person School

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On July 12, 2021, the United Nations Children’s Fund (UNICEF) and United Nations Educational, Scientific and Cultural Organization (UNESCO) jointly released a statement urging governments to reopen in-person school. Primary and secondary schools remain completely shuttered in 19 countries around the world due to COVID-19, increasing the likelihood of learning loss, reduced development of social skills, mental distress, exposure to violence and abuse, and missed school-based meals and vaccinations. Since March of 2020, schools in over 160 countries have been fully closed at one point. “The losses that children and young people will incur from not being in school may never be recouped,” the statement declares. [1] 

 

Over a year into the COVID-19 pandemic, with many schools around the world having cycled through periods of full closure and cautious or complete reopening, there is growing evidence that, in many scenarios, communities can resume in-person school in a safe manner with proper adherence to mitigation strategies. Research has consistently demonstrated that while children and young people are susceptible to COVID-19, they have had a lower incidence and a lower risk of severe COVID-19 outcomes than adults. [2] As of July 8, 2021, between only 0.1 to 1.9 percent of all child COVID-19 cases have resulted in hospitalization. [3] 

 

The Centers for Disease Control and Prevention (CDC) is promoting the reopening of in-person school in accordance with newly released guidelines. A July 9 report recommends indoor masking at all times, at least three feet of distancing, weekly testing, and maintaining small groups/pods. The report promotes, but does not mandate, vaccination for teachers, staff, families, and students. [4] Encouragingly, a July 2021 national polling update from the Morning Consult indicates that nearly three-quarters of teachers have been vaccinated. [5] The new CDC report removes speculation that schools will be required to separate vaccinated and unvaccinated individuals, which could foment division and create major logistical challenges.  

 

Evidence supports the principle that layering prevention strategies can reduce or eliminate the occurrence of COVID-19 outbreaks in school and make it safe for reopening in-person, according to a comprehensive literature review by Resolve to Save Lives, an organization led by former CDC Director Tom Frieden. The report cites an English study finding no differences in COVID-19 positivity rates between teachers and other professions involving in-person interactions. Studies of schools in Australia and Europe have indicated that school outbreaks are generally associated with 10 cases or fewer, with protective measures limiting outbreaks. [6] Even in tight spaces, transmission can be contained: a new article in the Journal of School Health reports that universal testing and contact tracing revealed no transmission linked to school bus transportation serving 462 students. Although the buses were operating at near capacity of two students in every seat, universal masking and simple ventilation techniques were in place and appear to have been effective. [7]  

 

Notably, the CDC guidance incorporates language emphasizing the importance of in-person learning even in the absence of the full implementation of these measures. [6] Such guidance testifies to the concern elicited by growing evidence of the detriments of keeping schools closed, with students suffering socially, emotionally, and academically. [8] It also acknowledges that fully implementing prevention strategies is a major challenge in the U.S., where divisive debates over public health guidance continue, with some parents saying they won’t send their children to schools without masks, and some saying they’ll only send their children without them.  

 

While in the United States, virtual learning remains an option, as well as a tool of untapped potential, in lower-resource settings, school closures have been more prolonged while virtual learning tools have remained less accessible, according to UNICEF data. Even though vaccine shortages have plagued many of these countries, the UNICEF-UNESCO statement asserts that “reopening schools for in-person learning cannot wait.” [1] In the absence of vaccines — or in the context of vaccine hesitancy and refusal in the United States — the layering of mitigation strategies outlined by the CDC remains all the more critical. 

 

References 

 

  1. Reopening schools cannot wait: joint statement by UNICEF and UNESCO. United Nations Educational, Scientific and Cultural Organization. Published July 12, 2021. https://en.unesco.org/news/reopening-schools-cannot-wait-joint-statement-unicef-and-unesco 
  2. Leidman E, Duca LM, Omura JD, Proia K, Stephens JW, Sauber-Schatz EK. COVID-19 trends among persons aged 0-24 years – United States, March 1-December 12, 2020. MMWR Morb Mortal Wkly Rep. 2021;70(3):88-94. 
  3. Children and COVID-19: State Data Report. American Academy of Pediatrics. Published July 8, 2021. https://downloads.aap.org/AAP/PDF/AAP%20and%20CHA%20-%20Children%20and%20COVID-19%20State%20Data%20Report%207.8%20FINAL.pdf  
  4. CDC. Guidance for COVID-19 Prevention in K-12 schools. Centers for Disease Control and Prevention. Published July 10, 2021. https://www.cdc.gov/coronavirus/2019-ncov/community/schools-childcare/k-12-guidance.html  
  5. Teachers and K-12 Education: A National Polling Report. Morning Consult. Published July 2021. https://edchoice.morningconsultintelligence.com/assets/123916.pdf  
  6. Cash-Goldwasser S, Jones SA, Wu AC, Subramaniam HL and Frieden TR. In-Depth COVID-19 Science Review. Resolve to Save Lives. Published July 16, 2021. https://preventepidemics.org/covid19/science/review/july-15-2021/  
  7. Ramirez DWE, Klinkhammer MD, Rowland LC. COVID-19 transmission during transportation of 1st to 12th grade students: Experience of an independent school in Virginia. J Sch Health. 2021;(josh.13058). doi:10.1111/josh.13058 
  8. Duckworth AL, Kautz T, Defnet A, et al. Students attending school remotely suffer socially, emotionally, and academically. Educ Res. Published online 2021:0013189X2110315. 

Atrial Fibrillation Ablation: Anesthesia Considerations

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Atrial fibrillation is a medical condition that affects roughly 33.5 million people worldwide [1]. Underlying cardiac conditions such as hypertension and coronary heart disease, which are common in developed countries, are risk factors for this condition. In lower income countries, rheumatic heart disease is associated with a higher incidence of atrial fibrillation, though rates are decreasing worldwide due to access to antibiotics. A later stage treatment approach for atrial fibrillation is ablation, with the assistance of anesthesia.

 

The pathophysiology of atrial fibrillation involves rapid firing from a single focus in the atria that triggers a change in heart rate and rhythm. The most common location is from the pulmonary veins, which can be targeted with catheter ablation. Treatment is focused on prevention of future episodes in addition to prevention of thromboembolism. First line treatment for atrial fibrillation is rate or rhythm control with oral medications such as beta-blockers or amiodarone. Thromboembolism risk is reduced with a direct oral anticoagulant.

 

If patients continue to remain symptomatic with recurrent episodes of atrial fibrillation despite medication, ablation is a highly effective procedural technique that can be considered. It is associated with 70-75% of patients being symptom-free after 1 year with 4% risk of major complications like stroke, cardiac perforation, or damage to the surrounding structures, such as the esophagus and phrenic nerve [2]. Electrophysiology evaluation is used to determine the location of myocardial tissue which is most responsible for the repetitive firing. An electroanatomical map is made, creating a 3-D representation of the patient’s heart to determine where the physician will use radiofrequency energy, cryothermal energy, or laser balloon to ablate myocardial tissue [2].

 

Cardiac ablation is a technique that is highly dependent on the practicing physician, with variability in duration of the procedure and the type of ablative energy used. The anesthesia used for atrial fibrillation ablation is highly important as this procedure is associated with significant risks. Conscious sedation with fentanyl and midazolam used to be the most common technique until studies comparing conscious sedation against general anesthesia found lower rates of recurrence and pulmonary vein reconnection with general anesthesia [3]. New retrospective cohort studies comparing monitored anesthetic care (MAC) vs. general anesthesia (GA) demonstrated MAC was independently associated with shorter total laboratory time due to reducing non-procedure time with no significant changes in freedom from documented atrial fibrillation, atrial flutter, atrial tachycardia and no significant difference in complication rates [4,6].

 

Despite this evidence, in a 2021 retrospective review, researchers demonstrated GA was still the most common mode of sedation for 54,231 patients who underwent cardiac ablation in the U.S., with 94% of patients receiving general anesthesia and only 6% receiving monitored anesthetic care (MAC) [5]. Patients who received MAC were more likely to be >80 years old, female, and have American Society of Anesthesiologist physical status > III. MAC cases were mostly done in Northeast urban hospital centers.

 

Current literature demonstrates that MAC is a safe anesthetic option for atrial fibrillation ablation that is not currently used widely in the United States. Due to its benefits, including shorter time in the laboratory with equitable outcomes to general anesthesia, more anesthesiologists may choose to use MAC over GA in the future.

 

References 

 

  1. Lip GYH, Brechin CM, Lane DA. The global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe. Chest. 2012 Dec;142(6):1489-1498. doi: 10.1378/chest.11-2888. PMID: 22459778. 
  2. Oral H, Knight BP, Ozaydin M, Tada H, Chugh A, Hassan S, Scharf C, Lai SW, Greenstein R, Pelosi F Jr, Strickberger SA, Morady F. Clinical significance of early recurrences of atrial fibrillation after pulmonary vein isolation. J Am Coll Cardiol. 2002 Jul 3;40(1):100-4. doi: 10.1016/s0735-1097(02)01939-3. PMID: 12103262.
  3. Price A, Santucci P. Electrophysiology procedures: weighing the factors affecting choice of anesthesia. Semin Cardiothorac Vasc Anesth. 2013 Sep;17(3):203-11. doi: 10.1177/1089253213494023. Epub 2013 Jul 3. PMID: 23827944. 
  4. Dada RS, Hayanga JWA, Woods K, Schwartzman D, Thibault D, Ellison M, Schmidt S, Siddoway D, Badhwar V, Hayanga HK. Anesthetic Choice for Atrial Fibrillation Ablation: A National Anesthesia Clinical Outcomes Registry Analysis. J Cardiothorac Vasc Anesth. 2021 Jan 5:S1053-0770(20)31393-8. doi: 10.1053/j.jvca.2020.12.046. Epub ahead of print. PMID: 33518460. 
  5. Wasserlauf J, Knight BP, Li Z, et al. Moderate Sedation Reduces Lab Time Compared to General Anesthesia during Cryoballoon Ablation for AF Without Compromising Safety or Long-Term Efficacy. Pacing Clin Electrophysiol 2016; 39:1359. doi: 10.1111/pace.12961. Epub 2016 Nov 10. PMID: 27747896. 
  6. Kuck KH, Brugada J, Fürnkranz A, et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med 2016; 374:2235. doi: 10.1056/NEJMoa1602014. Epub 2016 Apr 4. PMID: 27042964.