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Heart Disease: How One Gene Makes All The Difference

May 22, 2019

With a regular human genome consisting of 46 chromosomes and around 20,000 genes made up of 3 billion base pairs of DNA, just a slight alteration to our genetic code is enough to cause us disease.

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Keolu Fox, Geneticist and National Geographic explorer, explains how DNA editing can be used in the future to proviide treatment for common, complex diseases.

Deep within a healthy human body a cell divides and replicates itself, reproducing the precisely detailed double helix of our DNA, the genetic code that makes us what we are. But a mistake is made, a tiny error in the copying of a single base pair of the deoxyribonucleic acid making up gene MYBPC3. It’s a small change, but with huge consequences: It causes a hereditary heart disease. The fact is that for all the significant good a positive lifestyle can bring, some of us are still destined to develop a disease—it’s literally in our genes.

The normal human genome consists of 46 chromosomes with around 20,000 genes made up of three billion base pairs of DNA. Almost every cell in our bodies has a complete set of chromosomes, the microscopic thread-like structures that carry our hereditary genes. These contain the unique arrangement of DNA base pairs that not only give us our fundamental shared anatomy but also our individual characteristics, such as hair color, height, athleticism, and even memory.

Our DNA is constantly replicating itself, but occasionally it makes a mistake called a mutation, and this permanently alters the DNA sequence within the gene. Most gene mutations are harmless, and some can even be beneficial—it’s how humans have evolved. However, other mutations have been identified as the cause of particular diseases, and it doesn’t take a big change to produce problems. Altering just one base pair of DNA—out of three billion—is enough to cause cystic fibrosis, sickle cell anemia, or the common heart disease hypertrophic cardiomyopathy (HCM).

Heart disease is the biggest killer in the United States and HCM is the most common inherited cardiac condition, affecting as many as 1 in 500 people. A gene mutation triggers a thickening of the heart muscles that makes it harder to pump blood around the body. Symptoms range from a slightly irregular heartbeat to sudden cardiac arrest or heart failure, often at a prematurely young age. Because HCM is a hereditary condition, if a child has one parent with the gene mutation there is a 50 percent chance they will inherit it and perhaps develop HCM. There is no curative treatment, but there might be a way to prevent it. As the disease is caused by a mutation in just one gene, correcting that one mutation eliminates the disease. And this is something we may be able to do in the future.

Gene editing is a technique by which scientists can change the DNA of a living organism—plants, animals, and even humans. It can remove, add, or replace segments of human DNA to change physical traits in a way that are either somatic, affecting only one individual for their lifetime, or germline, where they are passed on to future generations. While gene editing could potentially be used to make non-medical enhancements such as specifying eye color or muscularity, the immediate focus is on making therapeutic changes to fight disease—including HCM. “In what may portend a major medical breakthrough, in 2017 a team of scientists working in America claimed to have edited embryos fertilized by sperm carrying the HCM mutation, successfully cutting the occurrence rate from 50% to 28%.

The controversy around testing on human embryos remains (it is illegal in some countries), however the claim is extraordinary. The technology used is called CRISPR-Cas9, and it was adapted from a naturally occurring defense mechanism found in bacteria. Some bacteria capture extracts of DNA from invading viruses and store them as DNA segments called CRISPR arrays, which are used to recognize the virus in the future. If attacked again, the bacteria release an enzyme called Cas that cuts the virus DNA to disable it. CRISPR-Cas9 synthesized this process by creating a guide molecule with the same DNA sequence as the target, in this case the mutation in gene MYBPC3 that causes HCM. The guide molecule was attached to a Cas9 enzyme to create the CRISPR tool that was then microinjected into each embryo. The guide molecule directed the Cas9 enzyme to the matching DNA sequence, where it cut out the mutated strand of MYBPC3 and then copied a healthy version into the sliced section.

CRISPR claimed incredible accuracy, cutting the DNA in the correct position every time. They also claimed to cut the occurrence of HCM nearly in half. The embryos then continued to develop normally until they were terminated as planned. Since then, CRISPR has gone on to edit the HCM mutation into healthy DNA sequences to create samples for medical trials, and studies have been conducted on using CRISPR to help diagnose HCM. There is even research into whether a particular gene mutation that actually protects against coronary heart disease could be inserted into the human genome as a preventative measure.

CRISPR-Cas9 may allow scientists to make precise changes to the human genome more quickly, easily, and cost effectively than before. This moves the world of medicine a significant step closer to the possibility of using therapeutic genome editing to eliminate some diseases from humankind forever. And that brings its own problems. The question of whether we can change a gene has been answered; the question of whether we should now hangs in the balance. There are strong and passionate arguments on both sides, but sometime in the very near future we will have to decide how far we are prepared to go to defeat disease—because changing a single gene really can make all the difference.

To learn more please go to www.natgeo.com/science/questions-for-a-better-life.

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