Johnson & Johnson Vaccine Update

By Afifa Zahid

Published 9:49 PM EST, Thurs March 18, 2021

Introduction

As vaccine distribution ramps up  in the United States, the end of the COVID-19 pandemic becomes more feasible to imagine. Additionally, President Joe Biden’s goal to vaccinate the entire country within his first 100-days becomes much easier, as this J&J will alleviate the distribution pressure and help many American’s get off the vaccine waitlist.

Perhaps one of the most notable differences between the Johnson & Johnson vaccine and the vaccines currently available (Pfizer and Moderna) is Johnson & Johnson’s lower efficacy rate. In the latest clinical trial, the vaccine had a 72% efficacy rate, a notable difference from both  the Pfizer and Moderna vaccines that had a 95% efficacy rate. However, this statistic does not tell the whole story. The Johnson & Johnson vaccine demonstrated an overall 85% efficacy rate against severe forms of COVID-19 cases and a 100% efficacy rate against hospitalization and death, just like the Pfizer and Moderna vaccines.

Regardless, this isn’t a numbers game. It’s more important to acknowledge the fact that we now have three vaccines. In response to the FDA approval of the new vaccine, Dr. Anthony Fauci stated “ ‘Rather than parsing the difference between 94 and 72, accept the fact that now you have three highly effective vaccines. Period.’ “. 

The Johnson & Johnson Vaccine Mechanism of Action 

A significant differentiator for the Johnson & Johnson vaccine is that it is a single dose; while both vaccines currently available are double dose vaccines. Furthermore, the Johnson & Johnson can be refrigerated for up to three months, between temperatures of 36°F and 46°F. The Pfizer and Moderna vaccines, on the other hand, have to be used shortly after it comes out of refrigeration. Further complicating vaccine storage, the Pfizer vaccine must be stored in dry ice for up to only 5 days. The Moderna vaccine has to be stored at -94°F . 

Now that the key differences between the J&J vaccine and double doses have been discussed, the J&J vaccine’s mechanism of action can be better understood. The coronavirus is covered with spiky protein structures, that the virus uses to latch onto cells inside the body. Specifically, the virus attaches to receptors on healthy cells, especially those in our lungs. Once inside, the coronavirus hijacks healthy cells and takes command, eventually killing healthy spells.

The Johnson & Johnson vaccine is based on the virus’s genetic code for building proteins. While the Pfizer and Moderna vaccines focus on single-stranded RNA, the site of protein development, the Johnson & Johnson vaccine uses a double-stranded DNA mechanism. 

The coronavirus spike protein was added to another virus, Adenovirus 26. Adenoviruses cause flu-like symptoms or colds. However, by using a modified version of this virus, it could enter the cells but not replicate or cause an illness. Immediately after the vaccine is injected into one’s arm, the adenovirus latches onto proteins found on the surface of healthy cells. As the cell completely engulfs the virus and pulls it inside, the adenovirus then travels into the nucleus. Here, the cell reads the gene for the coronavirus spike protein and its copied into a molecule called mRNA, messenger RNA.

The mRNA then leaves the nucleus and begins to assemble spike proteins. The spiked proteins produced by the cell travels to the surface of the cell where the either cling to the surface or are broken up into fragments. The spikes and spike fragments are then recognized by the immune system, programming the immune system to attack spiked proteins – like those on the surface of the coronavirus. 

Additionally, the adenovirus also triggers the cell’s alarm systems, sending out a warning to nearby cells to activate immune cells. Allowing the immune system to initiate a stronger response against spike proteins, such as those found on the coronavirus. 

Further, B cells, a type of immune cell found in the body, can also bump into the coronavirus spikes on the surface of vaccinated cells or free-floating fragments. These B cells then attach themselves to the spike proteins. Once they’re activated by helper cells, like T cells, the start to introduce antibodies that target the spike protein. These antibodies latch onto coronavirus spikes and mark the virus for destruction as well as prohibit the spikes from attaching to other cells. 

It’s also important to become familiar with the effects associated with the J&J vaccine. The most common effects are pain at the injection site, headaches, and flu-like symptoms. While these side effects are also common in people who received either the Pfizer and Moderna vaccines., it’s notable that in clinical trials fewer people experienced side effects, relative to those who took one of the mRNA vaccines. These side effects are common; approximately 55% of people who participated in J&J clinical trials experienced these symptoms. Though, these side effects resolve in an average of two days. 

Conclusion 

While the effectiveness and efficacy of the vaccine is questioned, due to its expedited development process, one must remember that these vaccines are the result of decades of research on adenovirus and SARS. And they’ve been proven effective after several clinical trials. They’re safe. So, as soon as you become eligible to take the vaccine, do it. You’d not only be helping yourself, but helping the United States overcome the COVID-19 pandemic.  

Afifa Zahid, Youth Medical Journal 2021

References

1. Ferran, Maureen. “How Does the Johnson & Johnson Vaccine Compare to Other Coronavirus Vaccines?” PBS, Public Broadcasting Service, 26 Feb. 2021, http://www.pbs.org/newshour/health/how-does-the-johnson-johnson-vaccine-compare-to-other-coronavirus-vaccines. 
2. Press, The Associated. Johnson & Johnson Begins Covid-19 Vaccine Distribution. 1 Mar. 2021, http://www.nytimes.com/video/us/100000007630214/johnson-johnson-coronavirus-vaccine.html?searchResultPosition=2.
3. “We Thought It Was Just a Respiratory Virus.” We Thought It Was Just a Respiratory Virus | UC San Francisco, 2 Mar. 2021, http://www.ucsf.edu/magazine/covid-body. 
4. Weiland, Noah, and Sharon Lafraniere. F.D.A. Clears Johnson & Johnson’s Shot, the Third Vaccine for U.S. 27 Feb. 2021, http://www.nytimes.com/2021/02/27/health/covid-vaccine-johnson-and-johnson.html?searchResultPosition=3. 
5. Corum, Jonathan, and Carl Zimmer. “How the Johnson & Johnson Vaccine Works.” The New York Times, The New York Times, 18 Dec. 2020, http://www.nytimes.com/interactive/2020/health/johnson-johnson-covid-19-vaccine.html.
6. Johnson & Johnson. http://www.jnj.com/johnson-johnson-covid-19-vaccine-authorized-by-u-s-fda-for-emergency-usefirst-single-shot-vaccine-in-fight-against-global-pandemic.
7. Kollewe, Julia. “From Pfizer to Moderna: Who’s Making Billions from Covid-19 Vaccines?” The Guardian, Guardian News and Media, 6 Mar. 2021, http://www.theguardian.com/business/2021/mar/06/from-pfizer-to-moderna-whos-making-billions-from-covid-vaccines.
8. Piper, Kelsey. “We’re Not Looking at the Most Important Vaccine Statistic.” Vox, Vox, 11 Feb. 2021, http://www.vox.com/22273502/covid-vaccines-pfizer-moderna-johnson-astrazeneca-efficacy-deaths. 

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New Developments in Treating Mental Maladies

By Afifa Zahid

Published 8:22 PM EST, Sat February 6, 2021

Introduction

The growing conversation about mental health in the United States has sparked necessary change in treating mental health.

Patients at Taube Pavilion wake up with views of the scenic Santa Cruz Mountains and the sun flooding through the massive windows in their private rooms. Upon awakening, patients can choose to have their meals or coneven together in communal spaces and courtyards. While this description may initially sound like that of a holiday resort, it’s actually a new mental health facility at El Camino Hospital in Silicon Valley. 

Approach

The shift from the grim and sterile environment previously associated with mental health facilities has been a long time coming. As the mental health conversation in America continues to spread, several experts have inquired if solitude has been the best way to tackle the mental health crisis in the United States. This new approach, embodied by the Taube Pavillion, is one that is focused on fostering healing and therapeutic experiences for the patients. In order to create these experiences, these new centers try to replicate residential areas. Meaning, Taube Pavillion, has large entrances, gathering spaces, and welcoming bedrooms — a stark contrast to the crowded rooms common in psychiatric hospitals for decades. Additionally, nature played an important role in its design choices. Patients have extensive views of greenery and access to a vast array of outdoor areas. 

Mardelle McCuskey Shepley, the chair of the department of design and environmental analysis in Cornell’s College of Human Ecology stated, “We’ve been talking about this for a really long time. It’s only now that it’s gaining momentum.” Not only does Shepley emphasize how switching to a more patient-experience centered change to mental institutions is a necessary change, she also brings up an important point: reforming these facilities has gained traction due to the COVID-19 pandemic and while it has unfortunately increased mental health struggles in the United States, America has been dealing with the mental health crisis long before. Prior to the pandemic, 1 in 5 Americans were affected by mental illnesses such as depression, bipolar disorder, schizophrenia, post-traumatic stress, and other ailments. Furthermore, a study, conducted by the National Institute of Mental Health, has also revealed how mental health  disproportionately affects many communities: mental health maladies affect about 50% of adolescents and 30% of young adults. Additionally, young adults in Black and Latino communities have reported higher levels of depression, anxiety, and substance abuse. Lastly, a Gallup poll conducted in December of last year, revealed that a significant portion of Americans reported that their mental health was “worse than it has been at any point in the last two decades.”. 

The emotional toll the pandemic has caused increased the desire for effective mental health treatment. In fact, in 2020, 40% of the speciality hospitals under constructions were psychiatric hospitals and related to behavioral health. 

New Measures

However, designers of new mental health facilities face a number of challenges in creating new and improved facilities. The first of which is safety — for both patients and healthcare staff. Traditional mental health institutions have harsh rules and features  in the name of patient safety. These amenities include window glaze made out of polycarbonate compounds to prevent breakage, quick release door hinges for east entry, and plumbing fixtures have been altered to prevent the possibility of patients inflicting self harm. Safety measures for all parties are a crucial aspect of running effective mental health facilities, so it becomes difficult to balance patient autonomy and necessary precautions. Some design firms such as Hammel, Green, and Abrahamson have found some remedy to this dilemma. For example, they implemented manual thermostats and dimmer switches in order to give patients some control over their surroundings.

The second challenge they face is the fact that mental health does not have a “one size fits all” solution. Unlike other medical ailments which can be treated with a standard set of medication or surgical procedures, mental health is an incredibly personal and nuanced experience. It cannot be expected that the same approach can be used for every person. Despite these significant challenges, new facilities have been taking efforts to make the patient experience as pleasant as possible by trying to eliminate stress. Directors of these institutions have taken conscious efforts in order to eliminate stress — few to none crowded places and lowering/controlling excessive noise to name a few. The idea behind these steps is to reduce the potential for patient and employee aggression. If patients are not stressed, they may experience a faster recovery process  during treatment.  

Though, those aren’t the only modifications; the location of these facilities have been changing as well. Previously, these centers were located in remote areas. However, today, they are conveniently located or attached to a hospital. For example, Montage Health, a non profit provider, recently unveiled plans for  a new psychiatric center named Ohana — the Hawaiian word for family– in California. Their state of the art approach includes a collaborative effect from friends and family. Further, they particularly concentrate on treating young adults and adolescents. This is because 50% of all lifetime mental illnesses present themselves by the age of 15 and 75% by the age of 24. With these statistics in mind, Ohana contains classrooms, treatment wings, areas for yoga and spaces for group and individual therapy. Further, the building itself will be surrounded by cedars, pines, rosemary, & lavender  and overlook a verdant valley. 

Ohana and Taube Pavillion are just two of the many new mental health centers challenging the status quo of psychiatric centers. Further, they represent tangible effects of the growing awareness surrounding mental health. As research into the health effects of these innovative facilities becomes more accessible, the United States will be able to properly tackle the mental health crises. 

Afifa Zahid, Youth Medical Journal 2021

References

1. Margolies, Jane. “A New Tool in Treating Mental Illness: Building Design.” The New York Times, The New York Times, 5 Jan. 2021, http://www.nytimes.com/2021/01/05/business/mental-health-facilities-design.html?searchResultPosition=12. 
2. “Mental Illness.” National Institute of Mental Health, U.S. Department of Health and Human Services, http://www.nimh.nih.gov/health/statistics/mental-illness.shtml. 
3. “Montage Health.” Ohana, http://www.montagehealthohana.org/ohana.html. 
4. Ulrich, Roger S., et al. “Psychiatric Ward Design Can Reduce Aggressive Behavior.” Journal of Environmental Psychology, vol. 57, 2018, pp. 53–66., doi:10.1016/j.jenvp.2018.05.002. 
5. Czeisler MÉ , Lane RI, Petrosky E, et al. Mental Health, Substance Use, and Suicidal Ideation During the COVID-19 Pandemic — United States, June 24–30, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1049–1057. DOI: http://dx.doi.org/10.15585/mmwr.mm6932a1external icon

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The Historical Development of Fentanyl

Introduction

Fentanyl has become one of the most valuable drugs for pain treatment throughout the world. Most commonly, it is used intravenously for intraoperative analgesia: drugs used during surgery.¹ Additionally, fentanyl’s patch form is often prescribed for cancer patients who experience intense pain. Since its creation, fentanyl has been administered in a number of ways, including patches and sprays.¹  

Research

 Dr. Paul Janssen, founder of Janssen Pharmaceutica, was interested in creating a fast acting analgesic for treatment. While morphine and meperidine were both available during this time, they often performed poorly or were not fast-acting enough.² With this research in mind, Janssen’s team desired to create new molecules that were more powerful than both of the former drugs. To begin their pursuits, Jassen’s team began by working with meperidine, which was easier to manipulate, as it is not as complex as morphine.³ The research team hypothesized that the piperidine ring, a cyclohexane in which one of the carbons is replaced by a nitrogen that is found in morphine and meperidine, was crucial in the production of analgesia.^3,4 However, they discovered that the rate of production was not fast acting, as morphine and meperidine were unable to easily penetrate into the central nervous system.³ In order to create drugs that were capable of doing this, the team began removing a number of chemical structures like ethyl and methyl groups to create lipid-soluble drugs.³ In doing so, Janssen and his team were able to create dozens of far more potent and lipid-soluble drugs, including phenoperidine in 1957.² 

Results

Phenoperidine was proven to be an incredibly potent drug; it is 25 times more potent than morphine and 50 times more potent than meperidine.³ Phenoperidine’s strength led the team to continue to synthesize molecules related to phenoperidine in hopes of creating even more effective drugs.³ Finally, in 1960, they created fentanyl.³ Fentanyl was more than 10 times more potent than phenoperidine, and 100 to 200 times more potent than morphine.³ Additionally, it had a much greater liquid solubility than the molecules that came before it: its octanol/water partition coefficient, a method of expressing the lipophilicity of a compound, was 813.^3,5 Furthermore, it had the fastest onset action rate at the time of its creation.³ Fentanyl’s onset rate was 277 compared to 4.7, 71, and 39.1 for meperidine, morphine, and phenoperidine respectively.³

However, the Janssen Company experienced difficulty in getting the Food and Drug Administration’s (FDA) approval for use in the United States.³ In particular, Dr. Dripps, a professor of anesthesiology at the University of Pennsylvania, believed that fentanyl was far too strong of a drug to administer,  and it would consequently lead to abuse.³  To ease his concerns, Dr. Janssen met with Dr. Dripps, and they reached a compromise: fentanyl would only be administered in a 1: 50  ratio with droperidol.³ This ratio convinced Dr. Dripp that fentanyl would be safe to use, as both him and Dr. Janssen knew that droperidol did not have a pleasing effect if used recreationally.³ The 50:1 ratio of droperial to fentanyl,  Dr. Dripps believed,  would decrease the chances of fentanyl being abused.³ The FDA subsequently approved, and fentanyl began to be administered in the United States only in a 1-mL vial containing 50 µg.³

Soon, this was not the only way fentanyl began being administered in the United States. Fentanyl’s success as an analgesic prompted Alza Corporation to develop a fentanyl patch in the 1980s.³ This patch would later be known as Duragesic.³ 

Developments

The next major development in fentanyl administration was not as intentional.³ Dr. Janssen suggested to Dr. Ted Stanley to study the effect of carfentanil, a cousin of fentanyl, on several animals including rats, dogs, and ferrets.³ Yet, it was not until Dr. Stanley observed the Rhesus monkeys, when the idea of a new fentanyl product was created.³ The monkeys did not respond well to the carfentanil delivery techniques implemented by the research team, but Dr. Stanley knew that monkeys were fond of sugar cubes and grew curious as to whether or not carfentanil could be injected into sugar cubes.³ This prompted researchers to deliver two sugar cubes that had been injected with different doses of carfentanil to two monkeys.³ Within minutes, the monkeys finished eating the sugar cubes.³ The monkey that had eaten the sugar cube with the larger dose became narcotized and the monkey who had the smaller dose became mildly sedated.³ 

This experience caused Dr. Stanley to wonder if there was a similar technique to deliver fentanyl to children.³ Days later, fentanyl on a lozenge stick, essentially a lollipop, was being developed.³ In 1984, Oralet produced a product resembling a red lollipop that was marketed as a child friendly method of administering fentanyl.³ Their creation was fast-acting: the onset was approximately 5-15 minutes and the effect lasted between 1-2 hours, which was one of Dr. Janssen’s main goals in creating fentanyl.³ Thus, a new company, Anesta, was formed in order to get oral transumyatcocan fentanyl citrate, OTFC, approved by the FDA and then launched into the market.³ 

While Oralet was available for clinical use, it was not until Dr. Perry Fine and Dr. Michael Ashburn, clinicians at University of Utah, grew curious as to whether or not OTFC could relieve severance to chronic pain in cancer patients that Oralet was prescribed more frequently.³ Dr. Fine and Dr. Ashburn determined that Oralets works as an effective analgesic for patients who experienced breakthrough pain, BTP, in ten to fifteen minutes.³ This was faster than any opioid available on the market at the time.³ Furthermore, they discovered that the unit was not necessary to relieve pain; this was another benefit of an OTFC Unit: clinicians now had the capability to titrate the correct dosage of fentanyl for their patients.³

Dr. Fine and Dr. Ashburn’s results prompted Anesta to develop a new OTFC unit: Actiq.³

Oralet was specially designed to look more like a lollipop and less like traditional medicine, as it was created for out of hospital use.³ Its counterpart, Actiq, maintained a more traditional medical design as it was approved to be used in hospitals only.³ By the end of 2000, Anesa was purchased by Cephalon, making Actiq experience commercial success.³

Conclusion

Actiq’s widespread use convinced many more companies to develop similar products.³ In 2006, Cephalon created Fentora, which is essentially the same product as Actiq, except it contains no sugar.³ Also, Fentora’s main achievement was starting the search for effective methods of administering fentanyl that were not OTFC, such as OraVescent.³ OraVescent drug delivery systems release carbon dioxide when a tablet containing fentanyl makes contact with saliva. This release alters the pH causing the tablet to dissolve at a faster rate.³ Finally, when the tablet is completely dissolved, the carbon dioxide is gone.³ OraVescent’s biggest value is that it produces faster blood levels of fentanyl when compared to Actiq.³ Finally, a more recent method of administering fentanyl has been by spray.³ The spray encapsulates Dr. Janssen’s primary goal of synthesizing fentanyl, creating an even more fast-acting and effective opioid.³ The fentanyl spray uses un-ionized fentanyl and has an onset time of five minutes or less.³ Furthermore, the nasal spray shows promise of widespread use as it appears to treat approximately 80% of BTP cases.³ While more research needs to be conducted, these early results are incredibly promising.³ 

Afifa Zahid, Youth Medical Journal 2020

References

1. Peng, P. W.; Sandler, A. N. A Review of the Use of Fentanyl Analgesia in the Management of Acute Pain in Adults. Anesthesiology [Online] 1999, 90 (2), 576–599.
2. Stanley, T. H.; The History and Development of the Fentanyl Series. Journal of Pain Symptom Management [Online] 1992, 7 (3), 1-5.

Stanley, T. H.; The Fentanyl Story. The Journal of Pain [Online] 2014, 15 (12), 1215–1226

COVID-19 Vaccine Research and Development Update

Introduction

Early Monday, November 9th, Reuters announced that a vaccine for COVID-19 was being developed by Pfizer and that it had demonstrated extraordinary results with the conclusion of their Phase 3 trial. Their vaccine has proven to be effective over 90% of the time. Yet, creating a vaccine this effective has been a particularly hard experience, not just scientifically but emotionally for millions of people worldwide. Until the vaccine becomes widely available is it essential that we all must continue to wear masks to ensure the safety of ourselves and those around us. 

Past Developments

As of July, two vaccines had reached phase 3 in the world, both of which were being developed in Brazil. The first of these vaccines was developed by Oxford University in collaboration with AstraZeneca labs. The technical name of this vaccine is ChAdOx1 nCoV-19. ChAdOx1 is a non-replicating common cold vaccine, which was the foundation for this vaccine. ChAdOx1 nCoV-19 was tested on 5000 volunteers at an undisclosed location in Rio de Janeiro, São Paulo. Prior to this, the vaccine had already been tested on animals and smaller groups of people, showing promising results. This vaccine entered its final phase on July 27, and in less than a month, the Brazilian government began discussing the production of millions of doses with AstraZeneca. President Bolsanaro set aside $360 million for a licensing deal with AstraZeneca. These funds would have been able to cover up to 100 million doses of the vaccine if proven to be successful. However, at the beginning of the trial, the deal was to provide up to 30 million doses of the vaccine. It has also been said that if the vaccine works, then an additional 70 million vaccines will be produced by this company. The second major vaccine being developed in Brazil was created by China’s Sinovac Biotech. Sinovac Biotech worked in partnership with the Brazilian public health center, the Butantan Institute. The vaccine is called CoronaVac. Much like the Oxford vaccine, the Sinovac vaccine entered phase 3 of clinical trials relatively recently, on June 21. 9000 health care workers received the vaccine, and if the vaccine had proven to be effective, the Butantan institute had the right to produce 120 million doses. 

Despite how renowned Brazil’s research institute is, its public healthcare system has suffered in recent years, experiencing budget cuts and also fighting against the spread of misinformation. These experiences were so detrimental that 2019 was the first time in 25 years where Brazil didn’t fulfill its vaccination goal for any of the shots it routinely administers. Money alone is not enough; experts believe that this process could take up to 10 years due to the difficulty of transferring technology and the underinvestment of the facilities. If Brazil’s institutions are unable to meet their goals, not only would that mark yet another failure in President Bolsonaro’s efforts to combat the virus, but it would also cause Brazil vulnerable and in desperate need of medical supplies. 

Current Stance of Vaccine 

While the vaccines are being developed in Brazil, early November 9th Pfizer announced that current data from its COVID-19 vaccine demonstrates the vaccine is more than 90% effective. The Pfizer team determined this statistic by analyzing the first 94 confirmed cases among their 43,000 volunteers who either received the trial vaccine or a placebo. Their analysis showed that fewer than 10% of infections were in participants who had been administered the vaccine, meaning over 90% of the positive cases were from those who had received the placebo. 

While this is exciting news, it’s important to realize this does not mean that the vaccine is going to arrive in a matter of days; there is still much more testing left. On Sunday, November 8th, approximately 39,000 volunteers of the 43,000 volunteers who had participated in Phase 3 of trials received the vaccine. Their end goal is to reach 164 confirmed cases of COVID-19 infection. To achieve this goal, Pfizer has developed technology in which messenger RNA, mRNA, essentially tricks cells into producing a protein that resembles the virus. In theory, the immune system would learn to attack these placebos and would eventually respond the same way with the actual virus. Though it is unclear how long protection from the virus will sustain. The most likely case, of what’s to happen, is that the vaccine will be administered on a yearly basis. 

Additionally, Pfizer believes that they are on track to create over 50 million doses by the end of this year and over 1 billion next year. They will be able to reach this extraordinary number as they have multiple manufacturing centers and have already signed production contracts with multiple governments. 

Conclusion 

The importance of this vaccine goes beyond medical advancements. It’s fair to say 2020 has not gone the way anyone has expected it to. Emotions have run high since March and this news could not have come at a better time, especially when the United States is reaching upwards of 100,000 new cases. The emotional aspect of the vaccine is equally as important as the medical advancement. 

A highly effective vaccine is great news especially as we approach 8 months of quarantine. However, it is essential that we continue to listen to science these upcoming months. Until an effective vaccine is not only officially created, but also widely available, we have to continue to wear masks. Masks are currently the best way to combat the virus and until a vaccine is readily available this is the best way to protect ourselves and loved one from COVID-19. 

Afifa Zahid, Youth Medical Journal 2020

References

1. Almeida, Nelson. “Chinese COVID-19 Vaccine Starts Final Tests In Brazil.” Barron’s, Barrons, 21 July 2020,www.barrons.com/news/chinese-covid-19-vaccine-starts-final-tests-in-brazil-01595362806. 
2. McCoy, Terrence. “Brazil, Ravaged by the Coronavirus, Becomes Key Testing Ground for Vaccine.” The Washington Post, WP Company, 2 July 2020, http://www.washingtonpost.com/world/the_americas/brazil-oxford-astrazeneca-sinovac-coronavirus-vaccine-trials/2020/07/01/53db68fa-bad0-11ea-80b9-40ece9a701dc_story.html. 
3. Andreoni, Manuela, and Ernesto Londoño. “Coronavirus Crisis Has Made Brazil an Ideal Vaccine Laboratory.” 
4. Reuters. “Brazil’s Bolsonaro Says COVID-19 Vaccinations Won’t Be Mandatory.” NBCNews.com, NBCUniversal News Group, 4 Sept. 2020, http://www.nbcnews.com/news/latino/brazil-s-bolsonaro-says-covid-19-vaccinations-won-t-be-n1239298. 
5. Limited, Bangkok Post Public Company. “Chinese Covid-19 Vaccine Starts Final Tests in Brazil.” https://Www.bangkokpost.com, http://www.bangkokpost.com/world/1955559/chinese-covid-19-vaccine-starts-final-tests-in-brazil. 
6. Burger, L., & Weiss, P. (2020, November 09). BioNTech hopes COVID-19 vaccine will immunize for at least a year. Retrieved November 09, 2020, from https://www.reuters.com/article/us-health-coronavirus-vaccines-pfizer-du/biontech-hopes-covid-19-vaccine-will-immunize-for-at-least-a-year-idUSKBN27P1J2
7. Can face masks protect against the coronavirus? (2020, August 20). Retrieved November 09, 2020, from https://www.mayoclinic.org/diseases-conditions/coronavirus/in-depth/coronavirus-mask/art-20485449
8. Erman, M., & Steenhuysen, J. (2020, November 09). ‘Great day for humanity’: Pfizer says COVID-19 vaccine over 90% effective. Retrieved November 09, 2020, from https://www.reuters.com/article/us-health-coronavirus-vaccines-pfizer/pfizer-and-biontech-say-their-covid-19-vaccine-is-over-90-effective-idUSKBN27P1CT
9. Kounang, N. (2020, November 09). Pfizer says early analysis shows its Covid-19 vaccine is 90% effective. Retrieved November 09, 2020, from https://www.cnn.com/2020/11/09/health/pfizer-covid-19-vaccine-effective/index.html

“Tree Man” Syndrome: The Rare Genetic Disorder

Introduction

 Mahmoud Taluli of Gaza before undergoing surgery to remove the brace like lesions.

“Tree Man” Syndrome, formally known as epidermodysplasia verruciformis (EV), is a rare but physically and mentally taxing condition that causes warts that resemble tree branches to spread all over the body at rapid rates. EV is inherited through a gene  mutation which makes the people affected highly susceptible to human papilloma virus (HPV). HPV is extremely common; in fact over 100 different  strains of this virus exist. However, the Genetic and Rare Diseases Information (GARD) estimates that approximately 200 people worldwide are experiencing EV. Living with EV makes fighting off HPV extremely difficult to combat as the genetic mutation causes a defect in the immune system. Unfortunately, there are no definitive cures; treatments have been met with varying levels of success. 

What is it?

There has been an increasing amount of focus on EV after a Bangaldeshi man made headlines for this condition in 2016, though much remains unknown about this condition due to its rarity. What we do know is that this condition typically manifests itself from childhood with the presentation of small warts; in fact, approximately 7.5% of cases manifest during infancy, 61.5% of cases develop during childhood, and 22% of cases develop during puberty. As the child gets older, their lesions become increasingly larger and appear at a faster rate as EV causes a defect in the immune system that makes the individual more susceptible to HPV, particularly HPV5 and HPV8 are found in 80% of all cases. 

Eventually, some of these lesions can become cancerous. The most common skin cancer that presents itself in EV is squamous cell carcinoma. 30% – 60% of all patients with EV develop squamous cell carcinomas when they are around 40 to 50 years old. Squamous cell carcinoma is often caused by prolonged exposure to ultraviolet light from sources like the sun or artificial light. Thus, it is often recommended for those with EV to avoid staying in areas with high UV radiation exposure for extended periods of time. This recommendation arose from the fact that 30% – 60% of all patients with EV develop squamous cell carcinomas when they are around 40 to 50 years old. 

In terms of genetics, EV has often been associated with an autosomal recessive inheritance pattern (two mutated genes are required to inherit the disease, one from each parent), though other reports that EV is sex linked, sporadoic, or even autsomal dominant inheritance(one mutate gene is required to inherit the disease). Though, there is some agreement over which genes and chromosomes are affected: the EVER1 and EVER2 genes of Chromosome 17. It is here that the proteins that, “form a complex with the zinc transporter protein (ZnT-1) in the endoplasmic reticulum of keratinocytes (aka skin cells)” are created. Zinc is thought to play an important role in wound healing and it may provide an explanation as to why EV occurs. In order to confirm this hypothesis, extensive research must take place.  

Symptoms

The most notable symptom of EV are the growths that resemble branches. This is the most severe symptom of this condition. Other presentations of EV include flat topped papules, a small bump on the skin,  that can vary in color from pink, white, red, brown, or violet, scaly and inflamed patches of skin called plaques, and brown warts. These lesions most commonly develop in areas that are exposed to sunlight: hands, feet, earlobe, face.

In addition to these physical symptoms, EV can be particularly detrimental to one’s self esteem. EV gets in the way of daily tasks and the lack of research surrounding EV often causes those who suffer from the condition to feel stigmatized. Though, to the recent interest in this condition, researchers hope that there may be new opportunities to understand the mechanisms of this troubling disease. 

In July 2019, a 44 year-old man named Mahmoud Taluli underwent four successful surgeries over the span of two years to remove the lesions from his hands. His multiple surgeries included a team of doctors making deep, precise incisions in order to remove thousands of lesions. The doctors performed multiple skin grafts to help the body heal. Despite the fact Tauli underwent extensive treatment, the results of his surgeries are not permanent. His growths continued to develop and he is scheduled to have more surgeries. After receiving the surgeries Taluli was reported saying, “After years of suffering and solitude, I can finally live a normal life. I can play with my children. I can go to family events. I no longer need to cover my hands when I go out in public.” 

Treatment

However, not everyone who experiences this condition experiences the same results. Abul Bajandar, a Bangladeshi man, asked doctors to amputate his hand. He underwent over 20 surgeries to remove the branch-like growths but they have been met with mixed success; his growths continued to form typically larger and faster than before. Recent surgeries, have been tremendously more successful, removing majority of the lesions, but he must go back to return the remaining lesions. Though, some doctors are concerned that he returned too late and the lesions may be incredibly difficult to remove yet again,

Abul Bajandar, before undergoing any surgeries.

Bajandar after undergoing multiple intensive surgeries. He was reported saying “I can finally hold my kid again.

Finding a treatment is imperative as 50% of patients with EV have lesions that become malignant. However, researchers are met with a unique challenge as so little is known about this condition. Other than surgery, treatment includes topical retinoids (medications that reduce skin inflammation), interferon-alpha (a drug that contains compounds that suppress the cell cycle), and Cryotherapy (freezing off the growths). 

Conclusion

“Tree Man” disease, or epidermodysplasia verruciformis, is an incredibly detrimental disease to an individual. Not only does this disease cause self esteem issues, it can also be the cause of a number of much more serious, non-cosmetic medical issues like HPV and squamous cell carcinoma. Despite its rarity, researchers are optimistic they will be able to find a working cure for EV due to the recent interest in this disease. 

References

1. Headlines Suggest ‘Tree Man Syndrome’ Curable? (2017, January 28). Retrieved September 30, 2020, from https://www.acsh.org/news/2017/01/11/headlines-suggest-tree-man-syndrome-curable-10711
2. Rettner, R. (2019, July 10). ‘Tree Man’ Gets Pioneering Surgery for Rare Skin Condition. Retrieved September 30, 2020, from https://www.livescience.com/65907-tree-man-gaza-surgery.html
3. Epidermodysplasia verruciformis. (n.d.). Retrieved September 30, 2020, from https://rarediseases.info.nih.gov/diseases/6357/epidermodysplasia-verruciformis
4. Uddin, K., Amin, R., Majumder, S., Aleem, M., Rahaman, A., Dity, N., . . . Uddin, M. (2018, June 5). An ANKRD26nonsense somatic mutation in a female with epidermodysplasia verruciformis (Tree Man Syndrome). Retrieved September 30, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099040/
5. Ngan, V. (n.d.). Epidermodysplasia verruciformis. Retrieved September 30, 2020, from https://www.dermnetnz.org/topics/epidermodysplasia-verruciformis/
6. Orth G. Genetics of epidermodysplasia verruciformis: Insights into host defense against papillomaviruses. Semin Immunol. 2006 Dec;18(6):362-74. doi: 10.1016/j.smim.2006.07.008. Epub 2006 Oct 2. PMID: 17011789.
7. Pokharel, S., & Regan, H. (2019, January 21). Bangladesh’s ‘tree man’ is back in hospital and needs more surgery. Retrieved October 13, 2020, from https://www.cnn.com/2019/01/21/health/tree-man-bangladesh-surgery-intl/index.html
8. Stub, S. T. (2019, July 08). Patient With ‘Tree Man’ Syndrome Says He ‘Can Finally Live A Normal Life’. Retrieved October 13, 2020, from https://www.npr.org/sections/goatsandsoda/2019/07/08/738907620/patient-with-tree-man-syndrome-says-he-can-finally-live-a-normal-life

Lab Grown Mini Brains and the Future of Neurology

Introduction

Scientists attempting to grow human organs themselves are not an entirely new concept; in fact, scientists have been conducting this process for well over a decade, growing human organs ranging from kidneys to skin. Researchers have now been able to grow a mini-brain with neural activity that mirrors a preterm infant. This is an enormous stride forward as earlier work was unable to demonstrate brain activity that was similar to how the brain actually functions. 

This research was largely founded based on neural oscillations, rhythmic brain signals found across species. Neural oscillations are one of the many cellular networks that eventually develop into circuits in the human brain during the maturation process. While this eventual development of neural oscillations into circuits is known, it is unclear when these networks precisely develop. Recent students in mice have demonstrated that oscillations develop immediately after birth. However, due to the fact, there previously were not any adequate models of the human brain in the laboratory setting it is unclear whether the same course of events occurs in humans brains. 

Process

The team at the University of California, San Diego first grew human induced pluripotent stem cells (iPSCs), cells that can self renew, in neurons found in the cortex of the brain, which is responsible for controlling thought and behavior. The researchers opted to use iPSCs during this experiment as they have been shown in recent studies that they have the capacity to mimic various development features and the cellular and molecular processes of the human brain. In order to successfully grow the pluripotent stem cells, researchers created a solution that contained a mixture of transcription factors that regulate fetal development. Creating the perfect mixture was pivotal as it allowed for organoids to last long amounts of time. Many of these organoids were still usable after a year since the research was completed. These conditions allowed for the researchers at UCSD to mimic the neural oscillations and electrophysiological network activity. 

This process differed from earlier attempts to create mini-brains as the team created the most optimal conditions for mini-brain development at every stage. For example, unlike standard protocols which start with a clump of cells to construct the organoid, the team started from a single cell to build the organoid. In addition, they also changed the timings and concentrations of certain aspects in the mixture. While the process was meticulous, it certainly paid off. 

Fig 1: The mini brains the team at UCSD created

Results

The results of this study revealed that the mini-brains produced neural activity that mirrors a preterm infant; thus, mini-brains have the potential to serve as laboratory models for studying psychiatric conditions. The iPSCs used in the study, like most stem cells, can be differentiated to specialize in any cell; in this case, the iPSCs were directed to specialized into neurons and glia. 

Due to the team’s unique way of creating an organoid from scratch, the team was able to identify a particular neuron that has previously never been able to be created in a laboratory setting: the GABAergic neuron. Another example of the team’s diligent process paying off was seen when measuring the electrical activity of the mini-brains using an electroencephalogram (EEG). The test revealed the mini-brains following the new protocol had 300,000 electrical impulse spikes per minute. With the old process, the earlier mini-brains produced a mere 3,000 spikes per minute. 

The results are what lead the UCSD to compare their results with the electrical patterns in newborn baby brains. The neural oscillations discussed earlier in the introductions, change according to age. Newborn baby brains tend to be the least active in oscillations. Their brains tend to have almost no waves between spikes of electrical activity. As we get older, these periods with no activity tend to get shorter, and eventually become constant. Other than age, oscillation patterns can also be affected by cognition skills and various diseases. 

The team compared their mini-brains with a previously published dataset of 567 EEG recordings from 39 babies born prematurely (between 24 and 38 weeks gestation). This cross-analysis revealed that the organoids revealed similar patterns in their EEG levels for up to 9 months after being developed. 

Implications

The successful development of a functional mini-brain has far-reaching applications as it broadens the range of neurologic conditions that could be adequately studied. Further, in most psychiatric conditions the neuronal circuitry is impaired: mini-brains would allow for a better understanding of diseases such as autism and epilepsy. Prior to this study, there were no adequate models in the laboratory to study certain neurological diseases adequately. For example, Alysson R. Muotri, Ph.D., one of the lead scientists of the study, reported sending the brain organoids to the International Space Station, in an attempt to determine the effect microgravity has on brain development. Potentially, the results yielded from this experiment could determine the prospects for human life outside of Earth. 

While developing mini-brains further holds the potential to change the way we study neurological diseases, this study exists in a fine line between science and ethics. Critics of this study and other members of the scientific community ask, “Are we getting too close to re-creating the human brain?”. Muotri understands these concerns and responds to these concerns by stating that the mini-brains developed in the lab are far from being functional adult human brains. He points out that the mini-brains are not only much smaller than fully developed brains but also lack hemispheres and blood vessels. Muotri also stated, “They are far from being functionally equivalent to a full cortex, even in a baby… In fact, we don’t yet have a way to even measure consciousness or sentience…”. Muotri asserts that science is far ways from creating a fully functional, developed brain, but as the medical landscape changes faster than ever ethics dilemmas that arise similar to this situation cannot be ignored. 

References

1. “Lab-Grown “Mini Brains” Can Now Mimic the Neural Activity of a Preterm Infant.” 

Scientific American, 30 Jan 2020 https://www.scientificamerican.com/article/lab-grown-mini-brains-can-now-mimic-the-neural-activity-of-a-preterm-infant/ 

1. “Machine Learning Algorithm Can’t Distinguish These Lab Mini-Brains from Preemie Babies,” UC San Diego Health, 29 Aug 2019, https://health.ucsd.edu/news/releases/Pages/2019-08-29-algorithm-cant-distinguish-lab-m ini-brains-from-preemie-babies.aspx 2. “Mini Brains” Are Not like the Real Thing,” Scientific American, 30 Jan 2020, 

https://www.scientificamerican.com/article/mini-brains-are-not-like-the-real-thing/

 3. Cleber A. Trujillo, Richard Gao, Priscilla D. Negraes, Gene W. Yeo, Bradley Voytek, 

Alysson R. Muotri. 2019. Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development. Cell Press. Vol. 25; 1-12 https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30337-6?_returnURL=https %3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1934590919303376%3F showall%3Dtrue