In less than one-year, scientists created not one, not two, but three vaccines with over 90% efficacy for Covid-19. Which begs the question, what gives? Why don't we have cures for all our other ailments? After spending billions of dollars on cancer research for decades, where is that cure? Regrettably, there is none. And it's not in a vault protected by the government and big pharma either. The reality is, cancer is extremely hard to treat, study, and understand.

Infectious disease vs. cancer
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Infectious diseases are easily targeted in comparison to cancer cells. Bacteria have a unique cell wall compared to animal cells. Some antibacterial medications attack their membranes and cell wall synthesis, killing bacteria and minimally harming ourselves. Bacterial enzymes differ from animal enzymes, too. Newer antibacterials inhibit bacterial proteins, leaving our enzymes unperturbed. Viruses are also easily distinguished from our cells. They produce their own distinct proteins and have unique genes. We use vaccines to train our immune system to be alerted to their "foreign" presence.

But cancer cells? They're a bit trickier than bacteria and viruses.

What is cancer?

Cancer is a mass of our cells that have uncontrolled growth, avoidance of cell death, and the annoying habit of acquiring genetic mutations that enable unwanted behavioral adaptations. Ironically, killing a cancer cell is easy; we do it in test tubes all the time. The challenge is killing the cancer cells and not our healthy cells. Unlike bacteria and viruses, cancer cells have our genes, our proteins, and our molecular machinery. So how do we kill cancer cells inside a human body?

The answer lies in the research. Through years and years of experimental research, we are learning what makes cancer cells tick. By figuring out how cancer cells behave differently, anti-cancer drugs can be designed that do not harm non-cancer cells.  

What makes a cancer cell?

It all comes down to abnormalities in the DNA. Genetic mutations can be inherited from your parents, acquired over time due to general wear and tear, or result from environmental stress (cigarette smoke, UV, etc..). 

We have an increased susceptibility to cancer when an oncogene or tumor suppressor is mutated. Oncogenes are genes that contribute to cancer if they are over-expressed or hyper-activated, i.e., epidermal growth factor receptor (EGFR). Tumor suppressors are genes that, if turned off, contribute to tumorigenesis. The most famous tumor suppressor is P53, a protein that signals cells to die. When P53 is weakened or inactivated, cells don't die when they are injured or malfunction.

Having one mutation in an oncogene or a tumor suppressor may increase the probability of getting cancer, but it won't cause cancer on its own. An estimated 2-6 cancer-related genes must be mutated for tumorigenesis, and further mutations can contribute to disease severity.

Barriers to treating cancer.

​Cancer is a heterogeneous disease. When we refer to cancer, we are not mentioning one disease, but a family of hundreds of diseases. A treatment that works well for breast cancer might not necessarily work for pancreatic. To complicate matters further, each tumor can be characterized by its unique genotype, meaning that not every patient will respond to treatment similarly.  

Cancer cells mutate and adapt. After wrapping your head around the infinite permutations of cancer types and genotypes, also consider that an individual tumor may be heterogeneous as well. Cancer cells divide so quickly in stressful environments that they often incorporate mutations during DNA replication. Mutagenesis creates subpopulations within a tumor, causing issues such as metastasis and chemotherapy resistance. 

The difference is subtle. As mentioned, the drug designed to kill cancer cells shouldn't poison the rest of our body. But if the difference between the cancer cells and our cells are only 2-6 genetic mutations, designing a specific drug is no trivial task. Currently, most chemotherapies are designed with one of the following anti-cancer strategies:

• Attack proliferation: A hallmark of cancer is rapid cell division. A key component of cell division is complete replication of the cell's genome. Therefore, many cancer drugs impair DNA replication machinery, impede DNA repair proteins needed for replication, or create DNA damage that will block DNA replication. Unfortunately, these chemotherapies also attack healthy cells that divide quickly (hair, nails, muscle, and GI tract cells), causing common side effects like hair loss, loss of appetite, and fatigue. Toxicity to neuronal, kidney, and heart tissue is often the dose limitation for these drugs.
• Target the mutated protein: Drugs can be designed to recognize the mutated protein specifically while having limited recognition of the wild-type protein. For example, inhibitors have been created for EGFR with activating mutations found in some non-small cell lung cancers. Additionally, vaccines targeting mutated KRAS proteins, commonly found in lung, colorectal, and pancreatic cancers, are undergoing clinical trials.
• Induce synthetic lethality: Synthetic lethality is a phenomenon where disruption of two genes of similar function causes the cell to die, while only disrupting one of the genes allows the cells to live. The concept is simple, identify a mutated gene in cancer, and find a second gene to inhibit pharmaceutically to kill the cancer cell. The synthetic lethal concept was recently used to develop Parp inhibitors, a chemotherapy used to treat BRCA deficient cancers. The successful creation of Parp inhibitors jumpstarted a movement in cancer research to discover other genetic synthetic lethal relationships of genes commonly mutated in cancer.

Modeling Cancer. Early cancer research takes place in test tubes. Protein function and structure are investigated in solution, while cancer cells are manipulated in dishes. When in vitro studies seem promising, experimentation moves on to mouse models. Unfortunately, what works well in a test tube often does not work well in the body. And sometimes, a drug that works marvelously in a mouse is toxic to humans. Therefore, preclinical studies are tweaked and repeated extensively to ensure that clinical studies are as safe as possible. Computational models can help bridge the gap between animal testing and human testing, but with limitations. On average, it takes 30 years from drug design to clinical trial approval. And as careful as scientists are during those 30 years, cancer clinical trials have the highest failure rate. Most trials fail due to adverse side effects (aka: when the drug also attacks our healthy cells).

So, will there ever be a cure?

To answer that question, we'd have to define the word "cure." A cure is a gold-standard treatment to eradicate or alleviate a disease completely. To date, only two diseases have been successfully eradicated from the earth, smallpox and rinderpest (both viruses that were wiped out by vaccination — yay, vaccines!).

Likely an end-all cure to cancer is not in our near future. But wait! Before you close out of this blog post, annoyed by my pessimism, I have a message of hope for you. Although "cures" are not on our immediate horizon, adequate treatment and prevention are already here — with more to come. Let's look at breast cancer as an example. In 1971 the 5-year survival rate of all breast cancers was 53%. Today, the 5-year survival rate is nearing 90%! Encouraging numbers, to say the least, these stats are representative of the advancements made in cancer research.

Cancer researchers have chosen an arduous career, often riddled with disappointment and setbacks. Although earth-shattering, groundbreaking discoveries are preferred, in science, it's often the small victories that will culminate in clinically relevant treatments. Cancer research may seem slow, but it is undoubtedly progressing.

If the Rose Family of Schitt's creek can have their estate repossessed and forced to live in a motel within a one-horse town, you can survive any misfortune your research career throws your way. Rough patches are a given in research. Grant rejections, failed experiments, and criticisms; oh my! So, how do scientists cope during the downturns of the research roller coaster? We have our ways. But if you feel hung out to dry and have difficulty seeing through the fog, it's time to channel some experts at maneuvering through tough times.

Moira: Reality shifter
"You are blind to Reality and for that I am most Proud."

Johnny Rose: No school, like the old school.
"Let me explain something about business. It's a dance. And sometimes you lead. And sometimes you follow."

Alexis: The eternal optimist
"I don't skate through life, David. I walk through life in really nice shoes."

David: Classic overthinker 
“He told me he doesn’t want my help, so I’m just going to play the supportive partner and watch him fail.”

You learn a lot about yourself in graduate school. The same is true while running a marathon. Signing up for either is a great way to realize your masochistic tendencies. Jokes aside, continually working towards two immense challenges has taught me several valuable lessons that I share here.

Lesson 2: Focus
Whether it be training for a marathon or completing your PhD, it's essential to maintain focus on the goal, despite challenges. Marathon courses tend to pass through the main roads of whichever city is hosting the race. To not get lost (or disqualified), runners should not stray from the course -- no matter how intriguing side streets or trails along the way may seem! While many runners race without issue, others find themselves lost by accident. Those in the latter category will undoubtedly take longer to finish -- unless they pick up the pace once back on track! How stressful! Now, replace the concept of "marathon course" with "PhD timeline." You get the idea.

Lesson 3: Pace yourself
In each marathon I've run, there was always some person shouting reminders, "it's a marathon, not a sprint!" In my first two marathons, I failed to heed the warning. I tried to keep pace with more advanced runners early on. As a consequence, I would tire before I was even remotely close to the finish. I have since learned to avoid this miserable fate. In my last marathon, my mile splits were negative, meaning that I started at a slower pace and progressively ran faster as the race went on. As a result, I enjoyed the race more, performed much better, and I was happier overall. 

Progressing toward a PhD requires a steady pace as well. Before my qualifying exam, I frequently had 10+ hour days in the lab, usually running at least three experiments at once. I churned out data fast. On one occasion, I was mistaken for a more senior graduate student during a data talk because I had done so much. It felt good, but the compliments were unintentionally toxic; I craved more appraisal.

Long story short: I became burnt-out. After passing my qual in September 2019, I entered a lull period for a few months. Sprinting the start of my PhD has surely helped me look productive on paper, but I became worried that I would head to the finish fatigued. 

Lesson 4: Recovery is important
Before training for marathons, I didn't realize how many physiological systems are taxed and need recovery following a race. After a hard run, your muscles, central nervous system, and psyche need time to recover. Moreover, each has a different recovery timeline. The muscles may recover in a day or two, while the CNS needs more time, and who really knows about the psyche, TBH. 

The CNS needs to recover after working hard during research too. A typical week for a graduate student can involve planning, problem-solving, project management, writing, and executing experiments. These are strenuous activities, especially when done altogether. I've learned that a whole-body recovery from both physical and mental fatigue is essential for long term success.

Lesson 5: It's better with a buddy
I used to prefer solo running, convinced that it was easier to be self-sufficient. However, it's tougher to run alone, without much-added benefit. I realized having a running-buddy is way better. In particular, running with friends makes it easier to stay motivated, especially in the early mornings, through bad weather, and during the last mile of a race. I learned the value of a buddy translates to the lab for the same reasons. My labmate is a great friend, and his presence alone helps me feel motivated and keep going when the going gets tough.

Lesson 6: Fuel up 
Consuming sufficient nutrients before, during, and after a marathon is essential. In my first marathon, I neglected to fuel myself. So, during my second marathon, I grabbed fuel (i.e., sports drink, orange slices, gels) at every mile marker where it was available, and I was less fatigued because of it.

The academic equivalent of sports fuel is probably free food at seminars. In addition to nutrients, food can also provide a mental break. I'm borrowing Michael Pollan's idea of table fellowship here: the exchanges we have with our friends around a table can be equally as filling as the meal itself. Sitting down to share a meal is mentally rejuvenating and helps prepare me mentally for the next day in the lab or a morning race.

Recent developments of mRNA vaccines to protect people from SARS-COV-2 are making headlines. The first two successful mRNA vaccines, the immunization jointly developed by Pfizer and BioNTech and a second vaccine developed by Moderna, are turning mRNA vaccines into a household topic. For many scientists, this is not only great news for public health but also a proof-of-concept that mRNA vaccines can work! Today, I'll share with you some significant scientific discoveries and principles that make mRNA vaccines possible. 

What is mRNA?
mRNA is the abbreviation of Messenger RiboNucleic Acid. As the name suggests, it is responsible for relaying messages encoded in DNA molecules to protein production in cells. 

The synthesis of mRNA, a process called transcription, is carried out by RNA polymerase. tRNA molecules help to bring in the bricks needed for protein synthesis. For mRNA vaccine production, mRNA synthesis starts with a DNA template, and the mRNA molecules are synthesized using a phage RNA polymerase. 

How do mRNA vaccines work?
COVID mRNA vaccines function by delivering the mRNA that encodes spike proteins. Spike proteins are a protein on the surface of the SARS-COV-2 virus, and it plays an essential role in facilitating viruses to enter the cell. By delivering mRNA molecules that encode this protein into human bodies, cells inside the human body will synthesize this spike protein and prime the immune system accordingly. A diagram from Bloomberg news summarizes this well. 

How is mRNA delivered?
Most of the mRNA vaccines encapsulate mRNA molecules in lipid nanoparticles. Other delivery methods in RNA therapeutics include using polymeric nanoparticles comprising of RNA and cationic polymer. For small interfering RNA (siRNA), conjugating RNA to N-acetylgalactosamine, which targets receptors on hepatocytes for uptake, is also an option. 

What are the difficulties for mRNA vaccine development?
The hurdles for developing an effective mRNA vaccine can be divided into two parts: (1) mRNA cannot enter the cell intact, and (2) it cannot be translated into protein efficiently. 

• mRNA cannot enter the cell intact. 
  • Naked mRNA molecules are not stable. mRNA is easily degraded by nucleases. Thus, protecting these mRNA molecules is a hurdle that must be overcome. 
  • Naked mRNA cannot enter cells through free diffusion. mRNA molecules are large and negatively charged, meaning they cannot passively pass through cell membranes. 
• mRNA cannot be translated efficiently.
  • Naked, single-stranded RNA triggers cells' antiviral defense. Cells generate an immune response that results in active degradation of these mRNA molecules. Consequently, no protein-of-interest can be synthesized. 
  • Non-optimal codon usage (e.g., Use of rare codons or codons with low tRNA abundance). mRNA has a specific code wherein every three bases (drawn from a pool of A, U, C, G, and other modified bases) encodes an amino-acid needed for the protein. Strangely, some codes work better than others. Non-optimal choice of codes (base combinations) may result in bottlenecks in protein yield during translation. 
  • mRNA forms improper secondary structures. mRNAs can fold upon each other, causing secondary structures. Some secondary structures of mRNA hinder the binding of polymerase or other regulatory components that result in inefficient protein synthesis. 
  • Non-optimal regulatory regions (e.g., 5'UTR, 3'UTR, ployA tail). Non-optimized regions of mRNA that do not directly code for protein production may lead to insufficient binding of regulatory protein complexes that promote the translation of mRNA. 

What are the scientific discoveries that help to overcome these problems?
Most of the work falls into two categories: (1) direct mRNA modifications and (2) optimization of delivery particles. 

• Direct mRNA modification. 
  • Chemical modification of mRNA molecules. Most of the chemical modifications focus on either minimizing cells' antiviral defense or improving mRNA's stability. Modifications include capping mRNA at 5' end, modifying the sugar backbone of mRNA (e.g., methylate 2' hydroxyl group, add Amide-3 linkage), and modifying the mRNA (e.g., methylate cytidine, modify uridine to 5-Bromo-uridine). 
  • Codon optimization. mRNA codes can be changed to exclusively use codons with high tRNA abundance, and tRNAs expressed efficiently in a specific tissue. Codons can also be optimized to minimize pesky secondary structure formation. 
  • Regulatory region optimization can lead to improved binding of regulatory components to enhance protein translation and improve mRNA stability. No gold standard for this method has been developed yet. However, development in bioinformatics tools is improving this standard practice. 
• Optimization of delivery particles
  • Lipid nanoparticle engineering. Many efforts have been made to increase mRNA stability by adding lipids with positive charges (as mRNA are negatively charged) to improve cells' uptake of mRNA particles and promote endosome escape. 
  • Addition of chemicals in lipid nanoparticles. One example is to add MPLA, a chemical that impairs antiviral defense and promotes T-cell activation. 

What are the differences between the Pfizer and Moderna vaccines?
Both vaccines use lipid nanoparticles to deliver mRNA that encodes SARS-COV-2's spike proteins. However, because specific formulations are secret, the exact differences are unknown. Yet, it is speculated the differences in the lipid components are the reason why Pfizer's vaccine needs to be preserved at an ultra-cold temperature. In contrast, Moderna's vaccine can be shipped in a regular freezer. The difference in lipid composition may also explain why the Pfizer vaccine results in fewer side effects.

What else to look for?
Moderna's mRNA vaccines against other infectious diseases, such as its Zika vaccine currently in clinical trials, are worth watching. It posted encouraging Phase I clinical trial data and may come to the market sometime in the future. 

Other applications of mRNA vaccine technology include immunizations for cancer, such as a cancer vaccine jointly developed by Moderna and Merck that targets common mutations in KRAS, an oncogene that is often mutated in cancer patients. ​