BOLDED SCIENCE
  • Home
  • Blog
  • About
  • FAQ
  • Contact Us
  • Posts By Category

Why is there no Cure for Cancer?

12/28/2020

2 Comments

 
Picture
Cell culture dish with pink liquid
In less than one-year, scientists created two vaccines with over 90% efficiency 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
​

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 cell wall synthesis, killing bacteria and minimally harming ourselves.
​
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 behaviors. Ironically, killing a cancer cell is easy; we do it in test tubes all the time. The challenge is killing the cancer cells in the body without harming 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 specifically kill cancer cells and 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 gene 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, causing abnormal growth.

Having one mutation in an oncogene or a tumor suppressor increases 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 DNA mutations. 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 cell division: 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 protein expressed in healthy cells. 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.
Picture
Diagram of synthetic lethality. Disrupting both BRCA and Parpi genes cause cell death
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.

Author

Kerry McPherson, @KerrySilvaMcph 
PhD Candidate studying biomedical sciences. Researches proteins implicated in cancer chemoresistance. Bolded Science creator and editor. Also co-founded a STEM education outreach program at her University.

Picture
2 Comments

Channeling the characters of Schitt's Creek to get you through your research rough patch

12/19/2020

0 Comments

 
Picture
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."
Moira is the queen of mental gymnastics. Although she hasn't acted in years and is eventually cast for an atrocious low budget film, no amount of failure can convince her she is anything but a star. Imposter syndrome and her peers' facial expressions will never creep past her mental defenses because her self-perception is ironclad. 

How to channel her: The most important opinion of yourself is your own. Self-confidence is the fuel that can propel you through any tough time. Stand tall, speak highly of yourself, and never give in to the nay-sayers. Always take time to celebrate victories — especially the small ones. 
Picture
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."
Picture
Mr. Rose believes that consistent hard work can dig you out of any situation. In the face of defeat, it's time to put your head down, consider a plan of action, and hit the salt mines. Even while unemployed, he rises early for his morning coffee while dawning a suit and tie; a new day is a new opportunity.  

Channeling Mr. Rose: Having a hard time in lab? Is there a lull in your project? There is no quick fix for these problems. Keep on keeping on and better days will come. Rise early and greet each day with a positive attitude, ready to work. Dress in a way that makes you feel confident and prepared for anything! 
Alexis: The eternal optimist
"I don't skate through life, David. I walk through life in really nice shoes."
Like her mother, Alexis holds a unique perspective that bolsters her confidence. She can perceive any situation as "cute," or "fun." Even community service is an exciting adventure with the right attitude and accessories. 

Channeling Alexis: There's a silver lining to everything if you look hard enough for it:
​
PI: I had hoped you would be further along in this project by now.
You: That may be true, but the obstacles in this project teach me patience, and I feel like being a struggling graduate student is a cute look for me right now. 

**Working late to finish an experiment**
You: This is an excellent opportunity for me to enjoy my own company and catch up on my fav podcasts.

Coworker: These experiments are just not working. 
You: I wouldn't say they aren't working, more that adjustments need to be made to make the experiment work. 
Picture
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.”
Picture
David detests test-taking and new ventures because he assumes the worse is going to happen. He also assumes everyone is constantly judging him. Although this mode of thinking contributes to his anxiety, the upside is that he is pleasantly surprised when things work out. 

Channeling David: Set the bar high, set yourself up for failure. Set the bar low, and you set yourself up for success. But don't go so far that you're a pessimist! Although you may worry, remember that you can find success, even when you find yourself with unexpected setbacks.

Author

Kerry McPherson, @KerrySilvaMcph 
PhD Candidate studying biomedical sciences. Researches proteins implicated in cancer chemoresistance. Bolded Science creator and editor. Also co-founded a STEM education outreach program at her University.


Picture
0 Comments

Lessons from training for marathons during my PhD: I can do anything but not everything

12/15/2020

0 Comments

 
Picture
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 1: Don't sign up for everything 
When I initially became interested in marathons, I scoured the internet for advice. A recurrent tip I discovered is to sign up for two marathons per year. This limit allows the body time to recover and helps me stay within my budget as a graduate student. I can't afford to drop $100 for multiple race entries (not to mention additional expenses for travel, hotel, etc.…). I don't sign up for every awesome marathon I come across (at once) because my legs and my wallet would suffer. 

Similarly, graduate students need to resist the potential urge to sign up for every resume-boosting extracurricular opportunity that presents itself. I did this during my first two years in graduate school (and suffered). Moreover, I was superbly stressed out all of the time. While a STEM graduate student's activities should extend beyond the lab bench, it's important not to overextend. Figure out what is manageable and what is worth the additional efforts. For me, I (finally) learned that I enjoy writing-related activities, like contributing to my department newsletter and maintaining my blog, PhDistance.

Training for marathons gave me a second context to evaluate my own urges to sign up for everything, which helped me see it more clearly and reign in the problem. If signing up for "one more thing" seems stressful, don't sign up. 

Picture
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.
Picture
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.
Picture
Lesson 7: Always save a kick
Re: "It's a marathon, not a sprint!" totally applies here as well. When I compose my thesis dissertation that (hopefully!) ties all the work I've done together, I want to be writing with fervor and not fatigue. I want to deliver an entertaining and passionate thesis defense presentation to my department. In other words, I want to sprint to the finish, not hobble across it. I know the feeling of finishing a marathon in each case, sprinting or hobbling, and I prefer the former. Through each of the aforementioned lessons, running marathons has taught me that I can do anything, especially a PhD.  

Author

Ashley Peppriell, MS. @PhDistance
Ashley (Ash) Peppriell is a toxicology graduate student at the University of Rochester in Rochester, New York. In lab, she uses a fruit fly model to investigate how the environmental toxicant, methylmercury, is toxic to developing muscle. Outside of lab, she trains for marathons, supports local breweries, and writes for her own blog, PhDistance. After graduate school, she aspires to become a science writer who covers environmental health.

Picture
0 Comments

mRNA delivery: from bench to clinics

12/7/2020

2 Comments

 
Picture
Image of a syringe.
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. 
Picture

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. ​

Author

Yuezhe Li, @YuezheL
PhD candidate studying biomedical sciences at UCONN Health researching ciliopathy and diabetes. Also loves baking, reading, and traveling.

Picture
2 Comments
    Picture

    Archives

    February 2022
    January 2022
    December 2021
    November 2021
    October 2021
    September 2021
    August 2021
    July 2021
    June 2021
    May 2021
    April 2021
    March 2021
    February 2021
    January 2021
    December 2020
    November 2020
    October 2020
    September 2020
    August 2020
    July 2020
    June 2020
    May 2020
    April 2020
    March 2020
    February 2020
    January 2020
    December 2019

    RSS Feed

Proudly powered by Weebly
  • Home
  • Blog
  • About
  • FAQ
  • Contact Us
  • Posts By Category