The Science of Survivorship

As a cancer researcher, I often wonder about patients after their ordeal with cancer. How does the body change after facing a life-threatening illness? Do cells in our body hold the memory of disease in some way? Survivorship is a word that describes life after a traumatic event, a life in which many aspects of health, from the psychosocial to the physical, are changed. In this blog post, I hope to delve into the cellular level of survivorship and explore how surviving cancer and cancer therapy can alter our biology fundamentally.

All cells in our body contain DNA, which is an instruction manual for day-to-day duties that the cell must perform to sustain life. DNA is what we inherit from our ancestors, our parents, and what we pass on to our children. Therefore, the cells in our body are very careful about keeping DNA intact and unchanged through a biological process called “fidelity.” Interestingly, most cancer patients carry permanent changes to their DNA after treatment. One striking example is to think of patients that receive bone marrow transplants. These patients will always have two different types of DNA in their bodies: their own DNA and their donor’s! In other examples, the patient’s own DNA has minor or major alterations, changing the writing of the instruction manual, which in turn can affect how the manual is read and interpreted.  

If you were to take a look at many different cancer survivors, even long after they have stopped cancer therapy and have been cancer-free, DNA from various different parts of their body would show low levels of damage. What does damage mean? If you think about a china vase, and if you were to drop it so that it didn’t shatter, but merely cracked on the surface, that would be the closest metaphor for what’s happening here. If you consider the china vase to be the DNA, you can imagine that the DNA is damaged but not completely deteriorated. How does this damage occur? During the course of cancer therapy, patients are exposed to drugs or radiation that directly damage DNA. Most of the time, the cancer cells are the ones impacted; however, normal cells can also be affected. The major consequence of damage is accelerated aging in most survivors. Their tissues and cells look as though they are from an individual much older than they are.

Prolonged levels of stress and damage to the DNA from cancer treatment can change the way a cell reads its DNA. Epigenetics is the study of how DNA is read and interpreted in the cell and epigenetic marks on the DNA help the cell figure out which parts of the DNA to read. In cancer patients, epigenetic marks are globally changed over the course of therapy and remarkably these changes remain long after exposure to chemotherapy is stopped. Patients with cancer have more epigenetic marks signifying “do not read” being added to the DNA. In normal individuals, an increase in these marks has been associated with routine aging., In cancer patients, irrespective of chronological age, these marks can be present post therapy, signifying profound molecular aging. What remains to be investigated is whether these marks and their subsequent accumulation in survivors is a direct result of toxicity of therapy or a by-product of DNA damage leading to changes in epigenetics

With roughly 15.5 million cancer survivors currently alive in the US alone, it becomes absolutely critical to understand the biology of survivorship. The science of survivorship helps us understand the biological burden of going through cancer therapy and, in turn, this valuable knowledge allows us to develop less burdensome therapies as a result. From a physical and now a molecular standpoint as well, survivorship is a monumental feat of resilience that comes with an unwanted side-effect: aging.

Peer edited by Denise St. Jean and Eliza Thulson.

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Get Alternative with Epigenetics

Our bodies are marvels of precise control, synchronization and design. Every one of our cells has the same genetic sequence, but we have many different types of cells – heart, muscle, lung, skin. Amazingly, our body has a mechanism to determine which cell is which even though they all share the same code. The field of epigenetics dives into this phenomenon. Epigenetics is a study of changes to DNA that does not change the actual sequence but modify it by repressing or activating certain parts of DNA. In short, epigenetics can reversibly turn genes on and off without changing the DNA sequence.

The genes in our body are like words that have to be spelled a certain way in order for them to work properly. All genes are made up of “base” molecules, which are assigned a specific letter (A, C, G, or T). These bases combine to form 3-letter “words,” or amino acids.  Amino acids serve as the “words” that form the “sentences” or proteins in our body that govern all the biological processes necessary for life. However, none of these biological phenomena could be produced if there are misspellings in the genetic code. Mutations are a misspelling of the original genetic code through deleting, duplicating, substituting or inverting parts of a gene. Mutations are permanent changes to the DNA code which can be passed on from generation to generation. This is the cause of many heritable diseases.

For a long time, genetic changes were thought to be permanent, but reversible epigenetic changes were uncovered around 1950 and have led to an explosion of knowledge in understanding the human body. Conrad Waddington was the first scientist to propose the concept of epigenetics. He studied embryonic development and saw how an embryo gave rise to all the different types of cells, even though every cell had the same genetic sequence. He visualized this model with “Waddington’s landscape,” which used the analogy of a marble rolling down a hill into different troughs to represent the developing cell becoming a muscle cell, heart cell or any other cell.

https://upload.wikimedia.org/wikipedia/commons/5/54/Paisagem_epigenetica.jpg

The marble example that Waddington used to describe an embryonic stem cell becoming other cells.

Alternative splicing is one epigenetic mechanism that allows for cells to be able to choose multiple fates. This can happen all over the body, such as in the brain, heart, and muscle. Our body has many genes, but we only use 2% of those genes to code for proteins, the other 98% are genes that help regulate the protein-coding genes. Alternative splicing is one way that we fully utilize the 2% of our genes that code for protein and accounts for our complexity. Splicing allows for the “word” of one gene to be broken up into many different ways to make many other genes. The word “lifetime” can be broken up into ‘life’ and ‘time,’ but can also be rearranged to make the words ‘fit,’ ‘lie,’ and ‘tile.’ The parts of protein-coding genes can be also be broken down and mixed and matched to produce different proteins. The sites for splicing are determined by the tightness of DNA, the accessibility to DNA, and other epigenetic factors that are still being actively researched.

Emma Hinkle

An example of how alternative splicing can produce different protein products.

Dr. Jimena Guidice at the University of North Carolina at Chapel Hill is actively investigating the epigenetics of alternative splicing in the heart to try to determine why certain heart diseases cause the heart to revert back to fetal alternative splicing as opposed to adult alternative splicing. A few weeks postnatal, the muscle cells needed to contract the heart are not yet mature and have a different alternative splicing pattern to facilitate growth into adult muscle cells. Eventually, the muscle cells are spliced with a different alternative splicing pattern which is a mark of adult muscle cells since these cells are large and can pump blood to the heart more efficiently.

If you’re interested in reading more about epigenetics and its history, I highly recommend Nessa Carey’s Epigenetics Revolution and Siddhartha Mukherjee’s The Gene.  

Peer edited by Deirdre Sackett.       

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