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CRISPR

CRISPR and Ethics: a Tough yet Riveting Conversation

Jennifer Kraliz—McMaster University Honours Biology 2023

This past fall, biochemist Dr. Jennifer Doudna and microbiologist Dr. Emmanuelle Charpentier were awarded the Nobel Prize in Chemistry 2020 for their development of CRISPR/Cas9 gene editing technology (1). Charpentier and Doudna’s discovery has significantly progressed genome editing and has redefined the life sciences, unlocking new research avenues and an abundance of potential for further biotechnology and healthcare advancements  (1). Achieved through several different technologies, genome editing allows scientists to alter the DNA of organisms, which leads to phenotypic changes, such as in hair colour or disease susceptibility (2). The first of these technologies were invented in the late 1900s, essentially acting like scissors, cutting the organism’s DNA in certain places so that scientists can detach, add, or replace DNA segments (2). This procedure was drastically advanced in 2009 with the invention of the CRISPR method, making genome editing easier, cheaper, and faster than ever before (2).

Figure 1: CRISPR and other genome-editing technologies are often referred to as genetic scissors, or a “cut and paste” tool for DNA
SOURCE: Illustration by Johan Jarnestad, The Royal Swedish Academy of Sciences, for The Nobel Prize

Consisting of guide RNA and the DNA-cutting enzyme Cas9, the CRISPR (Clustered Regularly Interspaced Short Palindromic) tool was adapted from an immune defense against viruses observed in bacteria (3). With it, scientists can inactivate genes, add in new segments of DNA, and even edit single nucleotide bases (3). Due to the universal and foundational position DNA holds, genome editing tools have countless applications across many fields of the life sciences.

Gene therapy for humans, however, is arguably one of the most remarkable. CRISPR/Cas9 and other genome editing technologies have great potential to treat diseases with genomic bases, such as cystic fibrosis (2). Research on CRISPR-based cancer treatment exploded after the first U.S. trial tested it in 2019, and deemed it feasible (3). As full of potential CRISPR is, it is extremely important to remember its novelty, and therefore its imperfection. CRISPR is undoubtedly fascinating and influential, but it is far from being an errorless method of genome editing (2). In using the CRISPR method, there is risk of altering off-target DNA and mosaicism, which could have unpredictable, detrimental effects on the individual’s phenotype (4). The concerns surrounding the CRISPR/Cas9 technology and other technologies alike do not end there. The effects of germline therapies, which edit the genes of reproductive cells, are passed down from generation to generation. This raises concerns about interference with human evolution (2). Furthermore, it has also been proposed that germline editing could produce hierarchical classes or divisions among people, delineated by the quality of their engineered genome (4). Another potential aspect of genome editing that could cause further harm and alienation is its cost and accessibility. What if gene therapies are expensive and only accessible to the wealthy? This could worsen the health gap between the rich and the poor (2). Many believe that genome editing used to treat diseases could very easily lead to people using it for enhancement or non-health related purposes (4). Beliefs on what is considered a disease or an impairment to one’s health are not universal. How will genetic enhancement be managed by policy and regulation (4)? Who will make the decisions concerning this regulation? How will political agendas and religious beliefs affect the outcome of these decisions? 

In summary, genome editing technology is a powerful tool, and many fear it landing in the wrong hands. Current bioethical discourse on the issue often includes a comparison of gene editing technology to selective human reproduction, calling it a “renewal of eugenics” (5). Whether or not the potential benefits of genome editing technology outweighs its potential harm is an extremely difficult quandary to navigate. Many assert that restricting research and development in human genome editing is unethical because it completely eliminates any chance of a positive impact.Whatever one’s stance on the issue may be, it is undeniable that genome editing and CRISPR technology has opened a door for humankind that cannot be closed.

References

  1. The Nobel Prize in Chemistry 2020 [Internet]. NobelPrize.org. [cited 2021 Feb 19].Available from: https://www.nobelprize.org/prizes/chemistry/2020/popular-information/
  2. What is genome editing? [Internet]. Genome.gov. [cited 2021 Feb 19]. Available from:https://www.genome.gov/about-genomics/policy-issues/what-is-Genome-Editing
  3. How CRISPR Is Changing Cancer Research and Treatment – National Cancer Institute [Internet]. 2020 [cited 2021 Feb 19]. Available from: https://www.cancer.gov/news-events/cancer-currents-blog/2020/crispr-cancer-research-treat ment
  4. What are the Ethical Concerns of Genome Editing? [Internet]. Genome.gov. [cited 2021 Feb 19]. Available from: https://www.genome.gov/about-genomics/policy-issues/Genome-Editing/ethical-concerns
  5. Ranisch R. ‘Eugenics is Back’? Historic References in Current Discussions of Germline Gene Editing. Nanoethics. 2019 Dec 1;13(3):209–22.

Categories
CRISPR

CRISPR: the Future of Cancer Research

Paige Chandran Blair—McMaster University Biochemistry 2023

Introduction

Cancer has become one of the leading global public health issues, exemplified by its status as the second leading cause of death worldwide in 2015 (1). The magnitude of cancer’s impact is predicted to surge over the next two decades, with the instance rate expected to increase by 70%. Despite humanity’s long awareness of cancer, treatment design has proved to be incredibly difficult as cancer involves complex physiological alterations, several mutations, translocations and chromosomal insertions/deletions. Cancer involves changes in genetic material that either turn genes off (such as tumour suppressors), or turn genes on (such as oncogenes). This ultimately leads to unregulated cellular growth (2). Consequently, gene editing is rising to the forefront of developing treatments for cancer,with the CRISPR-Cas system leading the way. 

CRISPR Technologies

The CRISPR-Cas technique is based on a prokaryotic immune defence mechanism (1). Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) systems involve guide RNAs (gRNA) and an endonuclease known as the CRISPR-associated (Cas) protein (3). Guide RNAs are designed by researchers to identify and guide the Cas DNA cutting enzyme to the target DNA where Cas cuts the DNA to creates a double-stranded break, illustrated in the figure below.

How CRISPR Is Changing Cancer Research and Treatment - National Cancer Institute
Figure 1: Mechanism of CRISPR-Cas9 technology showcasing the recognition of a target sequence, its cleavage, and the insertion of new genetic material. 
SOURCE: National Cancer Institute (2020)

Once the target gene is cut, the DNA can either be altered to inactivate the gene and create ‘knockouts’ or new segments can be added to create novel cellular functions. Researchers have taken advantage of this system because it presents the opportunity to accurately and easily make modifications at the genetic level such as adding and removing specific nucleotides without requiring separate cleaving enzymes (4). 

Current CRISPR-Based Cancer Treatments: 

CRISPR is a valuable asset to cancer treatments because cancer consists of several mutations making it difficult to target. Due to CRISPR’s versatility, accuracy, and precision, it is widely applicable to many branches of cancer research. CRISPR is currently driving research in cancer screening technologies, and providing drastic improvement on immunotherapies such as Chimeric Antigen Receptor (CAR) T-cell therapy (5). CRISPR-based applications to cancer screening are currently being conducted to identify genes related to drug resistance/sensitivity, genes pertaining to cellular vulnerability to environmental toxins, and genes with a role in the development of diseases. CAR T-cell therapy is a leading immunotherapy in which a patient’s T cells are removed, altered to express the chimeric antigen receptor (CAR) so they are better able to bind and kill cancer cells, then grown in large quantities, and reinserted into the patient as illustrated in the figure below (6).

PDF] Neurological updates: neurological complications of CAR-T therapy | Semantic Scholar
Figure 2: General process of CAR T-Cell Therapy from synthesis of CAR T-cells to insertion back into patient. 
SOURCE: National Cancer Institute (n.d.)

CAR T-cell therapy has been previously limited due to a lack of proliferation and persistence of CAR T-cells in toxic tumour microenvironments common to patients with advanced stages of cancer (7). However, novel CRISPR-edited CAR T-cells have demonstrated increased potency against tumours. The CRISPR system is applied to enhance T-cell function by ‘knocking out’ a protein that limits CAR T-cell activation (8). 

The Future of CRISPR Research: 

CRISPR based technologies currently have several limitations which future studies must overcome. First, future technologies must improve the delivery of CRISPR treatments to cancerous cells (3). Currently, two major methods are being developed to address this delivery problem; viruses and nanocapsules. Viruses are exploited to deliver CRISPR components to a specific organ (e.g. liver) using a virus which naturally targets that organ, while nanocapsules are designed to bring CRISPR components directly to target cells. Human cancer research is solely ex vivo, meaning that cells are removed and edited outside of the body as described with CAR T-cell therapy. However, future treatments may move beyond this and begin in vivo treatment design. Finally, while treatments such as CAR T-cell therapy have had several positive results in treating hematologic malignancies (i.e. blood cancers) efficacy has yet to be demonstrated in treating solid tumours (7).With CRISPR based technologies rising to the forefront of personalized cancer treatments, new hope is growing in research to address cancer’s future health threat.

References

(1) Ratan ZA, Son Y-J, Haidere MF, Uddin BMM, Yusuf MA, Zaman S Bin, et al. CRISPR-Cas9: a promising genetic engineering approach in cancer research. Ther Adv Med Oncol [Internet]. 2018 Jan 1 [cited 2021 Feb 19];10:1758834018755089. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29434679 

(2) CRISPR Cancer Research [Internet]. Synthego. 2021 [cited 2021Feb19]. Available from: (3) NCI Staff. How CRISPR Is Changing Cancer Research and Treatment [Internet]. National Cancer Institute. 2021 [cited 2021Feb19]. Available from: https://www.cancer.gov/news-events/cancer-currents-blog/2020/crispr-cancer-research-treatment 

(4) Questions and Answers about CRISPR [Internet]. Broad Institute. 2018 [cited 2021Feb20]. Available from: https://www.broadinstitute.org/what-broad/areas-focus/project-spotlight/questions-and-answers-about-crispr

(5) Spencer NY. Overview: What is CRISPR Screening [Internet]. Integrated DNA Technologies. Integrated DNA Technologies; 2019 [cited 2021 Feb 19]. Available from: https://www.idtdna.com/pages/education/decoded/article/overview-what-is-crispr-screening

(6) NCI Staff. CAR T-Cell Therapy [Internet]. National Cancer Institute. [cited 2021 Feb 19]. Available from: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy

(7) Salas-Mckee J, Kong W, Gladney WL, Jadlowsky JK, Plesa G, Davis MM, et al. CRISPR/Cas9-based genome editing in the era of CAR T cell immunotherapy. Hum Vaccin Immunother [Internet]. 2019 May 4 [cited 2021 Feb 19];15(5):1126–32. Available from: https://www.tandfonline.com/doi/full/10.1080/21645515.2019.1571893

(8) University of Pennsylvania School of Medicine. CRISPR-edited CAR T cells enhance fight against blood cancers [Internet]. ScienceDaily. ScienceDaily; 2020 [cited 2021Feb19]. Available from: https://www.sciencedaily.com/releases/2020/12/201207161535.htm

Categories
CRISPR

CRISPR and Genome Editing: a Split Path

Areeba Imran—McMaster Honours Life Sciences 2023

Should scientists genetically modify children the way plant biologists genetically modify corn? Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing makes this a reality to take into consideration. This technology has the ability to edit human genomes to alter DNA sequences and consequently change gene function. (1) It does this by inserting cuts or breaks of DNA to disturb the natural sequence of the human genome. (1) The changed sequence can then be programmed to trick DNA repair mechanisms into deleting unwanted genes. (1)

SOURCE: Drug Target Review

CRISPR has the potential to remove unfavourable genetic mutations that have burdened the lives of many children and adults. Examples of common genetic diseases are down syndrome, cystic fibrosis and sickle cell anemia. (2) The root cause of genetic diseases, many of which have no cure, is in our DNA’s blueprint. As a result, people either live their entire lives suffering from their symptoms or die prematurely without the luxury of fulfilling their dreams.

Cómo se produce una mutación genética?
SOURCE: HealthWorld

CRISPR gene-editing has not reached its full potential in the medical field because of various ethical concerns and social implications. (3) One of the major concerns against CRISPR is that it is considered an unnatural intervention. However, the intention behind using this technology is no different from the reason we readily use prescription medications and allow other medical interventions like surgeries. The intention is to provide the best care to everyone, so they can wake up healthy every morning ready to turn their dreams into a reality. If used with the right intention, CRISPR has the ability to make genetic diseases a thing of the past. 

The most significant setback to making CRISPR a readily available technology is its impact on our society. (4) Would it lead to a society where everyone strives to be similar? Will differences no longer be celebrated? With a gene-editing technology available, people may look into it as a way to mitigate themselves from unfavourable genes and lead to a more uniform society. In doing this, diversity which is currently highly celebrated, especially in countries like Canada, with its multicultural idealism, will no longer hold such value.

Lorazepam pour dormir ce que c'est, les doses et les effets secondaires / Drogues psychotropes | Psychologie, philosophie et réflexion sur la vie.
SOURCE: Pharmaceutical Pain Management

In addition to its various social implications, CRISPR can also be a promising solution used for vaccinations. (5) This may be very beneficial in today’s world, where the COVID-19 pandemic has changed our lives. It has been shown that CRISPR can engineer white blood cells to produce antibodies to respond to a disease like COVID-19 without exposing the body to the disease. (6) However, more clinical trials must be done before this technology can be used in this way. (5) With the COVID-19 variants on the rise and no foreseeable end to this pandemic, further research into CRISPR technologies may help vaccinate our population quicker and thus warrants our attention. 

The question remains: Are we willing to overlook the drawbacks of CRISPR gene-editing technology if it means limiting the occurrences of incurable genetic diseases and future pandemics? It is important to realize that every new technology comes with its disadvantages, and investing more time and research may lead to discoveries on ways to limit these drawbacks. Do we have the right to stop technology from taking over our world, or is it our duty to advocate for these changes?

Coronavirus & COVID-19 Overview: Symptoms, Risks, Prevention, Treatment & More
SOURCE: WebMD

References 

1. Vidyasagar A. What Is CRISPR? [Internet]. LiveScience. Purch; 2018 [cited 2021Feb20]. Available from: https://www.livescience.com/58790-crispr-explained.html 

2. What You Need to Know About 5 Most Common Genetic Disorders [Internet]. Regis College Online. 2020 [cited 2021Mar29]. Available from: https://online.regiscollege.edu/blog/information-5-common-genetic-disorders/

3. Locke LG. The Promise of CRISPR for Human Germline Editing and the Perils of “Playing God.” The CRISPR Journal. 2020;3(1):27–31 

4. Doudna JA, Sternberg SH, Rosa WDL. Opinion: Should we use gene editing to produce disease-free babies? A scientist who helped discover CRISPR weighs in. [Internet]. ideas.ted.com. 2017 [cited 2021Feb20]. Available from: https://ideas.ted.com/opinion-should-we-use-gene-editing-to-produce-disease-free-babies -a-scientist-who-helped-discover-crispr-weighs-in/ 

5. Bussler F. 3 Ways CRISPR is Used to Fight the Coronavirus [Internet]. Medium. Data Driven Investor; 2020 [cited 2021Feb20]. Available from: https://medium.com/datadriveninvestor/3-ways-crispr-is-used-to-fight-the-coronavirus-33 19eddd6906 

6. Eatwell E, Maertens V, et al. Could CRISPR Create a COVID-19 Vaccine? [Internet]. BRINK. 2020 [cited 2021Feb20]. Available from: https://www.brinknews.com/crispr-and-the-fight-against-covid-19/

Categories
Cell Therapies

Cell Therapies for Cancer Treatment: How it Works

Nicol Vaizman—McMaster University Molecular Biology and Genetics 2023

An exciting new area of research in cancer biology has generated a great deal of attention as traditional treatments such as chemotherapy, radiation and surgery have not yet fully eliminated the reappearance of cancerous cells and resistance to drugs. Presently, the scientific field of regenerative medicine is advancing and so, the use of cell therapy has become a backbone in the development of cancer treatments. By doing so, scientists have even considered defining cancer as a stem cell disorder rather than that of abnormal cells dividing uncontrollably. Stem cells are unique in their ability to divide into specialized cells and the stem-cell origin of cancerous cells is due to the acquisition of damaged stem cells. 

SOURCE: The Canadian Cancer Society

Cell therapies are designed in such a way that the immune system of a patient is improved and thus, able to fight cancer on its own1. The immune system plays a central role in the body as it recognizes, targets and eliminates any unfamiliar substances to protect the body from disease. However, our own cells are capable of becoming cancerous when gene mutations develop thus, the immune system does not always recognize that they are a threat and need to be destroyed as they contain our own DNA which is recognized as natural and the body’s own tissues2. The spread of cancerous cells into the bone marrow weakens the immune system as less white blood cells are produced to fight infection3.

T cells are a specific type of white blood cell that are essential to the regulatory processes that take place within the body to counteract infections4. These specialized cells have receptors which allow them to attach to surface proteins found on foreign cells called antigens5. The relationship between immune receptors and antigens are analogous to a lock and key because just as every lock can only be opened with a correctly sized key, each foreign antigen has a unique receptor that is able to bind to it. These antigens are also present on cancerous cells but if the immune cells do not have the correct receptors for them, they cannot attach to the antigens and help destroy the cancer cells. This comprehensive knowledge is what led to the discovery of a specific type of immunotherapy as it harnesses the powers of the immune system to attack tumors and ultimately, cure cancer. 

Chimeric antigen receptor (CAR) T-cell therapy is the new promising type of immunotherapy as T cells are genetically altered to better find antigens on the surface of cancerous cells and destroy them. Through a procedure called leukapheresis, T cells are removed and separated from the patient’s bloodstream through an IV and then sent to a lab6. Chimeric antigen receptors are then engineered into the T cells through an inactive virus in order to make them stick to cancer cells. When these new cells multiply, they are ready to be infused back into the patient’s bloodstream and can now precisely attack the tumor by releasing toxins7. As different types of cancers have various antigens, CAR T-cells are specific to the disease that the patient is fighting. By doing so, this cell therapy can eradicate all cancerous cells and remain in the body to ensure long-term remission for the patient. 

CAR T-cell therapy
SOURCE: Cleveland Clinic

The delivery of anti-cancer agents such as CAR T-cells has had large success rates for cancers such as leukemia and lymphoma, as a 30-40% success rate for lasting remission with no additional treatment has been noted8. As larger sample sizes and longer time periods of remission are analyzed, this type of cell therapy is being further developed to treat solid tumors such as those found in breast and lung cancer. Therapeutic systems are constantly being designed in the overall aim to improve the outcome in the fight against cancer. 

References

1 Cancer Treatments: The Newest Tools Doctors Are Using To Fight This Disease [Internet]. WebMD. WebMD; 2020 [cited 2021Feb19]. Available from: https://www.webmd.com/cancer/cancer-new-research-treatment

2 The immune system – Canadian Cancer Society [Internet]. http://www.cancer.ca. [cited 2021Feb19]. Available from: https://www.cancer.ca/en/cancer-information/cancer-101/what-is-cancer/the-immune-system/

3 The immune system – Canadian Cancer Society [Internet]. http://www.cancer.ca. [cited 2021Feb19]. Available from: https://www.cancer.ca/en/cancer-information/cancer-101/what-is-cancer/the-immune-system/

4 CAR T-cell therapy [Internet]. Cleveland Clinic. [cited 2021Feb19]. Available from: https://my.clevelandclinic.org/health/treatments/17726-car-t-cell-therapy

5 CAR T-cell therapy [Internet]. Cleveland Clinic. [cited 2021Feb19]. Available from: https://my.clevelandclinic.org/health/treatments/17726-car-t-cell-therapy 

6 LaRussaA. Chimeric Antigen Receptor (CAR) T-Cell Therapy [Internet]. Chimeric Antigen Receptor (CAR) T-Cell Therapy | Leukemia and Lymphoma Society. 2015 [cited 2021Feb19]. Available from: https://www.lls.org/treatment/types-of-treatment/immunotherapy/chimeric-antigen-receptor-car-t-cell-therapy

7 Watson S. CAR T-Cell Therapy: What You Should Know Today [Internet]. WebMD. WebMD; 2021 [cited 2021Feb19]. Available from: https://www.webmd.com/cancer/lymphoma/features/car-t-gene-therapy-risks-benefits#

8 Bartosch J. Three years after CAR T-cell therapy for lymphoma, patient still cancer-free [Internet]. UChicago Medicine. UChicago Medicine; 2019 [cited 2021Apr2]. Available from: https://www.uchicagomedicine.org/forefront/cancer-articles/a-walking-miracle-car-t-cell-therapy

Categories
Pharmaceuticals

How Does Computational Drug Discovery Work?

A Brief Introduction To Computational Drug Discovery And Its Applications

Namya Mehan — McMaster University Integrated Biomedical Engineering & Health Sciences 2024

Over the past year, we all have been hearing a lot about molecules such as chloroquine, remdesivir, lopinavir/ritonavir, etc. But have you ever wondered what these are, what they aim to do, and where they come from? All of them are small-molecule drugs that were under trial by the World Health Organisation to test their effectiveness against COVID-19. All drugs, small or large molecules, are obtained through a process called drug discovery, by which a drug candidate is identified and partially validated for the treatment of a specific disease.

This process of drug design and discovery involves many steps, such as studying the mechanism of action of various drugs, target selection and validation, lead identification and optimization, drug toxicity, and other mechanical and chemical properties,  including pharmacokinetics and pharmacodynamics1.

Figure 1: Traditional Drug Discovery Process. Source: Drug Discovery, All About Drugs

Given the number of steps in the process of drug discovery, it is evident that it can be extremely time-consuming, risky, and costly. A typical discovery and development process takes about 14 years to introduce a drug to the market, costing about 0.8 to 1 billion USD!1 These statistics exemplify the significant drainage of time and money associated with the cycle of drug discovery and development. But the question is, is there a way to make it any faster and cheaper? Yes.

Like everything else, from calculations to writing, drug discovery can also be made faster by computational methods. Developments in combinatorial chemistry and screening technologies have enabled the screening and synthesis of huge libraries of compounds in a short period of time. Computational drug discovery consists of computer programs and tools for designing compounds, lead identification, and repositories to study drug-target interactions. By using these approaches for various stages of the discovery process, the cost of drug development can be halved! The computational drug discovery approaches that are commonly used can be classified into three categories, structure-based drug design (SBDD), ligand-based drug design (LBDD), and sequence-based drug design.

Figure 2: Computational Drug Discovery Approaches. Source: Nature Articles, Computational Drug Discovery1

SBDD methods include molecular docking and De novo drug design which both rely on knowledge of the target macromolecule from 3D structures of potential targets. In absence of these 3D structures, LBDD tools provide information about the drug targets and ligand interaction. These tools allow for the construction of predictive models suitable for drug discovery and optimization. Some examples include quantitative structure-activity relationship, pharmacore modeling, molecular field analysis, and 3D similarity assessment. In situations where neither the target nor the ligand information is available, sequence-based approaches that use bioinformatic methods have been developed to identify potential targets and conduct lead discovery. Considering the practical needs of drug discovery, usually, all three approaches mentioned are used in combination to deliver successful results.

There exist several methodologies to support various steps in the drug discovery process. These include using web servers such as TasFisDock that identify drug targets using reverse docking to seek all binding proteins for a given molecule, docking-based virtual screening (SBDD) using GAsDock, a docking methodology with an optimization algorithm that results in more reasonable and robust binding modes between ligands and macromolecules, computational methods such as Cyndi assist in conformational sampling as the algorithms optimize energy and diversity features, virtual libraries play an important role in de novo drug design as they help to overcome challenges in selecting fragment sets for new drug leads. These are some examples of how computational methods are revolutionizing drug discovery.2

While these methods have great potential, the drug discovery process is not completely reliant on computational techniques in a black-box manner. Computational components of research are, and should always be, supplemented and coupled with experimental resources. Future challenges would include the coupling of chemistry and biology with chemoinformatics and bioinformatics, to result in pharmacoinformatics.3 This integration would lead to an increase in the accuracy and effectiveness of computational methods, making them more reliable and trustworthy.

References and Further Reading

  1. Ou-Yang S-sheng, Lu J-yan, Kong X-Qian, Liang Z-Jie, Luo C, Jiang H. Computational drug discovery. Acta Pharmacologica Sinica. 2012;33(9):1131–40.
  2. Sliwoski G, Kothiwale S, Meiler J, Lowe EW. Computational Methods in Drug Discovery. Pharmacological Reviews. 2013;66(1):334–95.
  3. Schaduangrat N, Lampa S, Simeon S, Gleeson MP, Spjuth O, Nantasenamat C. Towards reproducible computational drug discovery. Journal of Cheminformatics. 2020;12(1).
Categories
COVID-19 mRNA

mRNA Vaccines and the Future of Vaccination

Rodrigo Hontoria — McMaster University Honours Life Sciences 2023

Over the past 3 decades, scientists have been working with messenger RNA (mRNA) as a potential new method of producing simpler and more effective vaccines1 2. mRNA is a promising topic to assess because of its ability to produce a vast number of proteins, all depending on the coding of each mRNA. In a cell, mRNA is transcribed from DNA and undergoes a series of modifications that provide protection from the cellular environment, before finally being released into the cytoplasm for translation. Incorporating mRNA into modern vaccinations would provide three very beneficial outcomes:

  1. Safety – unlike other vaccines that require a weakened/damaged strain of the virus, mRNA vaccines provide a non-infectious route to immunity1 2. Also, after translation has occurred, mRNA is quickly degraded by the cell avoiding any long-lasting effects1.
  1. Efficacy – mRNA vaccines provide a highly detailed method for producing an immune response by inducing the production of whichever desired viral protein. In other words, mRNA strands can be made to encode the exact viral protein, without any of the deleterious and self-replicating genes of the virus. The lifespan/stability of mRNA can also be adjusted through changes in its 5’ cap and poly-A tail, or carrier molecule to change the time span of its desired effects2.
  1. Cost of production – Synthetic viral mRNAs are significantly less costly to produce compared to the manufacturing of proteins and viral antigens1.
A diagram of an mRNA vaccine in action. It shows a synthetic mRNA being translated by a ribosome into individual proteins from SARS-CoV-2, which induce an immune response.
Source: The Conversation

Setbacks and Advancements

In 1990, a group of scientists performed the first successful mRNA injection using reporter genes to induce the production of the corresponding proteins in mice1. In follow up experiments, physiological effects were observed in mice after the uptake of synthetic mRNA that stimulates the release of different hormones1 2. Although these early successes were very exciting and provided a potentially prosperous technology, many advancements in research were still necessary to achieve safety and efficiency. mRNA vaccine setbacks have been outlined thoroughly in past research projects, some of the most notable being: 

  1. Passage of mRNA from the bloodstream into the cell – through vaccination, mRNA will directly enter the bloodstream but how will cells be encouraged to uptake the mRNA?
  1. Stability/protection of mRNA when inside the cell – how will the mRNA be protected to avoid mutagenesis or breakdown?

To overcome these problems, companies such as Pfizer, BioNTech, and Moderna invested a lot of time, money, and effort into making mRNA vaccines effective. To facilitate transport of mRNA into the cell, common transfection reagents such as cationic lipids, calcium phosphate, and cationic polymer liposomes are used3 4. mRNA stability was achieved with the addition of untranslated regions (UTRs) added to the 5’ and 3’1 3. 

COVID-19 and Future Applications

On January 9, 2020, the Global Health Organization along with Chinese Health Authorities identified the novel coronavirus as 2019-nCoV (COVID-19)6. 2 days later, the Chinese government globally released the genomic sequence of the virus6. Pfizer, BioNTech, and Moderna were quick to start working on the vaccine. Only 11 months after COVID-19 was identified, the United States and United Kingdom established the latest mRNA vaccines as safe and effective1. 

Pfizer-BioNTech and Moderna mRNA vaccines code for a spike protein found on the membrane of the virus. Cellular uptake of the mRNA induces the production of a spike protein inside the host cell. The spike protein by itself is harmless and non-infectious but nonetheless, causes an immunological response that is remembered by the immune system. Pfizer-BioNTech and Moderna both require two doses of the vaccine, Pfizer-BioNTech requiring 21 days of separation, and Moderna requiring 28 days. Pfizer-BioNTech has a high effectiveness rate of 95% while Moderna is slightly lower at 94.1%.

Further applications for mRNA vaccines are contributing to the treatment of many more viral agents, among these are Ebola, Zika and Influenza. Cancer treatments, and genetic therapies are also looking at mRNA vaccines as a potential treatment to produce proteins that the body requires. 

Image result for covid 19 vaccines
Source: Aljazeera

References

  1. Pardy N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines — a new era in vaccinology. Nat [Internet]. 2018 Jan 12 [cited 2021 Feb 12];17:261–279. Available from: https://www.nature.com/articles/nrd.2017.243
  2. Harvard Health Publishing: Why are mRNA vaccines so exciting? [Internet]. Komaroff A, editor. [cited 2021 Feb 12]. Available from: https://www.health.harvard.edu/blog/why-are-mrna-vaccines-so-exciting-2020121021599
  3. Kim TK, Eberwine JH. Mammalian cell transfection: the present and the future. Nat Lib Med [Internet]. 2010 Jun 13 [cited 2021 Feb 14];397:3173–3178. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911531/
  4. Pfizer.com [Internet]. THE FACTS ABOUT PFIZER AND BIONTECH’S COVID-19 VACCINE. c2002 [cited 2021 Feb 13]. Available from: https://www.pfizer.com/news/hot-topics/the_facts_about_pfizer_and_biontech_s_covid_19_vaccine
  5. Huang J, Yang C, Xu XF, Xu W, Liu S. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Nat [Internet]. 2020 Aug 3 [cited 2021 Feb 13];41:1141–1149. Available from: https://www.nature.com/articles/s41401-020-0485-4
  6. Whole genome of novel coronavirus, 2019-nCoV, sequenced. Sci Da [Internet]. 2020 Jan 31 [cited 2021 Feb 12]. Available from: https://www.sciencedaily.com/releases/2020/01/200131114748.htm
  7. Zhang C, Maruggi G, Shan H, Li J. Advances in mRNA Vaccines for Infectious Diseases. Front In Immu [Internet]. 2019 Mar 27 [cited 2021 Feb 12]. Available from: https://www.frontiersin.org/articles/10.3389/fimmu.2019.00594/full
Categories
COVID-19

A Closer Look at the Janssen Vaccine: How Effective is it?

Madison Norris — McMaster University Honours Life Sciences 2023


Over the last two years, the COVID-19 pandemic has completely changed the way in which we go about our everyday lives. The shift to online classes, working from home, social distancing restrictions and stay at home orders have left many yearning for a sense of normalcy. The only feasible solution to see us through the pandemic is the mass vaccination of the majority of the population.

Johnson and Johnson recently announced the completion of phase 3 clinical trials of the single dose Janssen vaccine. The Janssen vaccine contains viral DNA within a modified adenovirus that codes for the spike protein found on the surface of the SARS-CoV-2 virus. (1) Adenovirus-based vaccines use adenoviruses as vessels that will release genetic material upon entry into the cells of an inoculated host. The purpose of the vaccine is to protect against moderate to severe COVID-19 infections, including emerging variants of the virus, such as the B.1.351 variant proliferating in South Africa. (2)

In phase 3 clinical trials, 43,783 participants, 18 years of age or older, participated in a randomized double-blind study that compared the safety and efficacy of the Janssen vaccine to a placebo control. (2) The study population represented 8 different countries, including the United States, countries in Central and South America and South Africa. The study also included participants with comorbid conditions, such as obesity, type 2 diabetes, hypertension and immunocompromising conditions. (2) 28 days following vaccination, the Janssen vaccine demonstrated 66% efficacy. (2) However, it is important to note that differences in efficacy were found across geographical regions. The vaccine was observed to be most effective in the United States (72%) and less effective in Latin America (66%) and South Africa (57%). (2) In addition, the Jassen vaccine demonstrated similar rates of efficacy across age groups, including adults over the age of 60. The only side effect observed was a fever in approximately 9% of participants. As of March 5th, Health Canada has approved the Janssen vaccine.            

A notable difference between the Janssen vaccine and other competitor vaccines (Moderna and Pfizer) is that it can be stored for longer periods of time at refrigerator temperatures. To illustrate, the Janssen vaccine can be stored at 2°C to 8°C for 3 months, whereas the Moderna vaccine can only be stored at these temperatures for 30 days (3/4). Moreover, the Pfizer vaccine cannot be stored at refrigerator temperatures at all, and must remain in -60°C to -80°C conditions. (4) The ability to store the Janssen vaccine for longer periods of time at refrigerator temperatures presents the opportunity to transport vaccines to remote locations.

Another distinction of the Janssen vaccine is that while it has been observed to be less effective (66%) it only requires one dose. In contrast, both Moderna and Pfizer require two doses but are remarkably more effective at 94.1% and 95% efficacies, respectively. (5,6) This offers a potential solution to countries financially unable to fully vaccinate their citizens with a two dose vaccine. A more feasible alternative could be to vaccinate the elderly and at-risk populations with either the Pfizer or Moderna vaccines, as they are more susceptible and will experience more severe symptoms of the virus. The remaining population could then be vaccinated with the Janssen vaccine, as they have stronger immune systems that will allow for greater rates of recovery. (7)

In sum, the Janssen vaccine demonstrated an overall efficacy of 66%. The vaccine offers solutions to transportation, storage and financial barriers to vaccination. Following FDA approval, the administration of the Janssen vaccine brings the global population closer to herd immunity and one step closer to returning to normal life.

References

  1. Corum J. Zimmer C. How the Johnson & Jonson vaccine works. The New York Times. [Internet]. 2021 Feb 24 [cited 2021 Feb 24]; Health:[about 5 p.]. Available from: https://www.nytimes.com/interactive/2020/health/johnson-johnson-covid-19-vaccine.html.
  1. Janssen Vaccines & Prevention B.V. A randomized, double-blind, placebo-controlled phase 3 study to assess the efficacy and safety of Ad26.COV2.S for the prevention of SARS-CoV-2-mediated COVID-19 in adults 18 years and older. [Internet]. New Jersey: Janssen Vaccines & Prevention B.V; 2021 Jan 29 [cited 2021 Feb 24]. 184 p. Available from: https://www.jnj.com/johnson-johnson-announces-single-shot-janssen-covid-19-vaccine-candidate -met-primary-endpoints-in-interim-analysis-of-its-phase-3-ensemble-trial.
  1. CDC. Moderna COVID-19 vaccine: storage and handling summary. [internet] CDC; 2020 Dec 20 [cited 2021 Feb 24]. 2p. Available from: https://www.cdc.gov/vaccines/covid-19/info-by-product/moderna/downloads/storage-summary.pdf
  1. Pfizer Inc. Pfizer and Biotech submit COVID-19 vaccine stability data at standard freezer temperature to the U.S. FDA. New York: Pfizer Inc; 2021 Feb 19 [cited Feb 24]. P4. Available from:https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-submit-covid-19-vaccine-stability-data
  1. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021; 384: 403-416. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa2035389
  1. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N Engl J Med. 2020; 383: 2603-2615. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa203457
  1. CBC News. Johnson & Johnson single-shot COVID-19 vaccine appears 66% effective overall in global trial. The Associated Predd [internet]. 2021 Jan 29 [cited 2021 Feb 24]; Health: [about 1 p.]. Available from:https://www.cbc.ca/news/health/johnson-johnson-covid-vaccine-trial-1.5893009
Categories
AI Precision Medicine

Precision Medicine and AI: the Future is Here

Stephanie Chung—McMaster University Honours Life Sciences 2023

With all the advancements in the scientific community and precision medicine, artificial intelligence (AI) has become a reality. Precision medicine is health care tailored to an individual based upon characteristics such as genes, lifestyle, and environment, according to Hodson (1), a Supplements Editor for Nature Outlook supplements. Artificial intelligence is investigating intelligence agents and systems that are capable of solving complex goals (2). 

Diagram Description automatically generated

Source: National Aeronautics and Space Administration 

Precision medicine requires using all medical therapies/techniques that have been developed, clinical trials, along with individuals to order to create a customized treatment plan for a patient. Precision medicine has the goal of moving away from a general one-size-fits-all approach and into tailor-made programs for individuals with the same conditions and similar characteristics. In order to do so, extensive data must be collected from a large population. In 2015, Barack Obama announced an initiative to have over a million people enrolled in the All of Us Research Program (3). The resulting data contained personally reported information, digital health technologies, electronic medical records, and sequencing. In the future, the goal of precision medicine is to shift the focus of health care to assessing health, proactive management of disease risks and prevention (3). In order to do so, volunteers (anonymously) are going to be required to allow permission of their health records and genetic codes, as precision medicine requires patient data (1). The issue at hand is getting the public to trust precision medicine researchers with such personal (valuable) information.  

A person looking at a screen Description automatically generated with low confidence

Source: Corporate Finance Institute

Healthcare is already being influenced and shifted due to artificial intelligence. Some of the achievements made so far are in cancer and cardiovascular diseases (4). This is done through an integrating new and existing learning approaches, along with using the data gathered from artificial intelligence to benefit the patient, as well as advancing the scientific field (4). Artificial intelligence also has the ability to change the world and our everyday lives. Companies may use artificial intelligence to provide benefits for consumers, through wearable devices for health monitoring, smart household products that offer peace of mind, and voice-activated devices for assistance (5). These are all making our daily lives much more convenient and have become part of our daily routines. However, through these devices, data capturing is required, which may result in consumers feeling threatened by an invasion of privacy. This is technology most of us do not understand and in order to feel more secure, there need to be rules and regulations set on what companies can and cannot collect. Companies could also aid in this through actively educating consumers on the benefits of artificial intelligence along with what data they are recording (5). Artificial intelligence may result in less white-collar employees and qualified jobs (6). An example of this trend can be seen with physicians being outperformed with image recognition tools to detect skin cancer (6). However, we must acknowledge that as time passes, the job market is bound to change, however it is not certain where the workforce will shift to in the future (6). Therefore, we must cherish the jobs that cannot be automated, and regulations may need to be in place that require set businesses to allocate a certain amount of money to train the employees of non-automated jobs (6). 

In conclusion, precision medicine and artificial intelligence both require information collected from the public in order to keep advancing. As a society, it is our responsibility to keep up to date with what is being collected from us. It is still uncertain how artificial intelligence will impact our world; however, all we know is that in order to keep it from drastically changing our society, we must be aware of what it does and its limitations. 

References

  1. Hodson R. Precision medicine. Nature [Internet]. 2016 Nov [cited 2021 Feb 16]; 537(S49). Available from: https://www.nature.com/articles/537S49a
  1. Reddy S. Artificial intelligence applications in healthcare delivery. Boca Raton FL: Routledge; 2021. 4 p.  
  1. Ginsburg GS, Phillips KA. Precision medicine: from science to value. Health Aff [Internet]. 2018 May [cited 2021 Feb 16];37(5). Available from: https://www.healthaffairs.org/doi/full/10.1377/hlthaff.2017.1624?casa_token=uO0kuDXET1YAAAAA%3AmKUaknJodu-tBu89b6GoutcdHqOR3aByClgJiJtw62Zon6XW4V-Kk7Kpf15QojuX2VsBCWFKyieShw
  1. Uddin M, Wang Y, Woodbury-Smith M. Artificial intelligence for precision medicine in neurodevelopmental disorders. Npj Digital Medicine. 2019 November [cited 2021 Mar 8]; 2(112). Available from: https://doi.org/10.1038/s41746-019-0191-0
  1. Puntoni S, Reczek RW, Giesler M, Botti S. Consumers and artificial intelligence: an experiential perspective. J Mark [Internet]. 2020 Oct [cited 2021 Feb 16];85(1):131-151. Available from: https://journals-sagepub-com.libaccess.lib.mcmaster.ca/doi/full/10.1177/0022242920953847#articleCitationDownloadContainer
  1. Haenlein M, Kaplan A. A brief history of artificial intelligence: on the past, present, and future of artificial intelligence. Calif Manage Rev [Internet]. 2019 July [cited 2021 Feb 16]; 61(4):5-14. Available from: https://journals-sagepub-com.libaccess.lib.mcmaster.ca/doi/full/10.1177/0008125619864925

Reference list for images: 

  1. National Aeronautics and Space Administration. Precision medicine: announcement of the next workshop for NHHPC members. [Image on internet]. 2017 [update 2017 Aug 6; cited 2021 Feb 16]. Available from: https://www.nasa.gov/feature/precision-medicine
  1. Corporate Finance Institute. Artificial intelligence (AI). [Image on internet]. Available from: https://corporatefinanceinstitute.com/resources/knowledge/other/artificial-intelligence-ai/
Categories
Health Monitoring

Consumer Gadgets—The Future of Health Monitoring?

Bhargavi Venkataraman — McMaster University Bachelor of Health Sciences 2024

In the 21st century, technology pervades every facet of life and is increasingly allowing individuals to take control of more aspects of their lives at their own discretion. Health monitoring is one such area which has shown extensive progress through the use of consumer gadgets, primarily in the form of wearable technology. 

Smartwatch manufacturers like Fitbit and Garmin have become household names and their prevalence has allowed more and more consumers to manage their exercise regimen, heart health and dietary requirements in a convenient manner. Aside from the standard pedometer, heart rate sensing and sleep tracking features, newer smartwatches are also starting to include inbuilt EKGs, electrodermal sensors, blood oxygen level tracking and more.1These features can help users detect things like atrial fibrillation (a common sign of stroke), physical signs of excessive stress through electrical changes in sweat levels, and abnormal blood oxygen levels, which could be a sign of anything from lung function issues to neurological disorders.1 

This advanced kind of monitoring allows consumers to notice symptoms of critical illnesses earlier and get professional help before their conditions worsen, making these gadgets a valuable asset for monitoring individual health. Smartwatches are not the only health monitoring consumer gadgets that are gaining popularity. For example, biosensors are a class of self-adhesive patches that collect movement, heart rate, respiratory rate and temperature data while people are on the move.2 Research in Augusta Medical University Centre has shown that there is an 89% reduction in patient deterioration in preventable cardiac or respiratory arrest when regularly using biosensors.2These inconspicuous but effective patches are excellent in office environments as a method for reducing staff workload, opening up a whole new avenue of possibilities in the future of health monitoring.

Source: John Rogers. Tiny biosensor patches worn on skin show big promise [Internet]. CBS News. CBS Interactive; 2014 [cited 2021Mar7]. Available from: https://www.cbsnews.com/news/tiny-biosensor-shows-big-promise/

Besides these gadgets, our own smartphones have become instruments for health tracking through apps like Moodpath for anxiety and depression, Remente for water drinking and sleeping habits, and Flo for menstrual cycle tracking.6 With advanced tracking methods built into phones themselves, awareness about various health issues is rising, making for an overall healthier population. 

It is clear that health monitoring devices are becoming increasingly prevalent in the greater population, resulting in numerous implications. In terms of positives, data from these technologies could potentially influence insurer decisions, reduce hospital visits due to frequent personal health scares and even encourage healthier corporate culture by better management of workloads and stress.4

Nonetheless, there are also some negative implications. There are safety concerns about the devices malfunctioning, like a case in 2017 where a woman suffered second-degree burns from her FitBit allegedly catching fire.5 Furthermore, many of these gadgets collect private information in order to function and there are many issues surrounding the data security and privacy regarding the use and distribution of this information.3 

Ultimately, smart consumer gadgets have had a substantial positive impact on health monitoring and advancements in this field of technology shows great potential to increase universal health. However, there are still numerous concerns about the safety and security of the technology that is playing such an intimate role in daily lives. In order to utilize these gadgets to their full potential, these ramifications need to be addressed. If done properly, health monitoring technology will continue to lead to massive advancement in healthcare throughout the world.

References

1. Baig EC. 4 Smartwatch Features That Track Your Overall Health [Internet]. AARP. 2020 [cited 2021Feb21]. Available from: https://www.aarp.org/home-family/personal-technology/info-2020/smartwatches.html

2. Phaneuf A. Latest trends in medical monitoring devices and wearable health technology [Internet]. Business Insider. Business Insider; 2021 [cited 2021Feb21]. Available from: https://www.businessinsider.com/wearable-technology-healthcare-medical-devices

3. IoT Big Data: Consumer Wearables, Data Privacy and Security [Internet]. American Bar Association. [cited 2021Feb21]. Available from: https://www.americanbar.org/groups/intellectual_property_law/publications/landslide/20 15-16/ november-december/IoT-Big-Data-Consumer-Wearables-Data-Privacy-Security/

4. Drees J. How the new patient consumer is powering remote monitoring growth: 6 details [Internet]. Becker’s Hospital Review. [cited 2021Feb21]. Available from: https://www.beckershospitalreview.com/consumerism/how-the-new-patient-consumer-is power ing-remote-monitoring-growth-6-details.html 

5. Dispatch. The health impacts of wearable technology [Internet]. The NYU Dispatch. 2018 [cited 2021Feb21]. Available from: https://wp.nyu.edu/dispatch/2018/12/17/the-health-impacts-of-wearable-technology/

6. Jewell T. Best Healthy Lifestyle Apps of 2020 [Internet]. Healthline. Healthline Media; 2020 [cited 2021Feb21]. Available from: https://www.healthline.com/health/mental-health/top-healthy-lifestyle-iphone-android-apps#health-pal