Categories
Biomedical Research

Bioglass: A New Frontier in Biomedical Applications

Broken bone // Photo by Harlie Raethel on Unsplash.com

Introduction

Bioglass is an innovative biomaterial renowned for its bioactivity and ability to bond with bone and soft tissues. This class of bioactive materials, composed mainly of silica (SiO₂), calcium oxide (CaO), sodium oxide (Na₂O), and phosphorus pentoxide (P₂O₅), has seen significant advancements in recent years. Originally developed for bone regeneration, bioglass is now at the forefront of medical applications, including tissue engineering, antimicrobial coatings, and drug delivery systems. These advancements stem from cutting-edge research in surface modifications, composite materials, and functional coatings that enhance the properties and applications of bioglass in the biomedical field.

The Chemistry Behind Bioglass

The bioactivity of bioglass is rooted in its chemical composition and the reactions it undergoes upon exposure to physiological fluids. When a medical professional implants bioglass into the body, it undergoes a series of reactions starting with the leaching of sodium and calcium ions, which raises the pH, initiating the formation of a silica gel layer on the glass surface. This gel layer serves as a template for the nucleation of hydroxyapatite, the mineral phase of bone. Simultaneously, the release of calcium and phosphate ions into the surrounding tissue aids the deposition of new bone minerals, thus bridging the gap between the implant and the natural bone. Recent innovations have fine-tuned this process by introducing dopants like magnesium, strontium, and zinc. These dopants enhance the bioactive response, improve mechanical strength, and tailor the degradation rates to match tissue healing processes.

Surface-Modified Bioglass

Recent studies, such as those published in the Journal of Nanoparticle Research, have focused on enhancing the bioactivity of bioglass. By altering the surface chemistry, researchers have significantly improved the material’s antibacterial properties and its ability to promote angiogenesis ( the formation of new blood vessels, which is critical for tissue regeneration). Surface modifications, such as the incorporation of silver, copper, or zinc ions, make bioglass more effective in preventing infections in implanted materials. These ions disrupt bacterial cell walls, leading to cell death, while simultaneously promoting the formation of hydroxyapatite—one of the key components in bone mineralization. This dual function of bioglass is crucial in applications such as bone regeneration and wound healing.

Copper-Based Composites: Expanding the Horizons of Bioglass Applications

In addition to traditional applications, bioglass has found novel implementations in advanced electronic and biomedical devices through the development of copper-based composites. A study published in Nanoscale Advances revealed that incorporating nano-sized particles into copper matrices enhances the material’s mechanical strength, thermal stability, and electrical conductivity. These properties are crucial for next-generation electronic packaging and biomedical devices that demand both durability and high performance. The use of such composites is particularly promising for developing multifunctional implants and devices that require both bioactivity and robust mechanical properties​. The copper ions also play a role in angiogenesis, further supporting tissue regeneration.

Advanced Bioactive Glasses

The field of tissue engineering has benefited immensely from the development of novel advanced bioactive glasses. Recent breakthroughs involve the integration of elements such as strontium and boron into bioglass. Strontium ions mimic calcium ions and are readily incorporated into new bone tissue, where they not only enhance bone density but also slow bone resorption by inhibiting osteoclast activity. Boron, on the other hand, improves the glass’s solubility, allowing for more controlled degradation rates, which is essential for the gradual release of therapeutic ions. These additions not only enhance the material’s ability to regenerate bone but also improve its antibacterial activity. This dual functionality is essential for preventing infections and promoting the rapid healing of bone defects, making bioglass an increasingly attractive option for orthopedic and dental applications.

Portrait of scientist looking under microscope in medical development laboratory, analyzing petri dish sample // freepik.com

Functional Coatings and Hybrid Materials: Paving the Way for Next-Generation Implants

Bioglass is also being explored in combination with other materials to create hybrid systems that offer enhanced properties. For example, integrating bioglass with hydroxyapatite has led to improved osseointegration (the formation of a direct interface between an implant and bone, without intervening soft tissue) and mechanical strength. The hydroxyapatite layer mimics natural bone minerals, promoting the adhesion and proliferation of cells that form and heal bones (osteoblasts), while the bioglass beneath continues to release ions that support bone growth and fight infection. These hybrid materials are particularly useful in the development of long-lasting implants and prosthetics, where both bioactivity and mechanical integrity are crucial. The ongoing research in this area suggests that such multifunctional materials could revolutionize the design and functionality of future biomedical devices​.

Conclusion

The evolution of bioglass technology is a significant leap forward in biomedical science. The innovations in surface modifications, composite materials, and hybrid systems not only enhance the performance of bioglass in traditional applications but also expand its potential into new therapeutic areas. As research continues to advance the boundaries of what bioglass can achieve, it is poised to play a transformative role in regenerative medicine, tissue engineering, and beyond. The future of bioglass is bright, with its applications extending well beyond the realm of bone regeneration, into the development of smarter, more effective biomedical devices.

Resources

Abodunrin, O. D., Bricha, M., & El Mabrouk, K. (2024). Beyond bone: A systematic review on bioactive glass innovations and breakthroughs in skeletal muscle regeneration. Biomedical Materials & Devices. https://doi.org/10.1007/s44174-024-00220-1

Kaou, M. H., Furkó, M., Balázsi, K., & Balázsi, C. (2023). Advanced bioactive glasses: The newest achievements and breakthroughs in the area. Nanomaterials, 13(16), 2287. https://doi.org/10.3390/nano13162287

Taye, M. B., Ningsih, H. S., & Shih, S.-J. (2024). Exploring the advancements in surface-modified bioactive glass: Enhancing antibacterial activity, promoting angiogenesis, and modulating bioactivity. Journal of Nanoparticle Research, 26(2). https://doi.org/10.1007/s11051-024-05935-2Zhang, G., Zhen, C., Yang, J., Wang, J., Wang, S., Fang, Y., & Shang, P. (2024). Recent advances of nanoparticles on bone tissue engineering and bone cells. Nanoscale Advances, 6(8), 1957–1973. https://doi.org/10.1039/d3na00851g

Categories
Cancer Oncology

Common Skin Cancers & What to Look For 

Dermatologist examining patient’s birthmark with magnifying glass in clinic, closeup // Unsplash.com

Disclaimer: This article was not written by medical professionals. If you suspect any signs of skin cancer, please contact your dermatologist. 

Introduction

Skin cancer is the most common type of cancer worldwide, accounting for one-third of all cancer diagnoses. Fortunately, skin cancer is generally easy to diagnose and, when caught early, is very treatable, with a low mortality rate. 

Skin cancer can be broken down into two main categories: melanoma skin cancer and non-melanoma skin cancer. Non-melanoma skin cancer can be further broken down into basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).  According to Mayo Clinic, risk factors include excessive sun exposure, old age, radiation, having a fair complexion, immunosuppression, and a personal or family history of skin cancer.

Basal cell carcinoma is the most prevalent form of skin cancer and also the least dangerous due to its low probability of metastasizing. Squamous cell carcinoma occurs more often than malignant melanoma, however, it tends to be less aggressive and less invasive. All three forms of skin cancer can be diagnosed by a pathologist viewing a skin biopsy taken by a dermatologist.

Basal Cell Carcinoma

Basal cell carcinoma is the most common form of skin cancer, and is often the easiest to identify. BCC can look like a smooth waxy bump on the skin. Pain, tenderness, itching, and bleeding are all signs that indicate a bump needs to be examined by a dermatologist. Some patients also report persistent pimples that don’t go away, which can be a warning sign of basal cell carcinoma.

Squamous Cell Carcinoma

Most squamous cell carcinomas begin as rough, raised, dry spots called actinic keratoses. Medical professionals can treat these lesions with liquid nitrogen, topical fluorouracil cream, or red light therapy. If left untreated, actinic keratoses can develop into SCC. Skincancer.org states that SCC can look like “a persistent, scaly red patch with irregular borders that sometimes crusts or bleeds.”

Malignant Melanoma

Melanoma presents as one or multiple dark spots on the skin. This type of cancer expands rapidly and can metastasize to the lymph nodes and other organs. To differentiate melanomas from other skin spots, The American Academy of Dermatology developed the ABCDE memory mnemonic: asymmetry, border, color, diameter, and evolving. Following their guidelines, if a dark spot is asymmetrical, has jagged borders, various color shades, a diameter larger than a pencil eraser, or is changing in any way, it may indicate a malignant melanoma, and should be evaluated by a dermatologist. 

Malignant Melanoma // Healthline/Shutterstock

Treatment

There are many approaches to skin cancer prevention, but the most feasible is adopting measures like wearing sunscreen with at least 30 SPF daily (and reapplying every two hours) or simply avoiding significant sun exposure.

Skin cancer treatment begins with a visit to a medical professional who can perform a biopsy on the concerning area. Once skin cancer is diagnosed after a biopsy, treatment typically involves surgery. In some cases, mild forms of squamous cell carcinoma called SCC in situ (superficial squamous cell carcinoma that has not spread) can be treated with liquid nitrogen therapy. In other cases, skin cancers will have to be excised (removed surgically). If the cancer is located in a place with limited skin to work with, such as the face or nose, the patient may opt for a Mohs surgery. Mohs surgery is a tissue-sparing surgery technique that takes place in stages. The physician will operate in stages taking as little tissue as possible and looking at it under a microscope. If there is more cancer under the microscope, they will continue with another stage, and this process is repeated until all margins are clear and the patient is cancer-free with as little skin missing as possible. According to Dr. Tolkachjov, medical professionals do not begin reconstruction until after all the margins are confirmed to be histologically tumor-free.

References

What to look for: Abcdes of melanoma. American Academy of Dermatology. (n.d.). https://www.aad.org/public/diseases/skin-cancer/find/at-risk/abcdes 

Mayo Foundation for Medical Education and Research. (n.d.). Basal cell carcinoma. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/basal-cell-carcinoma/symptoms-causes/syc-20354187

professional, C. C. medical. (n.d.). Melanoma: Symptoms, staging & treatment. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/14391-melanoma

Squamous cell carcinoma warning signs and images. The Skin Cancer Foundation. (2023, January 9). https://www.skincancer.org/skin-cancer-information/squamous-cell-carcinoma/scc-warning-signs-and-images/

Tolkachjov, S. N., Brodland, D. G., Coldiron, B. M., Fazio, M. J., Hruza, G. J., Roenigk, R. K., Rogers, H. W., Zitelli, J. A., Winchester, D. S., & Harmon, C. B. (2017). Understanding mohs micrographic surgery. Mayo Clinic Proceedings, 92(8), 1261–1271. https://doi.org/10.1016/j.mayocp.2017.04.009 WebMD. (n.d.). Skin cancer: Melanoma, basal cell, and squamous cell carcinoma. WebMD. https://www.webmd.com/melanoma-skin-cancer/skin-cancer

Categories
COVID-19

How Telemedicine Impacts Healthcare Post-COVID

Doctor holding phone. // Unsplash.com/National Cancer Institute

Introduction

Throughout the COVID-19 pandemic, our systems and institutions were tasked with quickly adapting their services to an increasingly virtual audience. This is particularly true of the medical world, where telemedicine rapidly became the go-to solution for socially-distanced medical needs.

Telemedicine, or telehealth, is the delivery of healthcare services through digital platforms, allowing patients to connect with their healthcare providers remotely. The ability to meet with physicians from the comfort of your home became a necessity during the COVID-19 pandemic, and since then, telemedicine has remained a key aspect of nationwide healthcare. According to Stephanie Watson at Harvard Health, “76 percent of hospitals in the U.S. connect doctors and patients remotely via telehealth, up from 35 percent a decade ago.”

While it promotes accessibility and convenience for patients and physicians alike, the drawbacks of telemedicine include quality concerns and potential technological barriers for certain demographics. This raises the question: Is telemedicine obsolete in a post-COVID world, or do the benefits of remote healthcare outweigh the costs?

Benefits

The primary benefit of telemedicine post-COVID is the increased accessibility to healthcare for populations in rural areas, those without reliable transportation, and immobile or busy patients. Patients without the privileges required to attend regular, in-person medical visits are much better accommodated by a virtual model. This system also increases convenience for the vast majority of patients, whether or not they fall into one of these demographics. 

During virtual visits, clinicians are also less likely to be exposed to infection or disease, further maximizing the care they are able to provide long-term. 

Additionally, telemedicine provides support for patients’ continuity of care, offering easier opportunities for follow-up appointments and check-ins for those with chronic conditions. Further, the implementation of telemedicine can reduce “medication misuse, unnecessary emergency department visits, and prolonged hospitalizations.” 

Drawbacks

Although telemedicine provides increased accessibility to healthcare, this doesn’t mean patients are taking advantage of it. According to a Stanford study, “increased telemedicine access is associated with a modest, 3.5% increase in the utilization of primary care.” While 3.5% translates to a large number of patients, it still represents a smaller population than expected.

One of the largest concerns regarding the wide implementation of telemedicine is the quality of care. The Institute of Medicine (US) Committee on Evaluating Clinical Applications of Telemedicine has identified three key quality issues: “overuse of care (e.g., unnecessary telemedicine consultations); underuse of care (e.g., failure to refer a patient for a necessary consultation); and poor technical or interpersonal performance (e.g., incorrect interpretation of pathology specimen or inattention to patient concerns).” 

Further, telehealth creates a digital divide, which causes particular difficulty in regard to older and low-income demographics. According to a Mayo Clinic study, the concordance of diagnoses between in-person and virtual appointments was 86.9%, and “for every 10-year increase in the patients’ age, the odds of receiving a concordant diagnosis by video telemedicine decreased by 9%.”

Doctor typing on computer. // Unsplash.com/National Cancer Institute

Physician’s Perspective

Dr. Maryam Kashi, a gastroenterologist with AdventHealth in Central Florida, operates on a hybrid model in providing patient care. Since 2020, she has run 2 days of in-person clinic and 3 days of virtual clinic each week. 

According to her own experience, Dr. Kashi believes that quality of care is held to the same standard in both in-person and virtual visits. She says that her hybrid model allows her to ensure that all patients with issues requiring physical exams or other in-person needs are able to be accommodated. Meanwhile, patients who only need a brief post-op check-in are able to meet with Dr. Kashi virtually at their convenience. 

Dr. Kashi contends that her current hybrid model, which includes a majority of virtual visits, elicits appreciative and receptive responses from patients as they experience greater convenience and access to healthcare. 

Conclusion

Telemedicine offers an accessible and efficient alternative to in-person care. While there are concerns regarding the quality of care and an obvious digital barrier, the great benefits of the service make a case for its continued usage beyond COVID restrictions. Hybrid models, like Dr. Kashi’s, ensure that patients are able to receive the care they need, regardless of physical or virtual limitations. Ultimately, adopting an inclusive system that includes telemedicine guarantees that the greatest number of patients acquire appropriate medical care.

References

Bart M. Demaerschalk, MD. “Clinician Diagnostic Concordance with Video Telemedicine at Mayo Clinic from March to June 2020.” JAMA Network Open, JAMA Network, 2 Sept. 2022, jamanetwork.com/journals/jamanetworkopen/fullarticle/2795871. 

Gajarawala, Shilpa N, and Jessica N Pelkowski. “Telehealth Benefits and Barriers.” The Journal for Nurse Practitioners : JNP, U.S. National Library of Medicine, 17 Feb. 2021, www.ncbi.nlm.nih.gov/pmc/articles/PMC7577680/#bib3. 

Institute of Medicine (US) Committee on Evaluating Clinical Applications of Telemedicine. “Evaluating the Effects of Telemedicine on Quality, Access, and Cost.” Telemedicine: A Guide to Assessing Telecommunications in Health Care., U.S. National Library of Medicine, 1 Jan. 1996, www.ncbi.nlm.nih.gov/books/NBK45438/. 

Watson, Stephanie. “Telehealth: The Advantages and Disadvantages.” Harvard Health, 12 Oct. 2020, www.health.harvard.edu/staying-healthy/telehealth-the-advantages-and-disadvantages. 

Zeltzer, Dan, et al. “The Impact of Increased Access to Telemedicine.” Stanford, 2023, web.stanford.edu/~leinav/pubs/JEEA2018.pdf. 

Categories
Biomedical Research

How Bacteriophages Could Stop the Antimicrobial Resistance Crisis

Bacterial colonies on a plate. // CDC on Unsplash.com

Introduction

Antimicrobial resistance (AMR) occurs when bacteria, viruses, fungi, and parasites evolve to become drug-resistant, pushing antibiotics and other antimicrobial medicines to practical obsoletism and thus increasing the difficulty of infection treatment. The prevalence of AMR is a pressing issue, cited by the World Health Organization (WHO) as one of the top 10 global public health threats facing humanity.

A promising threat to AMR is the use of “phage therapy”, a method of utilizing bacteriophages (phages) to eliminate specific bacterial strains.

Phages are viruses of bacteria that evolve to be extremely specialized, targeting only their certain type of bacterial cells and not affecting human cells. This opens a door for phage therapy to be used within the human body against bacterial infections, rather than solely antibiotics.

In the 1940s, the Western world saw chemical-based small-molecule antibiotics usurp potential research into phage therapies. Continued research into the potential of phage therapy allowed members of the former USSR to harness bacteriophages to treat disease. Phage therapy is now commonplace in Eastern Europe, specifically in Russia and Georgia where it is offered over-the-counter.

Dependency upon antibiotics has resulted in a fight against antimicrobial resistance, however, phage therapy may just be the method to bring us out of it.

Advantages of Phage Therapy

Bacteriophages occur abundantly on Earth, from the water of the oceans to the human GI tract. To attack bacterial cells, phages initiate the lytic cycle, wherein they first puncture the bacterium and then inject their own genetic information. The cell becomes a metaphorical warehouse for new phages, producing and assembling phages until the cell is full. Phages within the cell release endolysin, an enzyme that signals the end of the lytic cycle and causes the bacterial cell to explode, releasing brand-new phages.

There are many advantages to employing phage therapy over traditional antibiotic approaches.

Phage viruses bind to a bacterial cell, injecting their genetic material. // Biophoto Associates/SPL

Bactericide:

Phages are bactericidal, meaning they kill their host bacteria. However, some antibiotics are only bacteriostatic and cause a bacterium to become stuck within its stationary phase of growth rather than killing it, leaving behind the viable cell and opening a pathway for potential AMR.

Dosage:

As phages undergo the lytic cycle they self-amplify in an exponential fashion, which could potentially allow for a phage therapy to be effective with single or very low dosages. Lingering in the body after infection is not a worry, as phages only continue to multiply as they are killing bacteria.

Flora Bacteria:

Normal flora bacteria, “good” bacteria of the body, do not generally fall into the extremely specific target ranges of phages, which means they are almost totally unaffected by their presence in the human body. When antibiotics are introduced into the body, however, they tend to wreak havoc on any bacterium they come into contact with, including the normal flora that inhabits our bodies and aids us in many everyday functions.

Resistance:

When bacteria develop resistance to a chemical-based antibiotic it resembles an en masse revolt against one “villain”. Yet, bacteria find it relatively more difficult to develop resistance against phages due to their specific host ranges, since there is no single “villain”. Additionally, as bacteria evolve against phages, the phages have the capability to evolve right along with them, protecting the body against any bacterial strains that develop resistance.

FDA Approval

While phage therapy seems a promising opportunity, the US Food and Drug Administration (FDA) agency has yet to approve any therapies. As phage therapies are classified as biological products by the FDA, any manufacturing needs to adhere to standards like GMP, preclinical research, and all stages of clinical trials. This approval process is a tedious effort, however, as of October 2023 the US has the most phage-related Industry-Sponsored Trials (ISTs) on the worldwide scale, showing there is significant industry-related innovation on this front. Some examples of promising phage therapies in clinical trials within the US include WPP-201 for chronic venous leg ulcers and PreforPro for gastrointestinal distress.

Some of these ISTs are in their third phase of clinical trials, wherein the phage therapies are being tested for large-scale efficiency and comparison to currently market-available competitors. This is the final stage of testing prior to a drug or treatment to be submitted to the FDA for approval.

Despite the many advantages of phage therapy, there is still room for major disadvantages that are avoided through thorough testing prior to FDA approval. Namely, phages possess a narrow host range, inherent biological nature, and unfamiliarity within traditional Western medicine. For these reasons, along with the lengthy approval process, there is still time to go before Americans see phage therapies available to them for treatment.

Although the 1940s saw a shift away from bacteriophage research within Western countries, as time progresses, they could still very well be our savior from the self-inflicted antimicrobial resistance crisis.

References

Carroll-Portillo, A., & Lin, H. C. (2019). Bacteriophage and the innate immune system: Access and signaling. Microorganisms, 7(12), 625. https://doi.org/10.3390/microorganisms7120625

Durr, H. A., & Leipzig, N. D. (2023). Advancements in bacteriophage therapies and delivery for bacterial infection. Materials Advances, 4(5), 1249–1257. https://doi.org/10.1039/d2ma00980c

Furfaro, L. L., Payne, M. S., and Chang, B. J. (2018). Bacteriophage therapy: clinical trials and regulatory hurdles. Front. Cell. Infect. Microbiol. 8:376. doi: 10.3389/fcimb.2018.00376

Ledford, H. (2023, June 26). Why phage viruses could be the key to treating deadly infections – if they can be harnessed safely. Nature News. https://www.nature.com/articles/d41586-023-01982-2

Loc-Carrillo, C., & Abedon, S. T. (2011). Pros and cons of phage therapy. Bacteriophage, 1(2), 111–114. https://doi.org/10.4161/bact.1.2.14590

Strathdee, S. A., Hatfull, G. F., Mutalik, V. K., & Schooley, R. T. (2023). Phage therapy: From biological mechanisms to future directions. Cell, 186(1), 17–31. https://doi.org/10.1016/j.cell.2022.11.017

World Health Organization. (n.d.). Antimicrobial resistance. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance

Yang, Q., Le, S., Zhu, T., & Wu, N. (2023, September 6). Regulations of phage therapy across the world. Frontiers. https://www.frontiersin.org/articles/10.3389/fmicb.2023.1250848/full#:~:text=While%20there%20is%20no%20FDA,clinical%20trial%20(Table%201).

Categories
Commentary COVID-19

Debunked: RFK Jr. Claims COVID is ‘Ethnically Targeted’

RFK Jr. speaking at press event in NYC. / NYPost

Recent statements from 2024 Democratic presidential candidate Robert F. Kennedy Jr. have drawn great public attention. Speaking at a press event in New York City, he claimed that COVID-19 “disproportionately attacks certain races,” particularly Caucasians and Black people, with Ashkenazi Jews and Chinese being seemingly more immune. Kennedy attributed these disparities to genetic variations of the host cell receptor, ACE2, a key player in the virus’s infectious cycle. He insinuated that this is proof that SARS-CoV-2, the virus that causes COVID-19, was a biological weapon designed to target certain ethnicities. But how sound are these alarming claims?

First, let’s look at the specific study Kennedy linked to on Twitter to validate his claim. The paper investigated the correlation between allele frequencies of certain ACE2 variants and their predicted effects on its ability to bind the SARS-CoV-2 spike protein, a crucial step in the infectious cycle of the virus. For instance, the p.Met383Thr and p.Asp427Tyr variants, which the article alleges are linked to worse COVID outcomes, have frequencies of just 0.003% and 0.01%, respectively. Their rarity suggests that they are unlikely to meaningfully affect large population groups. Not only are these variants incredibly rare, but they are also based on alleles associated with adverse outcomes for SARS-CoV-1, not SARS-CoV-2, the virus causing the COVID-19 pandemic. Hence, the information from this study should not be directly applied to the current pandemic and certainly cannot prove an ethnic targeting of the virus.

Another critical study that disproves Kennedy’s claim revolves around ACE2 variants but examines them in relation to SARS-CoV-2 susceptibility, unlike the former study. Even in this research, the ACE2 variants that could affect susceptibility to SARS-CoV-2 are extremely rare, with maximum prevalence values ranging from 0.00003 to 0.006. For example, an ACE2 variant that was found to increase spike protein binding was found at a frequency of only 3 in 10,000 Latino/Admixed American samples. Consequently, the low occurrence rates of these variants indicates that their impact on broad racial or ethnic groups is statistically insignificant when it comes to widespread racial or ethnic susceptibility.

Upon close examination, it’s clear that Kennedy’s claims lack robust scientific backing. While it’s true that COVID-19 has impacted different communities in different ways, it’s not due to any supposed “genetic targeting” inherent in the virus. Instead, this disparity arises from a multitude of factors, including access to healthcare, occupation types, living conditions, systemic racial disparities in healthcare, and perhaps biological variations unrelated to host cell receptor ACE2.

The assertion that COVID-19 is “ethnically targeted” is not only scientifically unsound but also has the potential to sow confusion and fear among the public. As we continue to grapple with this global health crisis, let’s keep the discourse grounded in verifiable science and promote unity rather than divisive misinformation.

References
  • Hou, Y., Zhao, J., Martin, W., Kallianpur, A., Chung, M. K., Jehi, L., Sharifi, N., Erzurum, S., Eng, C., & Cheng, F. (2020). New insights into genetic susceptibility of COVID-19: An ACE2 and TMPRSS2 polymorphism analysis. BMC Medicine, 18(1), 216. https://doi.org/10.1186/s12916-020-01673-z
  • Levine, J. (2023, July 15). RFK Jr. Says COVID was “ethnically targeted” to spare Jews. New York Post. https://nypost.com/2023/07/15/rfk-jr-says-covid-was-ethnically-targeted-to-spare-jews/
  • MacGowan, S. A., Barton, M. I., Kutuzov, M., Dushek, O., Van Der Merwe, P. A., & Barton, G. J. (2022). Missense variants in human ACE2 strongly affect binding to SARS-CoV-2 Spike providing a mechanism for ACE2 mediated genetic risk in Covid-19: A case study in affinity predictions of interface variants. PLOS Computational Biology, 18(3), e1009922. https://doi.org/10.1371/journal.pcbi.1009922
Categories
Oncology

How AI Is Revealing New Targets for Cancer Drugs

Woman in cancer treatment. // National Cancer Institute at Unsplash.com

Introduction

Targeted drug therapy has proven to be a highly advantageous approach to cancer treatments, presenting high efficiency and low patient drug resistance. 

Yet, there are drawbacks to the use of targeted drug therapy for cancer, including a lack of identified druggable genomic targets that extend across the patient population. Artificial intelligence algorithms can help researchers better understand carcinogenesis and identify new cancer targets. 

Artificial Intelligence (AI) is a field combining computer science and extensive data sets to perceive, understand, and solve problems.

Two major branches of AI applied biologically are machine learning-based and network-based. Machine learning is an application of AI wherein a computer can learn without direct instruction through mathematical models and pattern recognition. Network-based AI sorts and compares data, providing and compensating different perspectives. 

The Food and Drug Administration (FDA) and the international community have presented an increased interest in trustworthy and ethical AI adoption and innovation.

Applications

The development of multiomics technology is a factor that has bolstered the process of identifying novel anti-cancer targets. Multiomics is an approach to biological analysis that consists of forming data sets out of “omics”, which in the case of cancer are epigenetics, genomics, proteomics, and metabolomics. AI can analyze these data sets to investigate for anti-cancer targets. 

BioRender image by You Et al. Artificial intelligence in cancer target identification and drug discovery. https://doi.org/10.1038/s41392-022-00994-0

Epigenetics

Unlike the changes in the nucleotide sequence characteristic of genetic mutation, epigenetics is similar to an “on-and-off” switch for the expression of specific genetic attributes without altering the genome. Cancer can be caused by both a genetic mutation or an epigenetic signal gone awry. 

A major problem facing epigenetics cancer research is finding specific gene patterns that predict which patients will respond to a cancer treatment. The study of the reversal of epigenetic modifications through AI can give insight into how exactly healthy cells become cancerous and which genetic marker within a patient will respond to cancer-treating drugs.

Genomics

The study of genomics involves the mapping of an entire genome including its structure, function, and evolution, through genome-wide assays such as sequencing. A network-based AI is capable of finding similarities in specific genetic sequences and patterns in their phenotypic expression and interactions. Cancerous biomarkers can be identified through genomic data sets, identifying which genes medical professionals should consider oncogenes of interest.

Proteomics

Proteomics refers to proteins and their interactions within the body. Protein-protein interaction (PPI) research classifies a certain type of protein as “indispensable” and associates them as a major site of disease-causing mutations and drug targeting. In a 2017 study, Ravindran et al. found by analyzing the human PPI data from cancer patients that there are 56 indispensable genes in nine cancers, 46 of which were associated with getting cancer for the first time. This protein interaction data can be harnessed through AI to reveal novel cancer-associated interactions and their potential drug targets. 

Metabolomics

Metabolomics is the study of metabolites: the substrates, intermediates, and products of the human metabolic pathway. A hallmark of cancer cells is that they work to alter these metabolites in order to support their rapid growth, providing energy to their biosynthetic pathways and changing their redox balance. Cancer can be detected through biological AI network analysis due to the presence of certain biomarker metabolites within biofluids, cells, and tissues of the body.

Conclusion

All aforementioned “omics” data can be presented for review in the form of multiomics integration analysis. Varied and interconnected data in a network format allows researchers to study carcinogenesis and drug targeting from an overarching perspective in a multifaceted group of patients. 

While treatment of cancer remains a formidable challenge, rapid technological advances in data collection and analysis through the use of artificial intelligence combined with robust information exchange may prove to be increasingly beneficial to the way cancer drugs are created and tested, leading to potential a safer and healthier world.

References
  • Breakthroughs Staff. (2017, December 12). Treating Cancer by Using Epigenetics, the ‘Software’ of Our Genes | Pfizer. Pfizer News. https://www.pfizer.com/news/articles/treating-cancer-using-epigenetics-%E2%80%98software%E2%80%99-our-genes
  • Guenthoer, J., Lilly, M., Starr, T. N., Dadonaite, B., Lovendahl, K. N., Croft, J. T., Stoddard, C. I., Chohan, V., Ding, S., Ruiz, F., Kopp, M. S., Finzi, A., Bloom, J. D., Chu, H. Y., Lee, K. K., & Overbaugh, J. (2023). Identification of broad, potent antibodies to functionally constrained regions of SARS-CoV-2 spike following a breakthrough infection. Proceedings of the National Academy of Sciences, 120(23), e2220948120. https://doi.org/10.1073/pnas.2220948120
  • Huang, S., Wang, Z., & Zhao, L. (2021). The Crucial Roles of Intermediate Metabolites in Cancer. Cancer Management and Research, 13, 6291–6307. https://doi.org/10.2147/CMAR.S321433
  • Ravindran, V., V., S., & Bagler, G. (2017). Identification of critical regulatory genes in cancer signaling network using controllability analysis. Physica A: Statistical Mechanics and Its Applications, 474, 134–143. https://doi.org/10.1016/j.physa.2017.01.059
  • U.S. Food and Drug Administration. (2022). Using Artificial Intelligence & Machine Learning in the Development of Drug & Biological Products. https://www.fda.gov/media/167973/download
  • You, Y., Lai, X., Pan, Y., Zheng, H., Vera, J., Liu, S., Deng, S., & Zhang, L. (2022). Artificial intelligence in cancer target identification and drug discovery. Signal Transduction and Targeted Therapy, 7(1), Article 1. https://doi.org/10.1038/s41392-022-00994-0
Categories
Public Health

Animal Tranquilizer ‘Xylazine’ Is Making the Fentanyl Crisis Even Worse

In recent years, the devastating impact of the fentanyl crisis has been felt by many Americans. The opioid epidemic, led by this potent synthetic drug, has claimed thousands of lives and shows no signs of abating. But now, a new threat lurks in the shadows, poised to exacerbate an already dire situation — a veterinary sedative known as xylazine.

First synthesized in the 1960s, xylazine is a non-opioid sedative, analgesic, and muscle relaxant used primarily in veterinary medicine for large animals such as horses1. However, it has started to creep into illicit drug markets, often used as an adulterant for opioids like heroin and fentanyl2. The rise of this trend is concerning, and it’s crucial to shed light on this development as it continues to evolve.

Xylazine vial. / Randlab Veterinary Medications
Chemical structure of xylazine. / PubChem

Xylazine, when used in humans, can induce effects similar to those of opioids — a deep sense of relaxation, sedation, and pain relief1. This might explain its allure for those entrenched in substance misuse, but these effects come at a steep price. Unlike traditional opioids, xylazine is not reversed by naloxone (Narcan), the standard emergency treatment for opioid overdoses3. This significantly complicates matters for first responders, who may be unaware that xylazine is present and find that their typical lifesaving interventions are ineffective.

Moreover, xylazine possesses several harmful side effects, including hypotension, bradycardia, respiratory depression, and, in some cases, even death4. Coupled with fentanyl — a substance already notorious for its fatal potency — the presence of xylazine is a ticking time bomb.

The issue of xylazine adulteration in the opioid supply is gaining recognition, yet its severity remains underestimated. According to a 2023 report in the New England Journal of Medicine, xylazine was found in more than 90% of illicit drug samples tested in Philadelphia in 20215. The report found that xylazine is typically found as an adulterant in polydrug mixtures, usually containing simulants like cocaine and amphetamines or opioids like heroin or fentanyl. Alarmingly, the report estimates that the number of xylazine-involved drug-poisoning deaths in the United States increased by 13 times from 2018 to 2021 (an increase from 250 to 3500 deaths).

This rapidly growing and evolving crisis calls for a broad, multi-faceted response involving policymakers, healthcare providers, researchers, and communities. Actions include tightening regulation of veterinary substances, amplifying harm reduction services, and research and development of new overdose drugs that work against xylazine.

The already formidable challenge of the fentanyl and opioid crises is deepened by the introduction of xylazine, adding another lethal layer to the issue. To protect those grappling with substance misuse, it’s crucial to adapt our strategies to this emerging reality. Through a combination of awareness, education, vigilance, and research, we can start to tackle the profound impact of xylazine on the opioid crisis.

References
  1. Ruiz-Colón, K.; Chavez-Arias, C.; Díaz-Alcalá, J. E.; Martínez, M. A. Xylazine Intoxication in Humans and Its Importance as an Emerging Adulterant in Abused Drugs: A Comprehensive Review of the Literature. Forensic Sci. Int. 2014, 240, 1–8. https://doi.org/10.1016/j.forsciint.2014.03.015.
  2. Kacinko, S. L.; Mohr, A. L. A.; Logan, B. K.; Barbieri, E. J. Xylazine: Pharmacology Review and Prevalence and Drug Combinations in Forensic Toxicology Casework. J. Anal. Toxicol. 2022, 46 (8), 911–917. https://doi.org/10.1093/jat/bkac049.
  3. National Institute on Drug Abuse. Xylazine. National Institutes of Health. https://nida.nih.gov/research-topics/xylazine (accessed 2023-05-25).
  4. Andrew McAward. Xylazine, an Emerging Adulterant. American College of Emergency Physicians. https://www.acep.org/talem/newsroom/oct-2021/xylazine-an-emerging-adulterant (accessed 2023-05-25).
  5. Gupta, R.; Holtgrave, D. R.; Ashburn, M. A. Xylazine — Medical and Public Health Imperatives. N. Engl. J. Med. 2023, 0 (0), null. https://doi.org/10.1056/NEJMp2303120.
Categories
Biomedical Research Genetics

First CRISPR-based Gene Therapy Could be Approved in 2023

Photo by Thavis 3D on Unsplash.com

CRISPR-based gene therapies have yet to be approved by the FDA, despite their relative affordability and ease when compared to traditional gene therapies. This may change in 2023, as CRISPR Therapeutics and Vertex Pharmaceuticals announced that their biologics licensing applications (BLAs) to the U.S. Food and Drug Administration (FDA) were completed, including a request for priority review, which would shorten the FDA’s traditional twelve-month review of the application to eight months. This timeline opens the possibility for the first CRISPR gene-edited therapy to be available for interstate commerce within the year.

Background

CRISPR/Cas9 complexes were initially discovered in the natural immune systems of bacteria to protect them from viral invaders. The CRISPR component is a sequence complementary to a specific “target” sequence in a patient’s genome. It is sometimes referred to as the Guide RNA, as it guides the entire complex to the place within the genome where editing will occur. The Cas9 enzyme is the protein commonly depicted as a pair of metaphorical scissors, as it cuts DNA to allow for the insertion/deletion of intended genetic material. In the medical field, CRISPR genetic editing can be harnessed to potentially edit the genomes of individuals affected by currently incurable genetic diseases.

The CRISPR/Cas9 complex binds to and cuts the target sequence. / Javier Zarracina via vox.com

CRISPR/Cas9 is much more accessible than other FDA-approved gene therapies, due to its relative affordability and ease of use. Yet the FDA has shown caution when it comes to its approval. Major limitations of CRISPR-based medicines include:

  • The potential for off-targeting, wherein the complex incorrectly recognizes and binds to a sequence similar to the target sequence.
  • The triggering of the body’s immune response by CRISPR/Cas9, as it originates from bacteria.
  • The multi-faceted ethical concerns that come with genetic editing.

Methods and results

Despite concerns, researchers with CRISPR Therapeutics and Vertex Pharmaceuticals are in the final stages of clinical trials and are up for FDA approval with their CRISPR/Cas9 therapy for genetic blood disorders, called exagamglogene autotemcel (exa-cel).

Patients with sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT) who are participating in these trials have stem cells collected from their own blood. These cells are then edited with CRISPR/Cas9 outside of the body. Once the edited cells are introduced back into the body the patients are treated in accordance with traditional hematopoietic stem cell transplant (HSCT) procedures to establish high levels of fetal hemoglobin (HbF) production. HbF is the protein that carries oxygen throughout the bloodstream during fetal development.

The addition of HbF to a patient with SCD allows for a reduction or potential elimination of vaso-occlusive crises, wherein sickled red blood cells block blood flow to specific tissues, depriving them of oxygen and triggering an extremely painful immune response.

Within patients with TDT, increased levels of HbF reduce or eliminate the life-long dependence on blood transfusions that come with the characteristic severe anemia of the disease.

A doctor drawing blood from a patient. / Nguyen Hiep via Unsplash.com

CRISPR Therapeutics and Vertex Pharmaceuticals are in stage III of clinical trials, assessing both adults and children with SCD/TDT. They presented the adult data from 75 patients (31 with SCD and 44 with TDT) at the European Hematology Association Congress in December 2022.

All of the 31 patients with severe SCD that had been experiencing recurrent vaso-occlusive crises saw an elimination of the crises at their follow-up after exa-cel infusion (follow-up ranging from 2.0 to 32.3 months).

Of the 44 blood-transfusion-dependent patients with TDT, 42 were transfusion-free after exa-cel infusion (follow-up ranging from 1.2 to 37.2 months) and two were at the 75% and 85% marks in transfusion-reduction.

These CRISPR-based therapies show solid potential to change the idea of “incurable” blood diseases.

This research supports the biologics licensing applications (BLA) of CRISPR Therapeutics and Vertex Pharmaceuticals. A BLA is a request to the FDA to introduce a biological product, in this case the exa-cel gene therapy, to the interstate market. Within the BLA, there is a request for Priority Review, which would shorten the FDA’s traditional twelve-month review of the application to eight months, potentially allowing for the first CRISPR gene therapy to be FDA-approved within 2023.

Although the exa-cel CRISPR gene therapy is not approved just yet, it is an exciting innovation for CRISPR research and patients affected by “incurable” genetic diseases.

References
  • Frangoul, H., Altshuler, D., Cappellini, M. D., Chen, Y.-S., Domm, J., Eustace, B. K., Foell, J., de la Fuente, J., Grupp, S., Handgretinger, R., Ho, T. W., Kattamis, A., Kernytsky, A., Lekstrom-Himes, J., Li, A. M., Locatelli, F., Mapara, M. Y., de Montalembert, M., Rondelli, D., … Corbacioglu, S. (2021). CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. New England Journal of Medicine, 384(3), 252–260. https://doi.org/10.1056/nejmoa2031054
  • Kingwell, K. (2023, April 3). First CRISPR therapy seeks landmark approval. Nature News. https://www.nature.com/articles/d41573-023-00050-8
  • Ran, F. A., Hsu, P. D., Wright, J., Agarwala, V., Scott, D. A., & Zhang, F. (2013). Genome engineering using the CRISPR-cas9 system. Nature Protocols, 8(11), 2281–2308. https://doi.org/10.1038/nprot.2013.143
  • Vertex and CRISPR therapeutics complete submission of rolling biologics license applications (Blas) to the US FDA for exa-Cel for the treatment of sickle cell disease and transfusion-dependent beta thalassemia. Vertex Pharmaceuticals. (2023, April 3). https://investors.vrtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-complete-submission-rolling
  • Vertex and CRISPR therapeutics present new data on more patients with longer follow-up treated with exagamglogene autotemcel (exa-cel) at the 2022 European Hematology Association (EHA) Congress. Vertex Pharmaceuticals. (2022, June 11). https://investors.vrtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-present-new-data-more-patients
Categories
COVID-19 Public Health

COVID Disease Severity Lower Than Ever, Most People Infected Unaware of Status

woman blowing nose
Photo by Karolina Grabowska on Pexels.com

As the omicron BA.5 subvariant has become dominant, many countries are heading into their third wave of Omicron cases. Japan reports its largest-ever surge in cases, recording over 200,000 new cases in one day.

Though omicron BA.5 has become the most dominant subvariant of COVID (accounting for 88% of new cases in the US) and is highly contagious, CDC data shows disease severity at its lowest point ever.

Intensive Care Unit (ICU) admission among hospitalized COVID-19 patients. (cdc.gov)

Among hospitalized COVID patients, about 1 in 10 are admitted to the ICU as of July 2022. This figure was as high as 1 in 3 in March 2020, and 1 in 5 as recently as December 2021.

Mortality among hospitalized COVID-19 patients. (cdc.gov)

Similarly, mortality among hospitalized COVID patients has decreased appreciably from 1 in 5 in March 2020 to 1 in 40 in July 2022.

These decreases in COVID disease severity follow the emergence of the omicron variant in November 2021 and its ever-growing share of new infections. The omicron variant, while of high concern and contagion, does not appear to be of proportionally high consequence compared to earlier variants.

The most common symptoms of COVID include cough, fever, and chills. Many report symptoms resembling a common cold with symptoms like upper respiratory congestion. Most people (56%) who are infected with the omicron variant are not aware of their positive status according to a recent Cedars-Sinai study.

Multiple factors could explain omicron’s lower severity, including widespread vaccination or immunity gained from prior exposure and infection. It is also possible that omicron has mutations that decrease severity while favoring infectivity.

Categories
Genetics

Antisense Therapy Explained: How Blocking mRNA Can Treat Genetic Disorders

Photo by Warren Umoh on Unsplash

Antisense therapy has proven to be effective at treating previously untreated genetic disorders including Duchenne muscular dystrophy and familial hypercholesterolemia. The therapy has also demonstrated promising results in Phase III clinical trials for amyotrophic lateral sclerosis (ALS).

What is antisense therapy, and how are antisense oligonucleotides used to treat genetic disorders?

Contents

Background

Genetic Disorders and Proteins

Genetic disorders are diseases caused by abnormal changes in our DNA sequence (mutations). Many diseases have a genetic basis, with mutations either being a direct cause or one of many contributors to a disease’s proliferation.

Some people are born with genetic disorders, acquiring mutations from one or both parents, while others acquire them during their lifetime due to mistakes made by their own cells or exposure to viruses, radiation, or mutagenic chemicals. Most mutations do not result in genetic disorders.

The reason why mutations can affect biological processes is because our DNA provides our cells with the blueprints necessary to build proteins, which are complex molecules responsible for carrying out the chemical reactions that occur within our bodies.

Humans are believed to have 25,000 unique proteins (some copied trillions of times throughout our bodies) that have very specific tasks and functions pertaining to growth, maintenance, structure, metabolism, immune defense, and much more. It follows that a mutation, which creates an error in the genetic instructions to create a specific protein, can have profound impacts on our health.

Genetic disorders that cause the creation of harmful proteins are notoriously difficult to treat. New genes can be introduced into cells to result in the creation of non-mutated proteins, but it is not yet possible to completely stop the production of specific proteins.

This limitation even applies with the recently discovered CRISPR-Cas9 gene editing technology, which can add, remove, inhibit, and activate genes–but not in all cells of the body, meaning some cells will still produce the harmful target protein. Therefore, gene therapy that could inhibit the expression of harmful mutated genes would benefit patients with such disorders.

Antisense Therapy

How It Works

When cells use our DNA’s instructions to build new copies of a protein, it must first be processed into a form that can be read by the ribosome, which is the site of protein synthesis in our cells. Messenger RNA (mRNA) is the final form into which a part of the DNA sequence is processed before the ribosome uses its instructions to build new proteins.

Antisense oligonucleotides (ASOs) are strands of DNA or RNA that are complementary to an mRNA strand that encodes for a mutated protein. Due to this complementary nature, the ASO and the faulty mRNA strand will bind together. This prevents the ribosome from ever translating the specific mutated mRNA strand into the harmful, mutated protein that is the basis of the target genetic disorder.

Implications and Discussion

Many genetic disorders are caused by single mutated proteins that have harmful effects. Some of the most serious neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) are caused by harmful mutated proteins.

Using ASOs to stop these proteins from being built by our cells can offer significant therapeutic effects in patients with this kind of genetic disorder.

For example, a mutation in the gene that encodes for the huntingtin protein causes the protein to take on an elongated shape. When metabolized, these mutated huntingtin proteins bind together and accumulate into increasingly large deposits in the brain, eventually becoming large enough to affect normal brain function. This is the basis for Huntington’s disease. Using ASOs to decrease expression of the mutated Huntingtin protein could provide therapeutic effects.

Antisense therapies could also treat diseases by inhibiting non-mutant proteins. For hypertriglyceridemia (excess triglycerides), ASOs could be used to inhibit the production of the APOC3 gene which encodes for a protein that regulates triglyceride metabolism.

Certain cancers could also be targeted by ASOs, as they could be used to block the production of proteins that facilitate the growth of a cancerous or precancerous mass of cells.

Solely using the antisense oligonucleotide is around 50% effective at preventing synthesis of a target protein. However, when combined with an enzyme that degrades the complex between the mRNA and ASO, this synthesis-blocking efficacy reaches 95%. This can slow the progression of or provide lasting relief from symptomatic disorder.

Limitations

Antisense therapy can not be used for all genetic disorders. Only those which are caused by a single protein mutated into a harmful form could theoretically be treated by the therapy. Also, stopping the production of an implicated protein could have unexpected side effects due to the discontinuation of normal functions of the protein. In one available ASO therapy, nusinersen (Spinraza), patients experienced varied side effects including increased risk of respiratory infection, congestion, constipation, and stunted growth in children–potentially related to the decreased presence of the target protein.

Another limitation of oligonucleotides is that it is very difficult to deliver them to the interior of our cells. However, surrounding them with fatty particles, like what is used to surround the mRNA in COVID-19 vaccines, can protect them from degradation and help them enter our cells. Though, it can still prove difficult to deliver antisense agents to places like the brain, where a drug must make it through the difficult-to-permeate ‘firewall’ that is the blood-brain barrier. For nusinersen (Spinraza), which has a target protein in the central nervous system, the antisense agent must be injected directly into the spinal canal.

In general, antisense therapy research faces an uphill battle. Since the prospect of using ASOs as drugs was first conceived by Harvard scientists in 1978, less than 10 antisense therapies have been approved by the FDA–the first was approved in 1998. Many antisense therapies have failed in the early phases of clinical trials due to low efficacy. Ionis Pharmaceuticals is the most notable biotechnology company researching antisense therapy, with nine current antisense drug candidates reaching Phase III trials as of June 2022.

Whether ASOs will play a wide role in the treatment of genetic disorders has yet to be determined, though recent innovations in drug delivery systems as well as dozens of such therapies being in advanced clinical trials makes them more promising than ever.

References