by Catherine Weiner
figures by Elayne Fivenson

Every cell in our bodies is constantly on the edge of danger. Our DNA, the molecular blueprints that tell our cells how to function, brought us to life. But it is also just one error away from catastrophe. Our cells are constantly fighting to preserve this fragile balance, for if they fail, they send us down a path towards cancer, aging, or disease. Let’s explore a few examples of how our own cells are fighting themselves to keep us alive.

1. Conception

One of the key lessons in pre-school is that 1 + 1 = 2.  But this math lesson is also the first thing our cells learn, too. Each cell in our body contains two nearly identical copies of DNA, one from our mother and one from our father. Each DNA copy is 3 billion bases (or letters) long and is broken into 23 segments, termed chromosomes. Fertilization happens when a sperm cell (carrying 1 copy of the father’s DNA) and an egg cell (carrying 1 copy of the mother’s DNA) combine to form a baby with two copies of DNA. Getting exactly one copy of DNA into an egg or a sperm (via a process called meiosis) is difficult. Our reproductive cells line up all the DNA in the middle of the cell and then physically pull the DNA apart. Ideally, the two resulting egg or sperm cells each have only one copy. If this process goes wrong, however, we can end up with a reproductive cell with the wrong number of chromosomes. 70% of all fertilization events will not result in a pregnancy, and 10% of pregnancies will result in miscarriage, largely due to incorrect chromosome counts. Of the ~300-500 eggs a woman releases in her life, only about 80 will have the correct number of chromosomes.

2. Development

Imagine you had to control 20,000 switches, turning each one on and off at exactly the right time and place. Seems impossible – yet our bodies do it with great accuracy as we develop from a single cell to an organism containing over 30 trillion cells! Embryos growing in the uterus carefully regulate which of our 20,000 genes are turned on and off, and the combination of genes that are “on” leads to that cell’s identity. In this way, our bodies can generate every cell type, from skin to stomach to spinal cord. There are around 8,000 common genes that every cell needs to be “on” to do basic cell things. But there are additional genes that each cell type needs to perform its specialized function (Figure 1). For example, our brain turns on an additional 7,000 genes! Regulating thousands of genes is a complex and challenging problem for developing embryos. Turning on the wrong genes (or failing to turn on the right ones) can lead to embryo lethality, developmental disorders, or birth defects.

Figure 1: Gene on/off status changes during development. During development, thousands of genes are turned on, while many others are turned off. In this example, we follow the on/off status of 4 example genes in both heart (cardiac; top) and brain (neuronal; bottom) development. Notice that each gene is turned on and off depending on both the time of development (embryo vs. fetal) and the type of tissue (heart vs. brain). Also note, that some genes are on in both tissue types (i.e. common genes), while others are only on in the heart or brain (i.e. tissue-specific genes).

3. Wound healing and regeneration

Skinned knees, broken bones, and growth spurts mean our bodies constantly need to generate cells even after we are born. But with all the excitement of embryonic development over, how does our body make new cells? A big part of the answer is adult stem cells. Unlike normal cells, which can only form identical copies of themselves, stem cells can also divide to make new cell types. To do this, stem cells keep the ability to change which genes will be switched on in their “daughter” cells, which normal cells cannot do. For example, a white blood cell can divide to make more white blood cells, but a blood stem cell can divide to make red blood cells, white blood cells, and other parts of the immune system. We also have skin stem cells that are activated when we scrape our elbows, and intestinal stem cells that regenerate our highly acidic gut every two months. Depletion of these adult stem cells with time is thought to be a major contributor to age-related disease.

4. DNA replication

As normal cells and stem cells divide, they must duplicate every single base of DNA, over 6 billion total, to function properly. The machinery that copies DNA is very accurate, only making an error once every 100,000 bases. Yet, this means that each time a cell divides, it makes tens of thousands of mistakes. Yikes! Luckily, the replication machinery has a proofreading ability that will fix 99% of those errors. Some mistakes that remain, however, can be harmful to our bodies and cause diseases like cancer.

5. Energy production

Our bodies are constantly cranking out the energy our cells need. However, the same chemical reactions producing this energy also make a harmful by-product: reactive oxygen species (ROS). Think of ROS as small bullets flying around our cells, damaging anything in their path. Our cells try to catch these pesky particles with a class of molecules called anti-oxidants (which is why people hype eating foods that are rich in anti-oxidants). However, not all ROS molecules can be sequestered, which can be especially dangerous if they collide with and damage our DNA. Any given cell can have up to 70,000 lesions a day from ROS alone! Luckily, our cells are very good at repairing most nicks (single-stranded breaks) in DNA. But, if the ROS snaps our DNA in half, it is catastrophic and will often lead to cell death.

6. Antibody generation

Figure 2: Antibody gene rearrangement. In immature immune cells, there are series of variable DNA segments (green, teal, and orange boxes) and constant segments (blue boxes). The constant segments produce the structure of the final antibody, while the variable regions encode what the antibody will recognize. During immune cell maturation, the variable DNA segments are broken, and a subset is selected and put back together. Through this process, the final mature immune cells will have a different DNA sequence. In this example, immune cell #1 randomly selected green segments 1, 4, and 5, while immune cell #2 selected 2, 3, and 6. Because of the difference in DNA sequence, the final protein antibody that is produced will also be different. The antibody produced by immune cell #1 recognizes the pink virus, while the antibody from immune cell #2 recognizes the green bacterium. For more reading, see this journal article on immune cell recombination.

We each produce upwards of a billion different antibodies that each recognizes a unique foreign entity. However, this is more antibodies than there are genes to make them. So how do our bodies generate antibodies to recognize potential infections? The answer is gene rearrangement. If you randomly draw three playing cards from a deck of 52, you can make upwards of 20,000 different combinations. A similar process happens with the antibody-producing gene in our DNA. Machinery in our cells breaks apart our DNA, picks three DNA segments out of hundreds, and combines them back together into a new gene (Figure 2). Because of the randomness of this process, our immune cells will sometimes produce antibodies that mistake our own cells as foreign. But don’t worry—the body has many ways to prevent these antibodies from attacking us, although sometimes they evade our own defenses (causing what are known as auto-immune disorders).

 

From the moment of conception, through development, and into adulthood, our own cells could turn on us at any minute. This may seem scary, but it is also awe-inspiring. We are alive. Our cells are flirting with extreme scenarios that can result in death, and are (mostly) coming away unscathed. Take it as an opportunity to live each day to its fullest – our cells sure are!


Catherine Weiner is a graduate student in the Department of Genetics at Harvard Medical School. She studies the relationship between transcription and genome stability in budding yeast in the Winston lab.

Elayne Fivenson is a second-year Ph.D. student in the Biological and Biomedical Sciences program at Harvard Medical School, where she is studying the genetics and biochemistry of the bacterial cell envelope.

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