BioQuakes

AP Biology class blog for discussing current research in Biology

Tag: mRNA

The Revolutionary mRNA COVID Vaccines

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On December 7, 2023

In Student Post

Biochemists Katalin Kariko and Drew Weissman have won the 2023 Nobel Prize in medicine/physiology. Why? Because they were the people behind the vaccines that just allowed us to control the worldwide COVID pandemic.

Usually, vaccine development takes about 5 to 10 years. However, more resources were put into the urgent battle of fighting the rapidly spreading COVID-19 than ever before: in record time, after the genetic sequence of the SARS-CoV-2 virus was discovered, several pharmaceutical companies, namely Moderna and Pfizer, created messenger RNA vaccines. Then, for the first time ever, the FDA approved mRNA vaccines.

Covid Vaccine

Typical vaccines consist of weakened viruses or bacteria that provoke the immune system to make antibodies to protect against future infections:

As I learned in AP Bio class, once those weakened pathogens are allowed to get through the body’s innate defenses (skin, mucus, tears, saliva, etc.), macrophages and dendritic cells engulf the antigens of the foreign pathogens (the spike protein for coronavirus) through phagocytosis, which the phagocytes can display on the outside of their plasma membranes on MHC proteins, while simultaneously releasing chemical messengers called cytokines. Activated by the cytokines, certain T-helper cells then recognize the antigens displayed on certain MHC proteins and call for an appropriate response. If this process is in a cell, T-helper cells activate cytotoxic T cells and T-memory cells. However, if it is in the blood, T-helper cells activate B-plasma cells and B-memory cells. B-plasma cells are the cells that create antibodies, which effectively neutralize pathogens and B-memory cells remember how to create those antibodies significantly more effectively for better future protection.

However, it is a very costly and tedious process for scientists to get loads of the coronavirus and weaken it for vaccines. The way Pfizer and Moderna created working COVID vaccines so quickly, based on the research that Kariko and Weissman began in 2006, is by creating vaccines with mRNA that tells cells how to create weakened coronavirus proteins; this process is instead of scientists manually putting weakened proteins into vaccines and is significantly more efficient since our bodies are already good at making proteins based on DNA/RNA code.

The reason why mRNA vaccines have never been FDA approved before the COVID vaccines is because pumping mRNA into the body releases cytokines itself. As mentioned previously, in AP Bio we learned that cytokines trigger helper-T cells. If helper-T cells are triggered when they shouldn’t be, that could create many problems. So, to fix this problem, Kariko and Weissman slightly altered the structure of the RNA to lessen cytokine triggering. Additionally, they encased mRNA in bubbles of lipids. As I learned in AP Bio class, lipids are nonpolar, meaning they can travel through cell plasma membranes. This lipid bubble, therefore, allows the mRNA to travel directly to and inside the nuclei of cells without causing harm elsewhere. Then, the mRNA can tell ribosomes to create the certain weakened coronavirus proteins that trigger the immune response of creating antibodies as previously described.

With the help of the research of the very deserving 2023 medicine/physiology Nobel Prize winners, Weissman and Kariko, the problems with mRNA technologies have finally been resolved (for now). Thus, this more efficient — and may we call it, revolutionary — mRNA technology is now being looked at to potentially defend other viruses and even cancers. The opportunities for this technology seem extraordinary, but what other challenges will scientists and researchers face when trying to explore these opportunities?

I would argue it is time for them to explore and find out.

The “Most Complicated” Cancer Treatment EVER

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On April 23, 2023

In Student Post

There are many approaches to treating cancer, ranging from invasive surgeries to extremely damaging radiation and chemotherapy.  The teeny-tiniest clinical trial ever began at UCLA in yet another attempt to find another way to eradicate cancer.  With only 16 participants, this trial combined two areas of research: gene editing and T-cell engineering.   The reason for the miniscule sample size is the intensely customized nature of the treatment.  Each patient’s tumor had completely unique mutations, so each patient needed equally unique T-cell engineering through gene editing.  

One reason cancer is so hard to treat is because they have adapted to be resistant to the body’s own immune response.  The patients that have cancers, especially ones in the later stages, have lost the battle against their cancer with their own immune system, so a new super-immune system must now be built.  This army of new T-cells (white blood cells, which identify and kill bad cells, seen below) will need “training” for its difficult battle ahead.  First, however, the researchers must determine how to train these cells so they will actually be successful.  They used algorithms to find identifiable mutations in the tumor, something that the T-cell can seek out to differentiate the cancerous cells from the normal cells.  Healthy Human T Cell

After testing to make sure that the T-cells can actually identify these mutations, T-cell receptors are designed specifically to their tumor.  Then, each patient’s blood is taken so that the DNA code for the new receptors can be inserted using CRISPR,  a genome editing technology at the cutting edge of genetic medical research.  The DNA code is transcribed to mRNA, which is then used in the ribosome to build polypeptides, in this case, the receptor proteins for the T-cells.  In order to ensure that these new T-cells (with the special receptors) are received, the patients had to take medication that suppressed the number of immune cells, so that the ones they are given can take hold.  

One month into treatment, 5 of the patients’ tumors stopped growing, and only 2 of the participants had associated side effects.  Although only 5 patients had the desired results, Dr. Ribas, one of the researchers, says that they “need to hit it stronger the next time” because they were limited to a small dosage of T-cells to start in order to establish safety.  Additionally, the technology will only get better and better as the research progresses and the T-cells can have more and more mutation targets to look for in a tumor.  

The Promise of Messenger RNA Therapy

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On February 25, 2022

In Student Post

A recent article about messenger RNA therapy outlines the evolution of messenger RNA therapy and how it has gone from an idea to a globally used treatment in just the past seventeen years. Recently, messenger RNA therapies such as the Pfizer-BioNTech and Moderna COVID-19 vaccines have been used by hundreds of millions of people around the world. 

The author Drew Weissman, a vaccine research professor at the University of Pennsylvania, and his colleague Katalin Karikó created mRNA molecules back in 2005 that would not cause harm when injected into animal tissue. Then in 2017, Weissman and Norbert Pardi found that this mRNA creation could be brought into human cells through a fatlike nanoparticle without harm, and that bringing this modified mRNA in protect mRNA from being broken down by the body and resulted in the immune system generating antibodies and more effectively neutralize the invading virus. Vaccines-09-00065-g001This mRNA fatlike nanoparticle is known as mRNA-LNP (pictured to the left). mRNA is able to enter cells without harm because it is carried in by this liquid nanoparticle which is known for its role in transportation. The Pfizer-BioNTech and Moderna COVID-19 vaccines use this mRNA-LNP, and in clinical trials have shown to successfully prevent over 90% of treated people from contracting COVID-19.

The positive results from many trials and studies of the Pfizer-BioNTech and Moderna COVID-19 vaccines have provided a lot of information on the success of mRNA-LNP. It has been found that mRNA-LNP is much more effective and quicker than other approaches to COVID-19 treatments such as growing vaccines in laboratory cell cultures. 

41541 2020 159 Fig1 HTMLMessenger RNA therapy works by making cells create proteins that induce a reaction from the immune system in response to invading viruses (pictured to the right). This reaction in response to invading viruses is called the humoral response, where cytotoxic T cells are made to release proteins that destroy infected cells. The humoral response also trains the immune system to respond to and attack that virus in the future by creating memory B cells to recognize it, which is called a secondary immune response.  This method of instructing cells to create these proteins yields a greater quantity at a time that conventional protein and monoclonal antibody therapies. 

The success of messenger RNA therapy in COVID-19 vaccines has inspired the further research and use of this method for other viruses, as well as cancers, food, allergies, and autoimmune diseases, and many clinical trials are underway. Messenger RNA therapy could be a much more time and cost efficient alternative for a lot of conditions and treatments. More research still needs to be done, and there are many improvements that could be made (such as smaller doses of or a better supply chain for the vaccine), but overall messenger RNA therapy is very promising for treatments of the future.

Optimus Prime, Megatron, Proteins? The New Transformer Vaccine Candidate!

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On January 17, 2022

In Student Post

Amid the global outbreak of COVID-19, with no end in sight after nearly two years, the future wellbeing of humans is in danger. Coughs, fevers, and shortness of breath have lent way to millions of deaths across the globe. As thousands of researchers relentlessly work to find solutions to this virus, multiple vaccine candidates have emerged. Specifically, in the United States, millions of Americans have received doses of the Pfizer-BioNTech, Moderna, and Johnson & Johnson’s Janssen vaccines. However, scientists at Scripps Research recently recognized a new, self-assembling COVID-19 vaccine as a potentially more efficient and effective way to fight this worldwide battle.

 

Primarily, it is critical to understand how vaccines function as they help protect the immune system. The COVID-19 vaccines currently in effect are mRNA-based; in other words, the messenger RNA signals one’s body to produce a harmless viral protein that resembles the structure of a spike protein. The body, with the help of T-Helper cells, recognizes this structure as a foreign invader as B cells bind to and identify the antigen. The T-Helper cells will then signal these B cells to form B-Plasma cells and B-Memory cells. When getting the vaccine, the B-Memory cells are especially important as they prevent reinfection. This is a process known as adaptive immunity. Here, in the event of future infection with the spike-protein COVID-19, the memory cells would help carry out the same response more quickly and efficiently. Essentially, this process acts as the body’s training in case of any future infections.

 

While the Scripps Research COVID-19 vaccine would evoke a similar immune response to that described above, it differs from other candidates in how it assembles in the human body; this new vaccine would be comprised of proteins that are able to self-assemble. On their own, these nanoparticle proteins would transform into a sphere protein structure surrounded by smaller proteins, mimicking the coronavirus’s shape. Here, the self-assembled spike proteins are more sturdy and stable than in an mRNA-produced structure. Thus, it more accurately prepares the body for future infection with COVID-19. In fact, multiple tests found that mice who were given the experimental vaccine were able to fight off not only SARS-CoV-2 but also SARS-CoV1 along with the alpha, beta and gamma variants.

 

Nonetheless, influencing the public to get a newer vaccine instead of the well-trusted vaccines already in production requires proof of the candidate’s benefits. Primarily, as mentioned, early results find that this new candidate would perform well with many different strains of COVID-19. Additionally, researchers assert that this vaccine would be relatively simple to produce on a mass scale. Lastly, scientists found that this vaccine may well be more protective and long-lasting than current vaccine candidates. Although the process of vaccine approval is lengthy and often difficult, I am hopeful for the future of the Scripps Research vaccine if it is put into production. Moreover, I believe that such experimentation with self-assembling nanoparticle proteins transcends the current pandemic. The benefits of this field present a wide array of opportunities, and I look forward to seeing what its future may hold.

 

What do you think? Are these transformer-like self-assembling particles a gateway to the future of medicine or an unnecessary distraction from effective treatments already in circulation?

Changing Course: How Scientists Can Update Vaccines With Emerging Variants

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On December 20, 2021

In Student Post

SARS-CoV-2 , the virus which causes COVID-19, is changing rapidly, which in turn warrants changes to the vaccines created to slow its spread. This virus is mutating fast, with a new mutation establishing about every 11 days. These mutations may not be different enough to cause an immediate difference, but each and every person who catches SARS-CoV-2 opens more possibilities for mutations.

Spike omicron mutations top

Omicron Mutation Spike Protein

The most recent large variant to be identified was B.1.1.529 Omicron originating in South Africa. The Omicron variant has more than half the amount of mutations as the Delta variant, raising concern among health officials, who fear that the virus may differ just enough from the original for vaccines to be less effective. This fear stems from the idea that the vaccine-created antibodies will no longer be able to recognize the mutated virus’ spike proteins, resulting in an ineffective vaccine.

The current mRNA SARS-CoV-2 vaccines work in a fascinating way. Scientists utilize harmless lab-grown mRNA that contain coded instructions on how to create the SARS-CoV-2 spike protein, and place that technology into a vaccine.

Then, once the mRNA vaccine is injected into the patient, the patient’s cells will create the identical spike proteins, prompting an immune response. As we have learned in AP Bio, the adaptive immune system would eventually churn out antibodies tailored to the spike protein, so any future SARS-CoV-2 virus that enters the body will be neutralized and destroyed, even before it has the chance to infect someone.

Solo-Viral Vector-vaccine-27

SARS-CoV-2 Vaccine Vial

Because of this technology, scientists are readily able to create an updated version of the SARS-CoV-2 vaccine within a matter of days, for distribution in around three months. How do they “update” the vaccine? First, the Omicron spike protein is sequenced into their nitrogen bases (A, T, G, and C’s). Once that is complete, scientists use this sequence to create a DNA template. They then mix in enzymes which build an mRNA copy of the DNA template through a process known as transcription.

This process unfolds in a matter of days… so why does it take three months? Creating the physical mRNA for the vaccine takes only three days, but then the vaccine makers need to produce enough mRNA for doses, which would be used the next six weeks in pre-clinical testing on human cells. Once pre-clinical testing is complete and proves the vaccine works as expected, then the manufacturing of the vaccine can begin. The vaccine wouldn’t be released just yet — the next five weeks would be clinical trials and testing, and after that, the updated vaccine can begin rolling out to the public.

Even though SARS-CoV-2 is evolving faster than vaccines can keep up with, past technology was no where near as quick as today’s. In my eyes, being able to produce an updated vaccine in a matter of months is nonetheless a scientific feat. Comment what you feel was a gigantic scientific leap during this pandemic below!

We have vaccines- is the pandemic over?

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On December 31, 2020

In Student Post

Does a vaccine mean the end of this pandemic?

For this portfolio project, I will be focusing on the vaccine development process and how the developing vaccines each prepare the immune system to fight COVID-19. The goal will be to explore the stages of development, testing, and distribution to the public and how these new vaccines function. Since there has been recent progress with a few vaccine candidates, namely the Pfizer and Moderna vaccines, this blog post will be about the implications of vaccine distribution in coming months.

Firstly, a new vaccine does not mean that it will be safe for society to return to normal just yet. While we’re all definitely excited about the news of successful vaccine trials, the effects of vaccination are not immediate, and the goal of herd immunity will not be reached for a little while. Also, the vaccines have not been tested yet on children and pregnant women, and since women around childbearing age are highly represented in the population of health care workers, it is important that the vaccine work for pregnant women. With the trials so far, we do know that there have been no unexpected negative side effects to vaccination, just the typical mild ones such as injection-site soreness and fatigue.

So why is getting a vaccine so important? It’s true that none of the vaccines are 100% effective, but they have been proven to decrease the severity of symptoms. (Both vaccines have reported about 95% efficacy rates in preventing COVID-19.) There are many good reasons to get a vaccine. Not only will it protect you, but it will be a safer path than widespread infection to build herd immunity. Since the trials did not measure rates of infection, it remains unclear whether the vaccines prevent infection and transmission, though results from another vaccine’s trials suggest that it might somewhat protect against infection. Either way, the rate of subjects who became severely ill was lower for those vaccinated in these two prominent vaccines’ trials. The high rates of hospitalization are due to development of severe symptoms, so reducing symptoms would also help to slow the pandemic’s adverse effects.

So, we’ve seen that the Pfizer and Moderna vaccines are effective in reducing symptoms, but that brings us to another question. How do these vaccines work? Both of these vaccines are mRNA vaccines. This means that they deliver synthetic messenger RNA that is taken in by immune cells that then produce the spike protein, just as would happen if the cells came into contact with the actual virus. However, since it is just the proteins, there is no risk of getting infected with COVID-19 from the vaccine itself. The immune system will then recognize the protein as a foreign substance and develop an immune response and produce memory cells that will respond swiftly in the case of seeing that protein again. As we learned, the adaptive immune defense depends on the recognition of the epitope of a virus, in this case the spike protein. After first infection, the memory B and Tc cells that are produced via clonal expansion remain in the lymph nodes until the same virus attacks again. However, this mRNA vaccine removes the need for a first infection in developing adaptive immunity because the spike proteins are produced without the rest of the virus needing to be introduced.

Diagram of how the mRNA vaccine produces the epitope

The lipid spheres surrounding the mRNA fuse with the cell membrane and ribosomes in the cell produce the epitope, beginning the sequence for the immune response.

Now, let’s imagine it’s a few months from now, and the distribution of vaccines has begun. Can we skip the precautions we have in place now? Do we still need social distancing and mask-wearing? Well, until most people are able to be vaccinated, it will be important to maintain safety protocols that reduce the spread. Even once somebody is vaccinated, they will need to follow guidelines, because it takes several weeks for the immune defense to build up, and both vaccines require a booster dose about a month after the first one. Also, we’ve already addressed the uncertainty about transmission after vaccination, so it’s best to err on the side of caution. 

So, even though these vaccines may not be perfect, they will help control the pandemic. The main question that remains is how efficiently and fairly vaccines can be distributed to best reduce deaths and bring about an end to the pandemic.

What is Nanotechnology, and How is it Transforming Vaccine Development for SARS-CoV-2?

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On December 30, 2020

In Student Post

1,000+ Free Covid-19 & Coronavirus Illustrations - PixabayCOVID-19 Spike Protein

In an era of mask-wearing and social distancing, the big question on everyone’s mind is when will things go back to normal? Scientists all over the world have been working quickly and intensely to develop a solution–one that is safe. 

Nanotechnology is the process of manipulating atoms and molecules on a microscopic scale. According to a UC San Diego ScienceDaily Article, scientists have been using this technique to design vaccine candidates for COVID-19. Nicole Steinmetz, a nanoengineering professor at UC San Diego, has been one such scientist. Instead of relying on older vaccine models, such as live-attenuated or inactivated strains of the virus itself, these “next-generation vaccines” are more stable, easier to manufacture, and easier to administer. 

Since June 1 of 2020, there have been more than one-hundred vaccines in play, with more than a few triumphing through clinical trials. Although many may be years away from deployment, the act of their development will prepare our nations’ leaders for future pandemics. 

There are three forms of these novel vaccines in the mix: peptide-based, nucleic-acid based, and subunit vaccines. All of these are alternatives to classic vaccines, which are slower to produce and sometimes pose the threat of inducing allergic responses.

scientist, microbiologist, virus, molecular biology, laboratory, coronavirus testing, COVID-19Vaccine Development

Peptide-Based Vaccines

Peptides are short chains made up of amino acid monomers. Simple and easily manufactured, peptide-based vaccines are typically made from VPLs, or virus-like particles, which come from bacteriophages or plant viruses. They are composed of peptide antigens, and mimic the patterns of pathogens, making those patterns visible to the immune system. However, they do not produce a strong enough immune response on their own, and thus must be accompanied by adjuvants.

Nucleic-acid Based Vaccines

In the midst of a fast-spreading pandemic, the world needs a vaccine that can be both developed and deployed rapidly. DNA and mRNA vaccines have this potential. DNA vaccines contain small, circular pieces of bacterial plasmids that are engineered to target the nucleus and produce parts of the virus’s proteins. They have a lot of stability, however, they also pose the risk of messing up a person’s pre-existing DNA, leading to mutations. In contrast, mRNA-based vaccines release mRNA into the cytoplasm, which the host cell then translates into a full-length protein of the virus. Because it is non-integrating, it does not have the same mutation risks as DNA-based vaccines.  

Subunit Vaccines 

Subunit vaccines have minimal structural parts of the pathogenic virus, meaning either the virus’s proteins or VLPs. These vaccines do not have genetic material, and instead, mimic the topical features of the virus to induce an immune response. 

The Power of Masks

Delivery Development

One of the most important aspects of a vaccine is accessibility and deployment. In the past, when dealing with live or inactivated vaccines, the lack of healthcare workers to administer the vaccines emerged as a significant concern. Yet, through nanotechnology, researchers have developed devices and platforms to ease these previous issues. They have created single-dose, slow-release implants and patches that can be self-administered, removing pressure from health care workers. Open reporting and the mass culmination of data has allowed for this rapid development of vaccine technologies. Because of these revolutionary advancements, some researchers optimistically predict that COVID-19 has the potential to become merely another seasonal flu-like disease over time.

What Lies Ahead

In these bleak times, it is promising to look at such amazing scientific developments. While a good portion of the general public feels skepticism towards the speed at which these COVID-19 vaccines are being produced, and thus claim they will not take it, I believe that the work of these scientists will not go to waste. As a nation, and as a global community, we will get past it, and come out stronger than ever on the other side. 

Now, ask yourself, would you take a COVID-19 vaccine? 

*Sing in Rihanna’s voice* Breath out, Breathe in (mRNA)… American Oxygen!

By

On January 14, 2019

In Student Post

Researches at the Massachusetts Institute of Technology (MIT) have designed a potentially groundbreaking tool for helping treat lung disease. Their design? One might find the answer rather surprising: inhalable mRNA.

What is mRNA?

Also known as messenger ribonucleic acid, mRNA is a subunit of RNA, and is responsible for carrying the genetic information copied from DNA in the form of a code. More specifically, mRNA is synthesized during transcription. As explained in the article, mRNA, “encodes genetic instructions that stimulate cells to produce specific proteins.” Click here to learn more about mRNA.

The Benefits:

Inhalable mRNA? Yes, you read that correctly. Essentially, patients would inhale the mRNA in an aerosol form. By doing such, the mRNA would come into direct contact with the patient’s lung’s cells, which would then trigger the production of “therapeutic” proteins. As stated in the article, such mRNA molecules, “[turn] the patients’ own cells into drug factories.” If done successfully, mRNA has the potential to treat a myriad of lung-related illnesses, cystic fibrosis among them. Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering, expresses confidence regarding the findings, stating, “We think the ability to deliver mRNA via inhalation could allow us to treat a range of different disease of the lung.”

Obstacles:

Presently, scientists face the challenge of targeting cells with the mRNA aerosol molecules by using methods which are both safe and efficient. Additionally, scientists are tasked with the challenge of transporting these mRNA molecules in protective carriers, as the body’s natural reaction is to break mRNA down.

The Experiment:

In order to determine the impact of inhalable mRNA, Dr. Daniel Anderson has successfully manipulated a mice’s lung cells to produce a target protein. Dr. Anderson and his lab have begun designing materials which can transport mRNA to organs such as the liver. In particular, he and his lab utilized polyethylenimine (PEI), as it doesn’t break down easily. However, this very aspect of the polymer has the potential to cause side effects. In an effort to avoid these unwanted symptoms, the team moved on to a biodegradable material called “hyperbranched poly”. To test this material, the scientists converted the material into a droplet form, using a nebulizer to deliver the inhalable mist to a group of mice. Twenty four hours later, the team found that the mice were indeed producing the sought-after bioluminescent protein. Moreover, with the decrease in mRNA dosage came the decrease in protein production.

Pictured above is polyethylenimine (PEI), the initial polymer used in Dr. Anderson’s experiment.

The Future of Inhalable mRNA:

Such developments, such as those performed by Dr. Anderson and his team, increase the potential reality of testing on patients. To read the full findings of the aforementioned experiment, click here.

Could Messenger RNA Be the Future Chronic Disease Treatment?

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On January 12, 2019

In Student Post

What is mRNA and what makes it a good treatment option?

Messenger RNA (mRNA) sends signals to the cells to make certain proteins by changing the genetic coding. So mRNA has the potential to treat a variety of diseases because it can induce cells to make therapeutic proteins. This essentially makes the patient’s body cells into a treatment factory which would give patients a less invasive treatment option.

One of the obstacles with this treatment is how to deliver mRNA to the diseased area safely and efficiently. Researchers at MIT have found a new way to provide patients with mRNA. They made an inhalable form of mRNA. The goal would be to administer the mRNA similar to an asthma inhaler where powered mRNA medication would be sprayed into the lungs but as of now, the medication is only available in nebulizer form. However, there needed to be a way to stabilize the mRNA molecules using an aerosol method. So the researchers experimented with positively charged beta-amino esters which are biodegradable and are more easily broken down by the body. The upside to using a biodegradable material is that there would be a minimal accumulation of the substance in the area it was administered. Accumulation would cause unwanted side effects to the patients’ health.

To test out their new product MIT scientists put the mRNA molecule and polymers in spheres.  Then suspended those spheres in water droplets and distributed a mist through a nebulizer to mice. But the mRNA molecules that they put into the spheres coded for the production of the bioluminescent protein luciferase. Using the code for the bioluminescent luciferase, the researchers would be able to see if the mRNA had effectively made the protein that it coded for if it glowed. 

After 24 hours since administering the medication, the mice were producing bioluminescent proteins in their lungs which hints that eventually scientists could inject the code for therapeutic proteins in the mRNA and the cells would respond.  But as the mRNA levels dropped so did the protein production. That showed that only with repeated doses of the medication the mice would be able to continuously produce their own proteins. They also found that mRNA was evenly distributed throughout the five lobes of the lungs so the mRNA reached all the areas of the lungs which would be helpful in treating cystic fibrosis. This process could be the future treatments for chronic lung diseases as researchers work to make this product into inhaler form instead of the nebulizer for convenience purposes.

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