Issues: Berkeley Medical Journal

Category: Spring 2022

  • Is Chemotherapy Right for Everyone?: Cancer Cell Markers as Predictors of Chemotherapy Efficacy

    By Daniel Voronel

    Chemotherapy is one of the most common ways of treating cancer but is not always a foolproof method to help patients gain remission. Oftentimes, it is difficult to tell if chemotherapy will actually eliminate cancerous cells or fail to take effect. A recent paper written by Hanbing Song and Simon Bucher et al. at UCSF  believes to have found a crucial answer to this issue.  Through their research on hepatoblastoma, a type of liver cancer that affects children and infants, the research team led by Prof. Franklin W. Huang, Amar Nijagal,and Bruce Wang, in collaboration with the UCSF BCH Pediatric Liver Center, believes they have discovered a mechanism that is involved in determining how effective chemotherapy will be by using single cell RNA sequencing. 

    Hepatoblastoma is one of the most prevalent and morbid types of cancer. Its ever-evolving nature means it is difficult to provide an umbrella treatment for.  After working with RNA sequencing models, the UCSF Franklin Huang Lab which Song works in, later partnered up with neighboring labs (UCSF Bruce Wang and Nijagal Lab)  to aid in the research about hepatoblastoma. In collaboration with one another, they used single cell RNA sequencing to categorize hepatoblastoma. 

    Single cell RNA sequencing is a technology that has been used in a variety of different studies. Compared to its predecessor, bulk sequencing, single cell sequencing is much more specific. According to Song, “with bulk RNA sequencing, you are sequencing tissue without knowing its detailed composition or cell types. But with single cell sequencing, you can sequence tissue on a cellular resolution.” Song also stated that single cell sequencing allows researchers to gain a greater understanding of the mechanisms involved in specific tumor signatures. This technology allows researchers to see what specific type of hepatoblastoma the patient has, which allows for further investigation for proper treatment.  

    Screening for these mechanisms is of major public health importance. Prices for cancer medications can range anywhere from 70,000 to 120,000 dollars every year for  people diagnosed with cancer (M. Siddiqui). This technology will have the ability to save countless people from paying for a medication that might not benefit the state of their cancer. Additionally, patients with hepatoblastoma typically have a poor prognosis. According to Song, “hepatoblastoma tumors have a high degree of heterogeneity and the five-year survival for them (hepatoblastoma patients) is among the lowest for childhood cancers, driven by cases that are chemotherapy-resistant or unresectable. This led the research team to investigate the different subtypes of hepatoblastoma, then determine how treatments can be synthesized to allow patients a better prognosis. Song predicts that the cancer treatment field is “transitioning to precision medicine” and can open up opportunities for a “customized therapy for each individual patient.” The Huang lab is currently still researching the specifics of hepatoblastoma in terms of its mechanisms in different sub groups.

    The research from this study has important future implications in diagnosing and treating other types of cancer. According to Song, UCSF Huang lab is “currently doing single cell RNA sequencing on prostate cancer patients. Our interest is studying the difference in other ancestral groups.” Song mentions that the death rate for prostate cancer in African Americans is twice as high compared to other populations. The lab’s findings will be able to discover different cancer types that might be congenital to different ethnic groups, further increasing the specificity of treatment for different patients.

    While Song admits that bulk RNA sequencing is cheaper and easier for labs to obtain, single cell sequencing opens up many more opportunities to understand cancer on a much more specific and precise level. 

    The research team led by Prof. Franklin W. Huang, Amar Nijagal, and Bruce Wang at UCSF is studying extremely important technology that has the ability to change the face of cancer treatment as we know it. Prescribing different chemotherapy treatments as umbrella medication is not a long term or responsible solution to reduce the rate of mortality from cancer. Their work allows patients to receive treatment that was specially made not only for their specific tumor signatures, but also for factors such as race, gender, and ethnicity. This change in mindset of cancer research and treatment will hopefully give patients an increased chance at remission.

  • TRPA1 Receptor and the Future of Pain Management

    By Cleo Lin

    A common but deleterious mistake many sushi lovers have likely made is taking ambitious serving sizes of the Japanese root wasabi with their rolls. Unfortunately, this mistake is quickly registered after the wasabi contacts our taste receptors, manifesting in tears and a minty heat filling up the mouth. This stinging, burning sensation, commonly associated with eating wasabi, stems from its interactions with the transient receptor potential cation channel, subfamily A receptor, shortened: TRPA1 Receptor. Scientists have fondly nicknamed this receptor the “wasabi receptor” due to its sensitivity to the pungent chemicals present in hot or spicy foods like wasabi and mustard. Dubbed as the “fire alarm” of the body’s nervous system, TRPA1 excites an autonomic response within the nervous system towards chemical irritants in the environment. It also carries a mechanical response within the body as a reaction to chemical activators due to its stress sensor. When this receptor encounters harmful chemicals, more specifically a class of chemicals containing reactive electrophiles (a group that accepts electron pairs), sensations of acute pain, cold, or itchiness can be passed through the sensory system. (Julius) 

    Recent discoveries by scientists at the University of California, San Francisco of TRPA1’s binding mechanisms towards reactive electrophiles could lead to the next big breakthrough for anti-inflammatory pain drugs and pain medications targeted towards chronic pain. Typical receptors usually recognize a specific shape of a substrate to be activated, using a lock and key model to bind to receptors. TRPA1 forgoes this type of shape dependent binding and instead recognizes many differently shaped irritant chemicals through covalent binding interactions with their electrophiles. This makes it much more receptive to a variety of substrates that could be used to regulate pain, rather than traditional receptors that are only responsive to singularly shaped substrates. On top of recognizing foreign irritants, TRPA1 receptors can also be triggered by pain-inducing mechanical and chemical signals from within the body usually stemming from inflammation and tissue damage. (Julius) Upon activation, the TRPA1 Receptor rapidly flutters open and closed to allow ions to flow into the cell, disrupting the cells’ electrochemical gradients. As the receptor flutters open and closed, it activates a positive reinforcement loop prolonging and stabilizing its activation loop. By allowing positively charged sodium and disproportionate amounts of calcium ions to flow into the cell, this gradient change causes acute signals of pain and localized inflammation due to the calcium ions. (Julius) These findings, especially that of TRPA1’s versatile viability and ability to hold prolonged signaling, are extremely exciting for the scientific community and medicinal field. With the newfound knowledge scientists are now looking at ways to possibly hinder the induction of TRPA1 receptors in controlling pain due to chronic inflammation, as well as using the receptors for targets of new pain medications. 

    One such prospective new development for pain medication is currently being tested in a joint effort from researchers at the University of California, San Francisco as well as researchers from the University of Queensland. Researchers have isolated a toxin called WaTx from the Australian Black Rock Scorpion. Although the scorpion toxin WaTx triggers the wasabi receptor in the same way as other environmental and chemical pollutants, using the same sites on the receptor, it activates TRPA1 in a different way that was previously unknown. By studying WaTx’s DNA sequence and using computational in silico models, researchers at UCSF and University of Queensland were able to discover that WaTx contains a specific amino acid sequence that allows it to directly pass through TRPA1 and the plasma membrane into intracellular sites known as allosteric nexi and wedge itself in the sites. (Julius)  By wedging itself into the intracellular allosteric nexi, WaTx is able to covalently bond with the receptor keeping the TRPA1 channel open. This abolishes TRPA1’s ability to actively pump calcium through the membrane resulting in overall ion levels that are high enough to trigger a pain response, but calcium levels that remain too low to cause inflammation in the area. (Julius)

    Taking these results, the research team has carried out their research into in vivo experimentation. By using mustard oil which is a known activator of TRPA1 and injecting it into the paw pads of mice as a control, scientists were able to trigger pain, inflammation, swelling, and hypersensitivity to touch and temperature within the mices’ paws pads. They then measured activity along the mice’s central neuronal pain receptor pathways using electrophysiology methods such as cell patch clamp recordings to quantify their pain responses. Contrastingly, mice injected with both mustard oil and WaTx still displayed sensitivity and acute displays of pain but did not display any signs of swelling or inflammation. Through these experimental results, scientists were able to deduce that while WaTx did not numb the body to experiencing pain, it is able to reduce and mitigate inflammation in mammals. 

    In addition to making headway in studies of pain and inflammation, scientists have also been able to deduce the purpose of toxins like WaTx in animals such as the Australian Black Rock scorpion. Many animals use venom to paralyze or kill their prey, but WaTx seems to serve as a defense mechanism. While virtually every animal, including worms and humans, have a form of TRPA1, the researchers found that WaTx only activates specific forms of TRPA1 found in mammals. Given that black rock scorpions don’t eat mammals, it’s likely that the toxin is mainly used to ward off mammalian predators. This information is of interest to researchers who are now trying to figure out ways to reverse engineer the pathway of pain using various venoms found in natural plants and animals. By figuring out the exact pathway of pain from stimulus to sensation and perception, scientists and drug developers can have a better understanding of how to properly manage pain by targeting specific steps along its pathway. 

    According to a 2019 CDC census, about 25 percent of adults in the United States are currently suffering from some form of chronic pain or disorder. This equates to about 50 million US adults experiencing chronic pain on a daily basis and 20 million experiencing high impact chronic pain. (CDC) Patients suffering from these types of ailments such as various skeletal pains (arthritis, back, neck), headaches, and muscle aches often are hindered in their everyday activities both mentally and physically, dramatically decreasing their quality of life. These pains can be classified by criteria such as pathophysical mechanisms (such as nociceptive, inflammatory, or pathological pain), duration, etiology (malignant or non malignant), and anatomical position. (CDC) Through targeting TRPA1 receptors instead of traditional lock and key receptors, scientists believe that they will be able to target many common types of pain such as inflammatory nociceptive pain which can be found in tissue damage as well as neuropathic pain which can be found in nerve damage. Additionally, by using TRPA1 as a therapeutic target, researchers are hoping to diminish the medical field’s reliance on opioids which pose a high risk factor for patients and come with numerous side effects. While results have only shown promising in rodents thus far, researchers are excited about the numerous possibilities TRPA1 represents in revolutionizing the treatment of pain and inflammation for the many that suffer from its propagating effects. 

  • Epilepsy Research

    By: Jacob Yinger

    Epilepsy is a disease that 50 million people worldwide suffer from, and 80% of those reside in third world countries with minimal access to healthcare. This disease causes irreversible brain damage due to unwarranted electrical activity in the brain, which results in regular seizures. There are many treatments for  epilepsy, mostly consisting of drugs with various side effects, risky surgeries, and devices that reduce this unwarranted brain activity. At the University of California, San Francisco, researchers are in the trials of developing a more permanent cure that has already shown promising results in Cronutt, a seven year old sea lion. Scientists in the team identified healthy pig neurons compatible with the sea lion’s brain and implanted them. The results in the years following are promising for human use in future trials and have allowed Cronutt  to live a seizure-free life.

    There have been more than 30 anti-seizure drugs developed to date attempting to treat epilepsy. However, one third of patients do not respond to these drugs, and the ones that do suffer potentially severe side effects because the drugs do not specifically target the damaged part of the brain, resulting in altercations with healthy brain regions. Other current treatments consist of neurosurgeons implanting pacemaker-like devices in the brain or extracting the damaged region altogether. These pacemaker-like devices are implanted in the skin under the chest and perform Vagus nerve stimulation, pulsing electrical energy to the brain via the Vagus nerve. However, these procedures are extremely invasive and come with a significant risk of behavioral and cognitive side effects. Prior attempts to utilize foreign organs to solve health issues have come with the high risk of immune rejection from the human body, but the brain has a significantly lower chance of rejection compared to other organs. This fact has spurred the research team at UCSF to investigate the effect of inserting pig neurons into the brain of a sea lion.

    This research study began after a warm water event called “The Blob,” stretching from Alaska to the coast of Mexico, resulted in algal and bacterial blooms. This event produced an excess of domoic acid, which is a neurotoxin that can cause neurological disorders like epilepsy. Domoic acid is on a steady increase around the world due to global warming and can bioaccumulate in the fish that marine animals consume. During “The Blob,” there were 244 cases of domoic acid poisoning in sea lions. Several years after UCSF researchers had first started working with Cronutt on curing his domoic acid-induced-epilepsy, all of the usual treatments had failed. They needed to try something new or Cronutt was going to be euthanized.  

    In a final effort to save him, Cronutt’s lead veterinarian Claire Simeone began working with Scott Barbaran, who had been researching the aforementioned epilepsy therapy utilizing pig neurons. Thus far, Barbaran’s lab had effectively restored cognitive and physical abilities in mice through implanting early-stage brain cells harvested from pig embryos. These cells become inhibitory neurons upon entering the Hippocampus and therefore serve the purpose of preventing hyperactivity in the brain. An epileptic-brain like Cronutt’s lacks these inhibitory neurons, and allows excess electrical activity resulting in seizures. X-rays of the seven-year old sea lion showed that in fact the left side of his Hippocampus was severely scarred and shrunken. Upon this discovery of the problem location in the brain, the UCSF research team administered four injections of 50,000 pig cells each into the most affected areas. The weekend prior to this surgery, Cronutt had eleven seizures, and now more than a year later, one has yet to be recorded, and he is expected to live to thirty years, the average lifespan of a healthy sea lion.

    This study that UCSF conducted could be critical to the future of epilepsy medication. There is still a lot of research to be done before this can be attempted in humans, but the fact that these inhibitory pig neurons effectively cured Cronutt the sea lion’s epilepsy so effectively is something that cannot be overlooked. Innovative research like this has the capability to improve countless epilepsy patients’ lives. The current medication does not target the specific diseased location nearly as well as these neurons did, which causes side effects that are arguably as uncomfortable as the disease itself. The utilization of transplants from other animals or even other humans could be the future of curing disorders in the brain given their accuracy in targeting the diseased area. The area of focus now will be to research how to make these foreign entities survive in the new body that is now its host, because that has been the struggle with transplantation in past studies. UCSF has made great strides in the path to curing epilepsy, and the future holds lots of potential research based on this approach.

    Jacob Yinger is a first year undergraduate student at UC Berkeley studying Molecular Environmental Biology and plans to minor in Journalism over the summer. He is writing for the Berkeley Medical Journal because he is interested in medical studies and enjoys interacting with professionals in the field as well as utilizing writing to communicate what is going on in healthcare.

  • ‘Tis the Season for Fires: Wildfire Smoke linked to Skin Disease

    By Shalini Saravanan

    Red skies, gray flakes, and the smell of something burnt. This is the reality of the wildfire seasons that come around to California on a yearly basis, although to the average native Californian, wildfire season simply marks the beginning of Fall. Due to decreased rainfall and the persisting drought, California wildfires have gotten increasingly dangerous and common throughout the state. With yearly fires, the result is periodic low air quality. Thus this prompted the question of how exposure to wildfire-related pollution could be linked to an increase in atopic dermatitis. Researchers from UCSF, Barbara Grimes and Albert T.Young, and UCB, Nicholas P. Jewell, joined together to track down the suspected correlation between air pollution and changes in skin health. They conducted an examination between the short bursts of hazardous wildfire air and patient visits to dermatology clinics over a period of years located in the bay area.

    Wildfires have been a public health issue since the 1930s, and with recent climate change issues, it has only gotten worse. California is prone to wildfires due to its dry vegetation and as stated before, the persisting drought. Despite many camps putting warning signs about leaving their campfires unattended, it is still one of the main causes for huge wildfires that blaze through huge forests. The consequences of such huge fires are felt throughout the state and even others by the rolling winds that push the soot and ash to the suburbs and neighboring areas — thus lowering the air quality, making it hard for people to go outside. 

    Many prior studies generally focused on the negative respiratory effects of the constant inhalation of ash and dry air that perpetuated the air following huge fires, but this study is the first of its kind to look at the relation to dermatology related effects. Dermatology is the study of the skin and its diseases, and it is a huge but complex field, as the skin is our largest organ. The study was a cross-sectional time-series that followed the flow of patients in a hospital based in San Francisco that was about 200 miles away from the wildfire site. Large wildfires have commonly occurred during recent years, compared to 5-10 years ago. So the researchers compared the influx of patients to this clinic between the months of October through February, compiling data found in 2015-2016 and 2018-2019. 

    The researchers tracked the increasing levels of fine particulate matter (PM2.5) and polycyclic aromatic hydrocarbons (PAHs) that result from the air pollution following wildfires. These pollutants are irritants to both normal and eczema-prone skin, so it becomes increasingly necessary to cover up. Because of their minute size, the pollutants contribute to dermatitis by seeping through the skin barrier with aversive chemicals attached to the PM2.5, triggering inflammation. It overall leads to the weakening of the skin barrier. People with pre-existing skin conditions (e.g. dermatitis) are prone to flare ups in response to irritants such as the ones mentioned above; however, even people without pre-existing skin conditions can succumb to the same symptoms. 

     They recorded the number of adults and children that came into the clinic for visits before, during, and after the duration of the fire and compared the rates of visits for AD and itch. For both pediatric patients and adult patients, the researchers found that the latter was around an average of 1.4 times the rate of non-fire weeks. A key observation they noted was that 89% of adults who complained of an itch were not previously diagnosed with AD, compared to ~55% of patients with itch in 2015 and 2016. The data followed a Poisson Regression, which is a type of statistical data used to predict the dependent variable given independent variables. It shows which independent variables have a statistically significant effect on the dependent variable. In this case, wildfire-associated air pollution was the independent variable, and weekly clinic visits for AD was the dependent variable. They concluded that there was a statistically significant increase in weekly visits to the clinic after exposure to wildfire-associated air pollution for atopic dermatitis and itch as well from both pediatric and adult patients. 

    The complex field of dermatology is constantly undergoing new research to adapt to these unprecedented climate changes. Following the rising temperatures, wildfire season is slowly becoming a natural part of Californian lifestyle as seen by the apocalyptic red skies from September of 2020. A combination of wildfire smoke and fog resulted in red-orange skies that covered the Bay Area for several days, documented by many people as they were faced with a harsh reality of how intense this deadly mix could get. During wildfire season, it is recommended that individuals protect their skin by staying indoors and wearing clothing that covers the skin. Currently, researchers are developing new medications that can help alleviate harmful symptoms. For now, all that can be done is to make sure we reduce the risk of a wildfire spread by human mistakes and try to have preventative measures to protect the forests and dry shrubs that are characteristic of an California ecosystem.