The Sequence 3/13-3/19
Gene Editing Prevents Hypertrophic Cardiomyopathy, Why Your Fingerprints are Unique, New Insights into the Three-parent Baby, Kenya May Be Turning to GMOs
Gene editing prevents hypertrophic cardiomyopathy in mice and human cells
Hypertrophic cardiomyopathy (HCM) is a condition in which the heart muscle becomes thicker than normal. The thick muscle makes it difficult for blood to leave the heart, forcing the heart to work harder to pump blood. HCM can be caused by some genetic mutations, or harmful changes in the DNA. Inherited HCM is associated with onset early in adulthood and with high rates of adverse outcomes, including heart failure, arrhythmias, stroke and sudden cardiac death. HCM is estimated to occur in one in 500 individuals, and is the leading cause of sudden cardiac death in people under 35 years. Two recently published articles both found ways to successfully prevent HCM using gene therapy.
Cool. What did they find?
The two papers that came out evaluated different strategies to ‘edit’ or ‘silence’ one of the well-known mutations causing HCM (R403Q in the MYH7 gene) in mice.
Let’s start with the basics: one of the ways to accomplish gene editing is to send tools to do that editing into the cells with a virus. Almost like a costume or a cover-up to get invited into the cell. Once the virus is in, the gene editing tools can do their thing. In the case of these experiments, the scientists used an adeno-associated virus-9 (AAV9) vector.
After sending in the AAV9 vectors carrying RNA-guided adenine base editor (ABE8e), the teams corrected the pathogenic variants 30-80% of the time, resulting in durable, normal cardiac structure and function.
Awesome. What’s the takeaway?
Gene therapy for HCM was successful! According to co-author David Liu, the mice who received gene therapy had “complete rescue of heart wall thickness”. Incredible, because no treatments currently exist to reverse HCM. Currently, the only preventative measure to take includes an implantable cardioverter-defibrillator (ICD), and sometimes medications such as beta-blockers and calcium-channel blockers.
Have a history of sudden death in your family that may be indicative of a genetic susceptibility to cardiac disease? Find a genetic counselor to speak with about your potential risk for cardiomyopathy here.
And more on these topics:
This article talks about how a history of atrial fibrillation (afib) affects your risk of cardiomyopathy
This article talks about others who have been treated with gene therapy
Why your fingerprints are different from everyone else’s
We all know our fingerprints are unique. This is why fingerprint-matching can be used to solve crimes, and why you may have been fingerprinted if you ever participated a background check. But why are they different? This is what James Glover and his team at University of Edinburgh have found out.
It has to do with epigenetics and math
As a reminder, epigenetic changes affect gene expression to turn genes “on” and “off”. You can read a fuller description in this past Sequence post. In this case, cells on the epithelium, the tissue forming the outer layer of the body’s surface, turn on genes that decide how epithelial cells migrate, differentiate, and mature. Glover and his team found that the process is actually very similar to the development of hair follicles, except while hair follicles go on to form tubes where hair will eventually grow, fingerprint cells prevent these tubes from forming.
This is where the math comes in. This constant process of activating cells and then inhibiting growth seems to set up a Turing pattern, a phenomena in physics that explains patterns from zebra stripes to stripes on sand dunes.
What’s the takeaway?
For me, it’s the incredible patterns surrounding us in nature that are, by definition not random but repetitive, that are awaiting our discovery. For many, it is the opportunity for therapeutics, for example for some conditions that affect the skin, that can be made by understanding how genetics forms parts of our epidermis, like our fingerprints.
On a personal note, I was fortunate to gain insight into Alan Turing’s work this past summer during a tour in Manchester, England where we made a stop at the University of Manchester in memory of Turing’s work on the Turing machine, and in memory of the incredible mathematician that Turing was. This connection to his work in my world of genetics is a beautiful one.
Finally, this website allows you to make your own Turing pattern. Give it a try! My artwork is below:
New insights into the three-parent baby
I remember clearly when the news broke in 2016 that scientists had done it: created a three-parent baby. It was exciting, although somewhat controversial, as this was an experiment that was certainly unprecedented. Seven years later, we have some insight into the results of such a procedure.
Why a three-parent baby?
People get half of their DNA from dad and half of their DNA from mom. That is to say, their nuclear DNA. There is a third source of DNA everyone also has- their mitochondrial DNA. Mitochondrial DNA can only be passed from mom. Just like nuclear DNA, mitochondrial DNA can have mutations that cause disease. The three-parent baby is a way to conceive with nuclear DNA from mom and dad, but the mitochondrial DNA from another person, so as not to pass on the mitochondrial disease. In the case of the first baby born out of this technique in 2016, mom had Leigh Syndrome, a condition characterized by a progressive loss of movement abilities. It typically results in death within two to three years, usually due to respiratory failure.
How does a three-parent baby work?
Mom’s nuclear DNA replaces the nuclear DNA of a donor egg. Now we have: an egg with mom’s nuclear DNA and the donor’s mitochondrial DNA, and dad’s sperm.
Got it. How did it turn out?
Interestingly, what we know about the results of this procedure comes from a recent trial using the same technique, but for couples in which the woman is experiencing infertility. There has been some evidence that mitochondrial DNA could be involved in infertility.
In a study by Costa-Borges et al., the team used a total of 122 maternal eggs and 122 donor eggs to generate 85 with donor mtDNA that were successfully fertilized with sperm. Twenty-four of these developed into healthy embryos, and 19 of them were transferred to a woman’s uterus, resulting in seven pregnancies. At the embryo stage of these seven pregnancies, less than 1% of the embryos’ mtDNA came from the original infertile mother, while over 99% came from the donor. Expected. Here’s the unexpected part: By the time the baby was born, between 30% and 60% of the mtDNA was coming from the original mother.
What’s the takeaway?
There are two big takeaways: a pretty clear pro and con.
Pro: This method, named mitochondrial replacement therapy, or MRT, could be a great option for couples with infertility issues due to mitochondrial DNA issues in the egg. This is because the eggs seem to successfully fertilize and become healthy pregnancies, and if some of the mitochondrial DNA reverts back to mom’s, no probem.
Con: This could be very bad for couples with maternal mitochondrial disease. This is because in this case, we really don’t want the baby to end up with mom’s DNA, and therefore a genetic condition.
This method needs to be studied further, and is currently banned in the US, although clinics in other countries, including the UK, Greece, and Ukraine, are offering it, and it was made legal in Australia last year. Although potentially unsafe for purposes of preventing mitochondrial disease, the potential for this type of therapy could benefit the multitude of couples suffering from infertility each year.
Kenya may be turning to GMOs
GMOs, or genetically modified organisms, are animals, plants, or microbes whose DNA has been altered using genetic engineering techniques. They are completely safe to eat and are widely grown in the US, Canada, Brazil, and India. Today, approximately 90% of the corn, soybeans, and sugar beets on the market are GMOs.
Right now, Kenya, whose government had banned GMOs since 2012, is debating a change in this policy.
Why are they suddenly changing their minds?
For survival. Kenya is facing a record-breaking drought that has left around 4.4 million Kenyans without enough to food to eat. Rivers are running dry, millions of livestock have perished due to lack of food, and crop yields have been lower than can sustain food for the country. Additionally, pests such as the fall armyworm moths have destroyed crops in the country.
GMOs are an answer to many of these problems. Genetically engineered crops produce higher yields, have a longer shelf life, and are resistant to diseases and pests. These benefits are a plus for both farmers and consumers. So, Kenya lawmakers have decided to grow pest-resistant GM maize.
Got it. How is it going?
It’s mixed. The Kenyan government already ordered 11 tons of pest-resistant GM maize seeds that are widely grown in South Africa. But then, in February 2023, Kenya’s GMO regulator was barred from releasing the seeds after four separate legal complaints were lodged. Some of the complaints include concerns that this decision violates the East African Community Treaty, which requires East African countries to protect natural resources. Other groups are worried that cultivating GM maize will shift the focus away from indigenous crops.
In the meantime, those open to GMO crops hope that bringing in pest-resistant crop varieties will help increase crop yields and food output, feed people in need, and actually help the environment.
While this debate continues, a decision will need to be made before the upcoming crop season in Kenya.
For more on GMs in the environment, see this article on GM trees being planted in the US, and this past Sequence post on the GM American chestnut tree.