The SARS – CoV-2 vaccine: Invisible tools fighting the invisible enemy

Author: Sudha Neelam

The invisible tool – Our Immune system

As we courageously social distance, embrace the elegance of facial masks, respect the discipline of personal hygiene, the human immune system is enacting its own version of courage, elegance and discipline. Our immune mechanisms are the invisible pillars of strength in this battle against the invisible enemy.

The immune responses are comprised of a series of players; each one orchestrating their unique role to protect our body. They can be broadly classified in to two types: innate immune responses and adaptive immune responses.

The innate immune responses are the body’s first line of defense against infections. Our skin acts as a physical barrier preventing the entry of the infectious agents(pathogens), fluids like mucous help in clearing the disease-causing agents and a cellular response in the form of phagocytic cells that have the ability to engulf and destroy the pathogens help in clearing the infection and alleviating disease symptoms. 

Once the pathogens overcome the innate immune response and gain entry into our system, the adaptive immune response takes charge. The adaptive immune response consists of cells called lymphocytes which secrete antibodies in response to the infection. These antibodies specifically bind to the foreign substances generated by the infectious agent known as the antigens. Pathogens whose antigens are bound to the antibodies are marked for destruction.

Initially the immune system takes several days to identify the pathogen, develop antibodies, bind specifically to its antigens and eventually destroy it. Once the process is complete the immune system remembers the protocol for future battles. It generates what are known as memory cells which hold on to the necessary information for antibody synthesis and once the body encounters the same infection for a second time, the memory cells jump the battle ground fully loaded with the ammunition of antibodies and clear the infectious agents in a much faster and effective manner.

While the innate immune responses cannot get better with repeated exposures to the infectious agent, the adaptive immune responses develop the finesse (in the form of immunological memory and antibody synthesis) to combat the infectious agents. The process of vaccine development takes advantage of this finesse.

 The invisible enemy – SARS-CoV- 2 virus

 Coronaviruses are a family of viruses that mainly cause upper respiratory infections including the common cold. In the year 2002 severe acute respiratory syndrome (SARS) caused by the coronavirus emerged as one of the first pandemics of the 21st century. Social distancing and quarantine measures helped in the eradication of SARS.  The SARS -CoV-2 (severe acute respiratory syndrome corona virus version 2) is a novel coronavirus that causes COVID-19 (coronavirus disease 2019). A virus that is not only invisible/uninvited but also an unknown guest. The SARS-CoV-2 spreads at a much rapid rate than the SARS virus causing severe upper respiratory symptoms and a high mortality rate.

Our immune system has to navigate through the unique novel characteristic of this virus to eliminate it from our bodies. The virus invades, establishes, and conquers its territory inside the host body. This leads to the yin and yang battle between our immune system and the virus. While our immune system works hard to restrain, contain, and destroy the virus, the virus on the other hand tries to dodge the immune responses to thrive and destroy the host.

The severity of the symptoms caused by the virus and the recovery period from the viral infection depends on the number of virus particles the person is initially exposed to and how strong and effective their immune responses are in fighting the virus. While the therapeutics and anti-viral drugs aid in alleviating the symptoms and enhance the survival rates, a stronger, regulated immune response is always beneficial.

A vaccine to the SARS CoV-2 will help in giving the necessary boost to our immune system. It will equip our bodies with significant levels of tolerance to fight the virus without succumbing to its deleterious disease symptoms. A vaccine will remind the uninvited, invisible guests that they overstayed their welcome and it is time to leave.

The Vaccine

Developing a vaccine for the novel corona virus is akin to creating characters that would enact an unwritten script. The script in this case revolves around the viral antigens. Antigens can be proteins, lipids or nucleic acids like DNA or RNA. They are responsible for the disease symptoms like sore throat, loss of sense of smell, chest congestion or cough. They activate the body’s immune response resulting in the generation of antibodies. They determine the plot line of the script (the incidence of disease, type of symptoms and severity/transmissibility of the disease) and when and how the story will end (the length of recovery times and the survival/mortality rates). In this case, we must carefully navigate the novelty of the SARS-CoV-2 antigens in designing and testing the vaccine.

Generally, vaccines are made up of viral antigen fragments, or the viral nucleic acids like DNA or RNA that are either inactivated or weakened such that when they are injected in to humans, they elicit a robust immune response without causing any serious disease symptoms. The viral fragments or the DNA/RNA are packaged into lipid coated liposomes.  The liposomes are spherical vesicles made up of lipids.  The viral antigen fragments or nucleic acids are enclosed within the liposomes and administered into our body. These liposomes will prevent the viral fragments from degradation once they enter the body and deliver them to the appropriate immune cells to induce the immune response and antibody production.

Animal models are used to validate the vaccines before introducing them to humans. Animal models are useful in designing the vaccine, determining the route (oral or intravenous injections)/dose of vaccine administration, the safety and efficacy of the vaccine in inducing an immune response and identifying the duration of the immune response.

Once the vaccine is validated in animal models, the next phase is human testing or what is referred to as clinical trials. This usually happens in several phases. Each phase is designed to test different aspects of the vaccine including the safety, dose, and the extent of immune response. The number of people being tested will gradually increase with each phase of the clinical trials.

Phase I

The primary goal of phase I is to identify the smallest dose of vaccine that can induce a strong immune response without any major side effects.

During this phase, the vaccine is tested in a small cohort of healthy volunteers without any underlying health conditions. The numbers usually are in the range of 10s or 20s. The effective route of administration of the vaccine such as oral or intravenous and the highest dose of the vaccine that can be tolerated without side effects are evaluated. While the preclinical studies in animal models give an idea of the dosage and safety of the vaccine, it is imperative to re-test those parameters in human volunteers. Phase I is not designed to determine if the vaccine is effective against the disease.

Phase II

Once the safety and dose of the vaccine is determined in phase I, scientists move on to testing the efficacy of the vaccine in phase II. The phase II will give an indication of how the vaccine helps in mitigating the disease symptoms, the progression of the disease and the time of recovery.

Phase II consists of patients with the disease symptoms and a cohort of subjects without the underlying disease. The numbers in this phase are usually in hundreds and this study is conducted in a blind manner where the volunteers randomly receive either the vaccine or the placebo. With this large group of people scientists gather information about dose, safety, efficacy, and the longevity of the vaccine over a period of several months.

Phase III

 Phase III will provide information on how effective the vaccine is in mitigating the disease spread, the severity of the symptoms and the recovery/survival rate.

In phase III thousands of volunteers are tested in a double blinded manner. Both the scientists and the volunteers are not aware of who is receiving the vaccine or the placebo. This will eliminate any bias in assessing the efficacy and side effects of the vaccine. Phase III is conducted in a larger group of people who are susceptible for the disease. At the end   Phase III if scientists can demonstrate the efficacy and safety of the vaccine, it will be sent to FDA (Food and Drug Administration)  for approval.

FDA approval and Phase IV

The FDA and will review the results from the clinical trials and determine if there is enough evidence to establish the safety and efficacy of the vaccine. Once FDA approves the vaccine, phase IV is launched. This involves testing the vaccine in hundreds and thousands of patients over a prolonged period of time. This will help in determining the long-term safety and efficacy of the vaccine. Around this time, the manufacturing facility where the vaccine will be produced will also undergo inspection to ensure safe mass production of the vaccine. The FDA will also screen safety, efficacy and purity of each vaccine lot manufactured by the unit.

Normally the entire process will take several years, however given the current pandemic circumstances scientists and FDA are expediating the entire process to come up with a safe and efficacious vaccine in the next 9-18 months. Even with expediated approval and manufacturing process the timeline for administering the vaccine to the general population in order to limit the virus spread will take several months to years.

Battling the invisible enemy

While we are gifted with an abundance of competence to win the battle against this invisible enemy, we seldom understand how to handle the good unless the bad and ugly re-teach us the laws of survival. Our immune system is our number one tool for survival. We need to guard it, nourish it, and cherish it.

Despite the rapid spread of this disease, the severity of symptoms and the disturbing mortality rates, if we can start the battle with a well-equipped army of immune responses, we have a very good chance of winning the battle. However, the ultimate goal for humanity should not be to just survive this battle, but to learn from the battle, win the battle successfully and avoid any uninvited future invasions.

In Greek mythology there is a king called Sisyphus, who was punished for his pompous, conceited, self-aggrandizing behavior by being forced to roll a huge boulder up a steep hill only to have it roll back down every single time it reached the top. Sisyphus ended up repeating this action of moving the boulder up and down the hill for eternity. None of us want to be like Sisyphus yet if we are not cautious, humble and prudent in our actions we all will become one.

Fighting the invisible enemy albeit challenging is not entirely impossible. Scientists are working hard to erase the invisibility and restore normalcy. Meanwhile, each and every one of us can pitch in by accepting the short-term inconveniences and learn to embrace the intangible warmth engulfing our world. 

50 years later: cancer treatment progress report

Author: Martyna Kosno

Despite millions of dollars spent on it and countless hours worked on it, cancer is still one of the primary hazards to humankind. It is so dangerous that WHO listed it as one of the top 10 threats to global health in 2019. So how is it possible that 50 years after moon landing, we still have not cured cancer?

Leading Sites of New Cancer Cases and Deaths – 2019 Estimates; American Cancer Society

According to the National Cancer Institute’s statistics, about 1.8 million people in the US will be diagnosed with cancer by the end of year 2019: over a quarter of a million – with breast cancer and a little under that number – with lung cancer; these are the two most common types. But what about all the rest? Well, it turns out that there is still a very long list of other types of cancer, all of which share one common feature: uncontrolled cell division.

Dividing human cells; red – genetic material (DNA), green – microtubules (fibers that help the cell divide the DNA equally between two cells); from left to right: 1) two cells before division, 2) cell reorganizing its DNA into more condensed form (chromosomes), 3) cell with its chromosomes doubled and aligned in the center, microtubules are attached to chromosomes, 4) cell is dividing the chromosomes evenly to two new cells, by pulling the chromosomes with the microtubules, 5) two new cells are reforming and the DNA comes back to its relaxed form; bigpictureeducation.com

Yes, you read it right – the uncontrolled cell division is the only common aspect amongst all cancer types. All other aspects of this disease are specific to particular kinds of cancer. The major types include:

• Carcinoma – the most common type of cancer, commonly occurs in lungs, skin, breasts and other organs or glands
• Melanoma – cancers of cells that make the skin pigment – they are different from skin carcinomas
• Sarcoma – group of cancers of bone, muscle, fat, cartilage and other types of connective tissue in our bodies
• Lymphoma – a type of cancer that attacks lymph nodes
• Leukemia – cancer of blood or bone marrow – usually does not form solid tumors.

As you can see, even under these major categories, there is still a more specific subdivision to many different organs or types of cells. So just like we cannot treat all bacterial infections with the same type of antibiotic, we cannot treat all cancers with one, magical medicine. What treatment a patient receives depends on a multitude of different factors: where is the tumor located? What stage of cancer is it? What molecular mechanisms govern this specific type of cancer? Are there any characteristic genetic alterations that have occurred in the patient’s organism? Because we are so diverse, every person will respond differently to a given type of treatment and that is why a specific cancer treatment needs to be tailored for the particular needs of a given patient.

Schematic illustration of DNA – one of the reasons why people are so diverse, also in terms of disease treatment; news.liverpool.ac.uk

When President Richard Nixon in his 1971 State of the Union Address declared the war on cancer, nobody expected that this war will take so long and that it will so often feel like we are losing. So are we losing or not? Despite the many diagnoses and many deaths projected for the upcoming years, there has been a lot of success in the cancer treatment and diagnosis, including among others:

• Major development in curing pediatric leukemia, which used to kill ~90% of children suffering from it decreased to ~10%
• The availability of Human Papilloma Virus (HPV) vaccine now protects women from the most common causes of cervical cancer
• Immunotherapy – based treatments, which use the defense system of our organism to fight pathogens earned a Nobel Prize in 2018 and have already helped multiple people around the world
• Generally, number of the cancer survivors has doubled over the past 40 years – as a more specific example, American Lung Association reports that the survival rate of lung cancer patients in the United States increased by 26% over just the past 10 years!

Therefore, even though some types of this horrible group of diseases are still frustratingly difficult to treat, the advancements of 21^st century’s research hold great promise for future cancer treatment development. Let’s see what new discoveries scientists will present to the world in the field of cancer treatment in the coming years.

Bioprinting: Phenomenon or Potential?

Author: Joshuah Gagan

I don’t think I am the first person to be astonished by 3D printing. Then again, I’m not sure if I am the second person to be astonished by 3D bioprinting, a phenomenon that has been consistently evolving in the past decade. The launch of such a huge biomedical advance has put scientists on a course to change the future, where every biomedical lab will have a bioprinter ready to disperse samples of cells, tissues, and one day organs. But a phenomenon can only last so long until it loses interest. By that I mean when, relatively, will we start inventing the next revolution in technology? As of today, the furthest advancement in bioprinting was the full-scale print of an artificial kidney, an almost-perfect structure with vascularity and function. But that was 2011. We’re close to 2019, and nothing has happened so far. So what will?

I’d like to think a ‘hype’, or as it is traditionally called a fad, can last as long as the audience can be engaged before it becomes a dud. But such a scientific field shouldn’t be necessarily a phenomenon, especially in our biomedical community. Yet, it’s treated as one. There aren’t many scientists utilizing the advances behind bioprinting as most underestimate it’s potential. Most labs even consider bioprinters as a paperweight, collecting dust in a corner. The possible reason: today, there is no use for bioprinting, as a majority of its industry has no real understanding of the field itself.

For what it is, it’s a great field to enter into. Besides it’s wow factor, bioprinting accelerates the scaffolding process for tissue engineers, increases accuracy, and rapidly develops structures in less time than it would by hand. This is a critical achievement, as tissue replacement and organ production can save millions of lives on the organ donor list. There are even multiple articles that reference advancements and treatments on bioprinting. Some examples include in situ wound healing/skin regeneration for burn victims, revitalized tissue replacements for sensitive tissue areas including the heart and lungs, and in some cases, regenerated full organs including ears, noses, and hearts (though pending).¹

Ergo it begs the question of what barriers prevent technologies like these from coming into healthcare. And the answer is overestimation. Several companies in the mid-2010s came out to claim bioprinting is capable of reproducing organs through their novel printers. Companies, such as BioBots, Organovo, and RegenMAT have all at some point claimed to conceive an organ in production. However, it was stated as more of an accessory to their long-term business plan, though advertised differently in media and conferences. Truth is, only one doctor has actually printing an organ, and that same doctor admits that there are many steps to take before producing organs on a larger scales. Bioprinting is not just by clicking a button and the organ comes to life.” this is actually a new technology we’re working on now. In reality, we now have a long history of doing this.”² There are multiple biomolecules and several other interactions that occur in the biomaterials that require investigation before pursuing these innovations.

He’s not wrong. In fact, bioprinting is summed up as printing out biomaterials with cells injected, in hopes of producing tissue. Overall, there are just a few more ink reservoirs with their own extruders, each containing growth factors or cells. The real question is: how do we organize all of the components to create artificial tissues or organs? And that is really the science behind it. It’s highly improbable to print out all of the materials in hopes of producing something organic. But what we can work on is understanding why and how these artificial tissues work to an advantage in bioprinting tissues. That is where it’s true potential lies.

Although vascularization is one thing, there are many more aspects of bioprinting to be researched. In the past few years, a couple of different advancements have come about to revitalize the field. Rather than try to resurrect it as a phenomenon, scientists are changing the community’s perspective into reality. Most focus has been on vascularization, a subfield in bioprinting has not yet been well developed. Carnegie Mellon is pushing boundaries by influencing new techniques into vascularization, such as FRESH printing. This allows the printer to dispense material into a gelatinous structure and keeps the mechanical integrity of the printed structure. It not only keeps it stable but also controls the rate of flow and prevents error in prints. The idea was conceived in 2015 and some articles have attracted keen scientists to the subfield. If there is enough evidence to support it, it can definitely accel the process of transplanting organs entirely.

But it’s promise and potential are enough to encourage scientists to give their support and reinvigorate bioprinting. Perhaps today from now, one will witness the potential behind artificial tissues as they are implanted into someone’s heart. Today from now, no one will have to be impatient to await tissue implants and skip the line. Today from now, we’ll see bioprinting at its pinnacle instead of imaging what good it can bring.

(The question is: what do you think the world will look like when you know you can print an organ?)

References

1. Nature, 2015, https://www.nature.com/news/the-printed-organs-coming-to-a-body-near-you-1.17320

1. TED, 2011, https://www.ted.com/talks/anthony_atala_printing_a_human_kidney/transcript
2. Science Advances, 2015, http://advances.sciencemag.org/content/1/9/e1500758.full

TCGA and Working in Big Science: A Medical Student’s Former Journey In Cancer Genomics

Author: Galen Gao

Two months ago, I had the opportunity to attend and present two posters at the TCGA Legacy Symposium in Washington, DC. As a sort of final capstone and celebration of The Cancer Genome Atlas (TCGA) and the associated Pan-Cancer Atlas, it was an exciting opportunity for me both to showcase my own work and to see what other scientists from across the world have been working on in the realm of cancer genomics. Spanning topics from genomic ancestries’ contributions to cancer risks, to improved identification of outliers in high-dimensional gene expression data, the quantity and diversity of projects presented at the symposium served as an excellent testament to the resources that TCGA was able to provide the scientific community.

Launched in December 2005, The Cancer Genome Atlas was a massive undertaking by the NCI and the NHGRI to comprehensively characterize a wide range of malignancies. Blossoming from a small pilot program of 206 glioblastoma patients, it grew to profile over 11,000 cancer patients representing 33 different cancer types through a diverse array of platforms encompassing SNP microarrays, methylation arrays, whole exome sequencing, and several more. Together, the information currently totals an impressive  2.5 petabytes of data. To summarize the findings of this extensive dataset, the Pan-Cancer Atlas was then launched as a collection of analyses across these multiple cancer types that explore broad themes of oncogenic processes, signaling pathways, and cell-of-origin patterns in these cancers. This September’s TCGA Legacy Symposium and the preceding publication of 30 PanCanAtlas papers in April 2018 have been fitting capstones of these endeavors and effective demonstrations of how applying large scale bioinformatic efforts to over 10,000 tumors can help uncover novel insights into tumor biology.

As a member of the Cancer Genome Atlas Research Network that spearheaded TCGA and the Pan-Cancer Atlas, I had the exciting opportunity at the symposium to finally meet many of my colleagues in person for the first time. It was wonderful to associate some faces to the countless voices I had listened to and worked with via telephone calls over the past 2 years before joining UT Southwestern. For me, working with TCGA was an eye-opening experience into the world of modern cancer genomics and its gradual evolution over the past decade. While I had taken classes in general biology and data analysis and statistics as an undergrad, I had no formal background in cancer genomics, and I remember spending much of my first few days of working on the Pan-Cancer Atlas wondering when my group would finally realize that they had made a huge mistake hiring a confused kid who had somehow stumbled his way through college and into the world of modern cancer research. Nevertheless, for two years, I had the privilege of working with and—very importantly—learning from many other researchers from across the nation and even the world, as we collectively tried to understand and characterize these cancers together.

As I left the hotel for the airport on the morning after the symposium had ended, I was able to reflect on my whirlwind 2-year introduction to cancer genomics and the role it had played in my scientific development. Although, with the symposium, TCGA has now officially drawn to a close, and my own daily worries have shifted from finding molecular associations in cancer to memorizing cranial nerves in medical school, the legacy of TCGA and the lessons I learned from my time there will carry on. Heralded as the “End of the Beginning” of cancer genomics, TCGA now serves as a template for “big” and “open” science, operating at a scale that far exceeded the capabilities of any single institution on its own to undertake at the time and making all of its data freely available to the general public for further mining and analysis through the Genomic Data Commons. Further, TCGA’s discoveries undoubtedly will affect my future in the clinic too. Already, starting with the earliest findings from the glioblastoma pilot project, discoveries announced in TCGA publications are beginning to redefine traditional, histological classifications of tumors in terms of molecular markers instead. While I had not planned for a 2-year hiatus between undergraduate and medical school, I can definitely say that I am more than happy to have both learned from, and played a small role in the story of TCGA. With the close of the TCGA Legacy Symposium, an entire decade’s worth of work can now help springboard the next chapter of both my career and that of many others in the scientific and medical community who have helped guide and inspire me. Here’s to the next decade of cancer genomics.

Protein Detective: Searching for Protections from Neurodegenerative Disease

Author: Sofia Bali

This summer SPEaC hosted its very first Science Sketches workshop with Dr. Lisa Dennison, Founder of Science Sketches. The workshop was a few weeks long in which a group of students described their research interests in 2 minute videos. Here is one of the videos made by our student and SPEaC exec board member, Sofia Bali.

Many neurodegenerative diseases, including Alzheimer’s, are characterized by large clumps of proteins called amyloid fibrils. Learn more about how these structures form and how Ph.D. student Sofia Bali is searching for regions within proteins that protect them from clumping together. Sofia is conducting her research in the lab of Dr. Lukasz Joachimiak – visit joachimiaklab.wordpress.com/ to learn more.

Brain Health and Awareness; How your mind can fool you.

UT Southwestern scientist trainees from the Science Policy, Education and Communication (SPEaC) Club presented several demos about the Brain at Bachman Lake Library on January 12, 2019. There was several exciting exciting demonstrations: how neurons signal, where you could model some of the different types of neurons; what the brain looks like, where you could use clay to model brains from different species; and a real brain for participants to see and hold. We connected with local families and got to share some of the intricacies of our mind. The demos were for all ages and there was lots of enthusiasm from young children all the way to their grandparents.