BioQuakes

AP Biology class blog for discussing current research in Biology

Author: lindphocyte

Revolutionizing Heart Health: The Promise of Gene-Editing Therapy

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On April 17, 2024

In Student Post

In a groundbreaking stride towards combating heart disease, researchers have pioneered a revolutionary approach: gene-editing therapy. This innovative treatment, represented by the experimental drug VERVE-101, offers hope to individuals suffering from familial hypercholesterolemia, a genetic disorder characterized by dangerously high levels of LDL cholesterol.

CRISPR Cas9

Traditionally, patients with familial Hypercholesterolemia face a lifelong battle against the debilitating effects of elevated LDL cholesterol, which significantly increases the risk of severe heart disease and premature death. Despite conventional cholesterol-lowering medications, some individuals find their condition resistant to treatment, leaving them trapped in a cycle of escalating health concerns.

Enter VERVE-101, a genetic medicine designed to tackle the root cause of familial hypercholesterolemia by targeting a specific cholesterol-raising gene, PCSK9. Utilizing advanced DNA-editing technology, including CRISPR-based tools, this therapy represents a paradigm shift in the treatment of cardiovascular disorders.

The mechanism of action behind VERVE-101 is simple yet profoundly impactful. Comprising two types of RNA molecules enclosed within a lipid nanoparticle, the drug navigates its way to the liver, where it infiltrates cells and initiates the production of an adenine base editor protein. Guided by genetic GPS, this molecular pencil meticulously rewrites the DNA sequence within the PCSK9 gene, effectively silencing its cholesterol-elevating effects.

In class, we have observed firsthand how alterations in DNA sequences can lead to changes in phenotypes, illustrating the principles of gene expression and inheritance.

What sets VERVE-101 apart from conventional therapies is its potential for a one-time intervention with lasting benefits. Unlike daily medication regimens, which impose a significant burden on patients, this gene-editing therapy holds the promise of a lifetime solution. By permanently altering the genetic blueprint, VERVE-101 offers the prospect of sustained LDL cholesterol reduction, mitigating the relentless progression of heart disease.

The initial results from the heart-1 clinical trial are nothing short of promising. Among the sickest patients enrolled in the study, those receiving the highest doses of VERVE-101 experienced substantial reductions in LDL cholesterol levels, with effects persisting for up to 180 days post-treatment. This milestone achievement begins a new era in cardiovascular medicine, marking the first instance of a DNA spelling change exerting tangible therapeutic benefits within the human body.

However, as with any innovation, concerns regarding safety loom. Adverse events observed during the trial, including minor reactions to the infusion and isolated incidents of cardiovascular complications, highlight the imperative of rigorous safety assessment. The potential for unintended genetic alterations and off-target effects necessitates thorough scrutiny to eliminate risks and ensure the long-term well-being of patients.

The journey towards widespread adoption of gene-editing therapy is fraught with challenges yet brimming with potential. Further clinical investigations, including expanded trials encompassing diverse patient populations, are essential to validate the efficacy and safety profile of VERVE-101. With continued advancements in base editing technology and meticulous regulatory oversight, the vision of a transformative treatment for familial hypercholesterolemia moves closer to realization.

How do you feel about gene-editing therapy? How do you think this could affect the future of medicine?



Promising Progress in Parkinson’s Treatment: The Role of Prasinezumab

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On April 17, 2024

In Student Post

Parkinson’s Disease, a neurodegenerative disorder affecting millions worldwide, has long remained a formidable challenge in the medical field. However, recent developments offer a glimmer of hope in the quest for effective treatment. A groundbreaking study led by Gennaro Pagano and his team at Roche Pharmaceuticals sheds light on a potential game-changer: prasinezumab, a drug designed to target the underlying culprit of Parkinson’s – the accumulation of misfolded alpha-synuclein proteins in the brain. Prasinezumab’s effectiveness in targeting misfolded alpha-synuclein proteins in Parkinson’s patients highlights the relevance of protein structure and function, a topic we have covered in class. Alterations in protein structure, such as misfolding, can disrupt normal cellular function and lead to the development of diseases like Parkinson’s.

Modeling the Molecular Basis of Parkinson's Disease

For years, researchers have recognized the pivotal role of alpha-synuclein in the progression of Parkinson’s disease. This misfolded protein wreaks havoc on dopamine-producing neurons, leading to the hallmark motor symptoms of the condition. While existing treatments aim to alleviate these symptoms by boosting dopamine levels, they fall short in addressing the root cause of the disease. Thus, the need for disease-modifying therapies that can slow or halt Parkinson’s progression remains urgent.

Enter prasinezumab, an innovative antibody engineered to bind to aggregated clumps of misfolded alpha-synuclein. Administered via intravenous infusion, this novel drug holds the potential to disrupt the neurotoxicity caused by alpha-synuclein, impede the spread of pathological aggregates between cells, and ultimately slow disease progression.

The pivotal clinical trial conducted by Pagano and his colleagues recruited 316 individuals with early-stage Parkinson’s disease. Participants received either a placebo or varying doses of prasinezumab over the course of one year. Initial results suggested minimal impact, but upon closer analysis, a ray of hope emerged.

Remarkably, prasinezumab demonstrated significant efficacy in individuals with more severe Parkinson’s symptoms. Those experiencing rapid eye movement sleep behavior disorder, taking MAO-B inhibitor, or rated at stage two on a symptom scale exhibited a notable reduction in the progression of motor symptoms compared to the placebo group.

This promising outcome suggests that prasinezumab may hold particular promise for individuals with rapidly progressing Parkinson’s, characterized by higher levels of misfolded alpha-synuclein in the brain. By potentially clearing these toxic protein aggregates, the drug could offer newfound hope for slowing disease advancement in this vulnerable population.

However, challenges remain on the path to conclusive validation. Critics point out the absence of biomarkers to monitor changes in alpha-synuclein levels within participants’ brains, raising questions about the drug’s disease-modifying effects. Vinata Vedam-Mai of the University of Florida Health highlights the need for longer-term data to assess both the safety and efficacy of prasinezumab comprehensively.

Looking ahead, further research is warranted to explore prasinezumab’s effectiveness in individuals with milder forms of Parkinson’s over extended periods. By exploring its potential across a broader spectrum of disease severity, researchers can unlock valuable insights into the drug’s therapeutic utility.

While the journey towards a definitive Parkinson’s treatment remains ongoing, the strides made with prasinezumab offer a beacon of hope for patients and researchers alike. With continued dedication and scientific inquiry, we inch closer to the elusive goal of transforming Parkinson’s disease from a life-altering diagnosis to a manageable condition. What do you think about the potential of prasinezumab? How do you think this can change the way we see a Parkinson’s diagnosis? 

 

The Mystery of Huntington’s Disease: A Potential Breakthrough in Treatment

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On March 14, 2024

In Student Post

In the ongoing search to understand and combat neurodegenerative diseases, scientists have recently made a significant breakthrough in unraveling the complex mechanisms behind Huntington’s Disease. This progress not only sheds light on why this devastating condition progresses slowly but also offers a promising lead in developing effective treatments to halt its fatal course.

Huntington’s disease, a hereditary disorder, is caused by a genetic mutation involving the HTT gene. This mutation results in the repetition of a specific DNA sequence, ultimately leading to the destruction of brain cells and the onset of debilitating symptoms. Until recently, it was believed that the number of repeats in the HTT gene remained constant throughout an individual’s life. However, groundbreaking research presented at the annual meeting of the American Society of Human Genetics has revealed a discovery: in certain brain cells, these repeats can multiply over time, reaching hundreds of copies. This expansion of repeats within vulnerable brain cells is now understood to be a driving force behind the progression of Huntington’s disease.

Geneticist Bob Handsaker of the Broad Institute of MIT and Harvard, who spearheaded this research, emphasized the pivotal role of these repeat expansions in triggering the cascade of events that culminate in the death of brain cells. By examining individual brain cells from both affected and unaffected individuals, Handsaker and his team uncovered a pattern of repeat expansion within a specific type of brain cell known as striatal projection neurons. These expansions, reaching up to 1,000 repeats in some cases, were uniquely concentrated in cells susceptible to Huntington’s disease.

Additionally, the research revealed an important threshold where the activity of thousands of genes within these brain cells changes significantly. This point, reached at around 150 repeats of the disease-causing gene, leads to a quick decline in gene activity, resulting in cell death within months. The exact reasons behind this sudden change are still unknown, presenting a mystery for further study.

However, amidst these uncertainties, the research offers a glimmer of hope for potential interventions. By targeting the process responsible for repeat expansion, namely the malfunction of a DNA repair protein called MSH3, scientists envision a novel approach to slow the progression of Huntington’s disease. By preventing further expansion of repeats, it may be possible to halt the relentless deterioration of brain cells, thereby halting the disease in its tracks.

​​As learned, Genetic mutations are changes in the DNA sequence that can lead to alterations in the proteins produced by genes. In the case of Huntington’s disease, a mutation involving the HTT gene leads to the repetition of a specific DNA sequence, ultimately causing the disease’s devastating effects on brain cells. By targeting the malfunction of a DNA repair protein called MSH3, scientists aim to address the underlying cause of repeat expansion, offering a potential avenue for intervention. This demonstrates how knowledge of genetic mutations can inform strategies for treating genetic disorders.

This research marks a significant shift in our understanding of Huntington’s disease and opens new avenues for therapeutic intervention. It highlights the importance of exploring innovative strategies that go beyond conventional approaches focused solely on reducing levels of the disease-causing protein. As we delve deeper into the intricate mechanisms underlying neurodegenerative diseases, such as Huntington’s, we inch closer to the prospect of effective treatments that could transform the lives of millions worldwide.

In the words of Dr. Leora Fox, Assistant Director of Research and Patient Engagement for the Huntington’s Disease Society of America, this research represents a pivotal moment in Huntington’s research, offering renewed hope. As we continue to unravel the complexities of Huntington’s disease, this latest breakthrough stands as a sign of progress in the ongoing quest to cure this condition. Are you confident in this breakthrough? What are your thoughts?

 

Deep Brain Stimulation Offers Promising Results for Traumatic Brain Injury Patients

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On January 15, 2024

In Student Post

Traumatic brain injuries can have profound and lasting effects on cognitive functions, impacting memory, attention, and mood regulation. Despite the prevalence of these challenges, there has been a lack of effective therapeutic interventions. However, a recent small-scale study conducted by Nicholas Schiff and his colleagues at Weill Cornell Medical College in New York City offers a glimmer of hope. The study explores the potential benefits of deep brain stimulation in treating cognitive impairment resulting from moderate to severe traumatic brain injuries.

The study focuses on the thalamus, a critical brain region acting as an early stop for sensory information. In the case of traumatic brain injuries, disconnections and cell death can occur, affecting the relay of information to the prefrontal and frontal cortexes responsible for executive function. By surgically implanting electrodes into the thalamus, the researchers sought to restore lost connections and improve cognitive function in individuals with traumatic brain injuries.

The groundbreaking success of deep brain stimulation in treating traumatic brain injuries resonates with the intricacies of cell communication, a topic in AP Biology. At the cellular level, effective communication is vital for maintaining homeostasis and responding to external stimuli. In the context of traumatic brain injuries, where neural connections are disrupted, the restoration of cognitive function through deep brain stimulation mirrors the intricate signaling pathways within cells. In both scenarios, the targeted transmission of signals plays a critical role in orchestrating responses and facilitating recovery. 

Deep brain stimulation involves the implantation of electrodes in the brain, powered by a pacemaker, to electrically stimulate targeted regions. This technique has a successful track record in treating conditions such as Parkinson’s disease, epilepsy, obsessive-compulsive disorder, eating disorders, and deep depression. Now, the focus has shifted to traumatic brain injuries, affecting over 5 million people in the United States alone.

Six patients, who had suffered traumatic brain injuries two to eighteen years prior, underwent surgery for electrode implantation. Targeting the central lateral nucleus of the thalamus, the researchers programmed the devices for a 12-hour on/off cycle and optimized them individually over a two-week period. The patients then underwent cognitive tests, such as the Trail Making Test.

The results were surprisingly positive, with five out of six patients showing improvement in attention and information processing. After receiving stimulation for at least three months, the patients demonstrated a significant reduction in the time it took to complete the Trail Making Test. This improvement suggests that deep brain stimulation may be a viable therapeutic option for addressing cognitive impairments caused by traumatic brain injuries.

In a separate publication, the researchers detailed the feedback from participants and their families. Patients reported improvements in everyday activities such as reading, playing video games, and watching television – tasks that had become challenging or impossible due to their injuries. Family members described the treatment as a “miracle,” with one mother expressing joy at having “got my daughter back.”

While the study has shown promising results, Nicholas Schiff plans to conduct larger trials involving more patients and for longer durations to gather more comprehensive data. The potential of deep brain stimulation in treating traumatic brain injuries raises important ethical considerations, as it not only benefits patients but also contributes to our understanding of fundamental questions about human brain function.

How do you feel about this study? How do you think this will affect the future of treating brain trauma?

The groundbreaking study on deep brain stimulation offers a ray of hope for individuals grappling with the lasting effects of traumatic brain injuries. As research advances, deep brain stimulation may emerge as a transformative therapy, offering improved quality of life and a chance for recovery for the millions affected by traumatic brain injuries.


Unveiling the Nobel-Worthy Breakthrough: The mRNA Pioneers Behind Life-Saving Vaccines

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On January 7, 2024

In Student Post

 

Solo-mrna-vaccine-3

In a historic announcement, the Nobel Prize in Physiology or Medicine for 2023 has been awarded to biochemist Katalin Karikó and Drew Weissman, recognizing their groundbreaking contributions to mRNA research. Their work laid the foundation for what has become one of the most influential medical advancements of our time: the development of mRNA vaccines against COVID-19.

Karikó, currently at the University of Szeged in Hungary, and Weissman from the University of Pennsylvania, received this prestigious honor for their pioneering research on modifying mRNA. These modifications were crucial in making the first COVID-19 vaccines possible, notably those produced by Pfizer/BioNTech and Moderna.

Revolutionizing Vaccines

Traditional vaccines typically use weakened or killed viruses, bacteria, or proteins from pathogens to stimulate the immune system. However, mRNA vaccines work differently. They contain genetic instructions for building viral proteins. When administered, these instructions prompt cells to temporarily produce the viral protein, triggering an immune response. The immune system then builds defenses, providing protection if the person is later exposed to the actual virus. This may sound familiar, as AP Bio has taught about immune response and cells. We learned that memory T cells are a crucial component of the immune system, formed after the body encounters a pathogen like a virus or bacteria. These specialized cells “remember” the specific characteristics of the invader, allowing for a rapid and targeted response upon subsequent exposures, effectively combating and neutralizing the illness. Memory B cells, a crucial component of the adaptive immune system, exhibit remarkable specificity and functionality. During the primary immune response, these cells undergo affinity maturation, producing high-affinity antibodies with increased binding capacity to pathogen-specific antigens. Notably long-lived, memory B cells persist in the body, ensuring prolonged immunity. Upon re-exposure, they swiftly differentiate into Plasma B cells, which serve as antibody factories, producing copious amounts of antibodies tailored to the familiar pathogen. On the other hand, memory T cells, including cytotoxic and helper T cells, play distinct yet coordinated roles. Cytotoxic T cells retain the capacity to directly eliminate infected cells, preventing pathogen spread, while helper T cells release cytokines that stimulate antibody production by B cells and enhance cytotoxic T cell activity. With immunological memory, memory T cells provide rapid and targeted responses upon reinfection, actively surveilling for cells displaying specific antigens associated with previously encountered pathogens. Together, these memory cells form a sophisticated and enduring defense mechanism, contributing to the immune system’s ability to combat and neutralize pathogens efficiently.

The technology behind mRNA vaccines has proven immensely effective in combating the COVID-19 pandemic. As of September 2023, over 13.5 billion COVID-19 vaccine doses, including mRNA vaccines and other types, have been administered globally. These vaccines are estimated to have saved nearly 20 million lives worldwide in the year following their introduction.

Modified mRNA and Its Potential

RNA, the lesser-known cousin of DNA, serves as the genetic instruction manual for cells. Messenger RNA (mRNA) copies genetic instructions from DNA and is crucial for protein synthesis. Karikó and Weissman’s pivotal contribution was modifying mRNA building blocks to overcome challenges in early trials.

Traditional mRNA injection would trigger adverse immune reactions, leading to inflammation. By swapping the RNA building block uridine for modified versions, the researchers found a solution. Pseudouridine and later N1-methylpseudouridine proved effective in dampening harmful immune responses. This breakthrough, dating back to 2005, enabled the safe delivery of mRNA to cells.

“The messenger RNA has to hide and go unnoticed by our bodies,” explains Kizzmekia Corbett-Helaire, a viral immunologist at the Harvard T. H. Chan School of Public Health. The modifications developed by Karikó and Weissman were fundamental, allowing mRNA therapeutics to hide while being beneficial to the body.

This technology extends beyond COVID-19, with potential applications against other infectious diseases, cancer, and even rare genetic disorders. Clinical trials are underway for these applications, though results may take several years to emerge.

A Journey Decades in the Making

The road to this groundbreaking achievement was not without obstacles. In 1997, Karikó and Weissman, working in separate buildings, collaborated to address a fundamental problem that could have derailed mRNA vaccines. Initial setbacks, including failed clinical trials in the early 90’s, led many researchers to abandon mRNA as a viable therapeutic approach.

Undeterred, Karikó and Weissman persisted. “We would sit together in 1997 and talk about all the things that we thought RNA could do,” Weissman reflected. The duo’s resilience led to the formation of RNARx in 2006, a company dedicated to developing mRNA-based treatments and vaccines.

Despite the groundbreaking nature of their work, Karikó’s contributions were initially overlooked. Ten years ago, she faced termination from her job and had to move to Germany without her family to secure another position. The Nobel recognition sheds light on her unwavering commitment to mRNA therapeutics.

The Nobel Committee’s decision to acknowledge this achievement swiftly, a mere three years after the vaccines demonstrated their medical importance, highlights the urgency and impact of mRNA technology. Emmanuelle Charpentier and Jennifer Doudna’s Nobel Prize for Chemistry in 2020, awarded eight years after the description of CRISPR/Cas 9, reflects a similar trend of more current acknowledgments.

In a press conference at the University of Pennsylvania, Weissman expressed his surprise at the recognition. “I never expected in my entire life to get the Nobel Prize,” he confessed. The laureates will share the prize of 11 million Swedish kronor, approximately $1 million.

A Nobel-Worthy Legacy and a Glimpse into the Future

The timely recognition of Katalin Karikó and Drew Weissman emphasizes the transformative potential of mRNA therapeutics, extending far beyond the current success against COVID-19. As we celebrate this Nobel-worthy legacy, it opens a new chapter in medical science, offering hope for innovative solutions to combat various diseases and improve human health.

The journey from a meeting in 1997 to the global impact of mRNA vaccines in 2023 showcases the power of perseverance, collaboration, and the pursuit of groundbreaking ideas. 

What do you think about mRNA vaccines? Did/Will you receive one?



Revealing the Potential of PF4: A Promising Molecule for Rejuvenating Aging Brains

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On November 5, 2023

In Student Post

As the global population ages, the quest to preserve cognitive function in older individuals becomes increasingly significant. New research has shed light on a promising candidate in the fight against age-related cognitive decline: platelet factor four (PF4). Studies of three separate techniques have shown that PF4 may play a pivotal role in rejuvenating aging brains, opening the door to potential breakthroughs in the treatment of cognitive decline. 

PBB Protein PF4 image

PF4 Protein

Published on August 16, three research groups reported their findings in Nature Aging, Nature, and Nature Communications. These groups independently investigated techniques to combat cognitive decline in aging individuals, and remarkably, they all found a common factor: increased levels of PF4. This protein, known as platelet factor four, was found to be associated with improved cognitive performance and enhanced biological markers of brain health.

One research group, led by neuroscientist Dena Dubal from the University of California, San Francisco, had initially been studying the hormone klotho, which is linked to longevity. Their earlier studies revealed that injecting Klotho into mice improved cognition. However, because klotho molecules are too large to pass through the blood-brain barrier, the researchers concluded that the hormone must act on the brain indirectly, possibly through a messenger.

In their pursuit to identify this intermediary, Dubal’s team injected mice with klotho and measured changes in protein levels in the animals’ blood. Surprisingly, they discovered that platelet factors, especially PF4, increased significantly.

Another team at the University of California, San Francisco, led by neuroscientist Saul Villeda, had previously demonstrated that blood plasma from young mice could rejuvenate the brains of elderly mice. They found that young plasma contained significantly higher levels of PF4 compared to older plasma. These findings led to a collaboration between these two research teams.

Tara Walker, a neuroscientist at the University of Queensland, Australia, also joined the collaboration, as her team had discovered that exercise boosts PF4 levels and delivering PF4 directly to the brains of mice stimulated the growth of new nerve cells, a process known as neurogenesis, particularly in the hippocampus, a brain region essential for memory.

But what does all this mean?

The results of these studies collectively suggest that PF4, when administered alone, can improve cognition in mice. Additionally, it enhances neurogenesis and neural connections in the hippocampus, potentially explaining the cognitive benefits observed.

Villeda’s team also found a link between PF4 and the immune system. Injecting PF4 into older mice restored their immune systems to a more youthful state, decreasing inflammatory proteins and reducing inflammation in their brains.

While the discovery of PF4’s potential is undoubtedly exciting, there are important caveats to consider. Most notably, translating findings from mice into effective and safe therapies for humans is a considerable challenge. Nevertheless, the observation that PF4 levels decline with age in both mice and humans suggests it may have relevance in the quest to alleviate age-related cognitive decline.

Furthermore, these recent studies represent significant progress, shedding light on one piece of a complex puzzle. Other molecules, like GDF11, have been linked to restorative effects, and researchers are striving to understand their roles better. Lida Katsimpardi, a neuroscientist at the Pasteur Institute in Paris, highlights the need to decipher how each factor fits into the broader picture of cognitive rejuvenation.

The researchers aim to begin human trials within the next few years, but vigilance for potential side effects will be a priority. Additionally, research is essential to precisely understand the mechanisms through which PF4 operates in the body and brain, as well as its potential integration into a broader therapeutic approach.

In  AP Bio class, we’ve began to brush the surface of the topic of neurons. it’s important to grasp that neurons are the fundamental building blocks of the brain’s complex communication network. These brain cells, often referred to as nerve cells, work by transmitting electrical and chemical signals to relay information. According to our AP Bio notes, “the neuron transmits message impulses which communicate information from the environment, process information, and signal parts of the body to respond to the information -all by the flow of chemicals in and out of the plasma membrane”.  As we age, this intricate network can deteriorate, leading to cognitive decline. PF4 facilitates better communication between neurons. This protein’s potential to boost cognitive performance and stimulate the growth of new nerve cells could be the key to maintaining mental vitality as we grow older. While this is still in the early stages of research, the prospect of PF4 as a crucial piece of the cognitive health puzzle is a promising development in our understanding of the brain’s inner workings and its resilience over time. What do you think about the possibilities of PF4? 

 

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