You can add Nov. 16, 2023, to July 16, 1945 the day nuclear power moved from the theoretical to the actual as an entry to the list of consequential moments for everyones favorite vertebrate, Homo sapiens.

The news was easy to miss, but there it was. The United Kingdom announced that it would be the first country in the world to approve the use of gene editing as a medical therapy, starting with two inherited types of anemia: beta-thalassemia, and the more widely known sickle cell anemia. The U.S. Food and Drug Administration (FDA) followed suit three weeks later.

Its official: we humans are going to mess with our DNA, our original blueprints. DNA is the genetic instructions dictating how we look and behave, and that define what diseases we may develop, be prone to or be free of. With our ever-improving gene-editing skills, we are now prepared to peel back the pages of this ancient and sacred text and write the story the way we want to hear it.

DNA makes up the letters of lifes instruction manual for humans or any living thing. Genes organize those letters into words and paragraphs. Chromosomes organize those genes into chapters. In humans, each cell has 23 pairs of chromosomes. Inside the cell, DNA provides the formula for manufacturing specific proteins. Its the blueprint that tells each cell what to build, and how to build it.

Unfortunately, DNA can get altered or damaged, an occurrence thats referred to as a mutation. A mutation can be either inherited or newly acquired. It can cause the gene to produce a faulty product or no product at all. In the case of sickle cell disease, a mutation in the gene that codes for hemoglobin a complex protein that allows red blood cells to shuttle oxygen from the lungs to the body can lead to a whole lot of pain and suffering.

Red blood cells are flexible, allowing them to scooch through tiny capillaries where they unload their oxygen. In sickle cell disease, the mutation in the hemoglobin molecule can cause a red blood cell to change shape from a circle to a sickle. Sickled red blood cells lack flexibility, so they plug up the very capillaries they were supposed to be sliding through. Just as a traffic accident can lead to a pileup of cars behind it, one stuck sickled cell can trigger an upstream backup of stuck sickled cells.

Traffic jams are a pain, but a sickle cell attack aptly termed a crisis produces a deep, aching pain that may be unrivaled in human suffering. As capillaries and small arteries plug up, downstream tissues are left without oxygen. These blood-starved tissues begin screaming for oxygen as if their lives depended on it which they do.

Although a sickle cell crisis can cause excruciating pain, thankfully it is only rarely lethal. With pain medications, intravenous fluids, blood transfusions and oxygen support, the pain eventually eases. But repeated episodes take their toll on the body, significantly shortening the life expectancy of those with the disease.

Those with sickle cell disease (SCD) carry two copies of a sickling-prone hemoglobin gene (HbS). One copy comes from each parent. Those with sickle cell trait (SCT) have just one copy of HbS, but thats not enough to cause sickling except in rare circumstances like scuba diving or mountain climbing.

The sickle cell gene seems to have originated in sub-Saharan Africa, where having a single copy of the gene having SCT protects against severe malaria infections. Thats because the parasite that causes malaria, which reproduces by infecting red blood cells, has a harder time doing that inside cells carrying a lone sickle gene.

Although the prevalence of the sickle cell gene remains highest in sub-Saharan Africa, slavery and migration patterns have expanded its global range, so that today SCD can affect people of Hispanic, Southern European, Middle Eastern or Asian Indian backgrounds.

In the United States, 7% to 8% of Black newborns carry the sickle cell trait. In addition, 0.7% of Hispanic newborns, 0.3% of white newborns, and 0.2% of Asian or Pacific Islander newborns carry the trait. One out of every 365 Black newborns will have SCD. In total, about 100,000 people in the U.S. and 20 million people worldwide have SCD. Thats a lot of people hoping for a cure.

Casgevy is the first FDA-approved therapy to use CRISPR gene-editing technology. CRISPR is an acronym we can all be grateful for because it eliminates a phrase we will never be able to remember: clustered regularly interspaced short palindromic repeats.

In the case of Casgevy, CRISPR is used to create a line of red blood cells that manufacture hemoglobin F (HbF) thats F as in fetus. HbF has stronger oxygen-binding characteristics than adult hemoglobin (HbA). Thats because in the womb humans are breathing through the mothers placenta, and not through the lungs, which are filled with amniotic fluid. HbF production typically gets turned off soon after birth. Thats unfortunate for those with sickle cell disease who carry HbS, not HbA because HbF helps prevent sickling.

Casgevy turns HbF production back on.

Lyfgenia works by giving people with sickle cell disease a line of blood cells that can manufacture a form of adult hemoglobin (HbA).

Neither Casgevy nor Lyfgenia completely eliminates sickle cells, but they dilute the concentration of sickle-prone cells, thereby preventing sickle cell crises.

No surprise treatment with Casgevy and Lyfgenia is more complicated than what I just described. It requires removing stem cells from the blood. Stem cells are a little like the queen bee in a hive: They produce all the cells that will keep the body vigorous and healthy. In this application, the stem cells of interest are the ones that manufacture the new red blood cells needed to replace those at the end of their 120-day life span (or 20 to 30 days for fragile sickle cells). After these blood stem cells are removed and sent to the lab for gene therapy, the patient is given chemotherapy to decrease the number of stem cells making sickled red blood cells. This makes room for the new-and-improved stem cells.

Chemotherapy comes in a variety of potencies, and in this case, its fairly potent the kind you need to be in the hospital for. Following the gene therapy infusion, itll be 3 to 6 more weeks in the hospital waiting for the body to recover from the chemotherapy and for the modified stem cells to start growing back in serious numbers.

Like nuclear power or artificial intelligence, the technology of gene therapy brings great promise but also serious risks and ethical concerns.

There are the risks of the treatment itself: Did the gene therapy get inserted into the right gene location, and is it functioning correctly? Or did it end up in the wrong spot, altering the function of genes that we meant to leave alone?

There is the ethical question of who will get stem cell therapy. The medical complexity and steep cost of stem cell therapy a cool $2.2 million for a Casgevy treatment, and $3.1 million for Lyfgenia make it a boutique item only the haves will be able to afford.

And there are the ethics of how and where we will apply the technology. Although history teaches us that H. sapiens is an inventive and curious creature, we also are a never-quite-satisfied, boundary-pushing and occasionally nefarious lot. While were using gene therapy to eliminate sickle cell disease or perhaps someday Alzheimers, cardiovascular disease or what have you someone is going to ask: Whats the harm in getting rid of things like nearsightedness, balding, belly fat, wrinkles? And while were at it, why not use gene therapy to make sure we or our offspring have what it takes to compete in the NBA or the Ivy League, Hollywood or the Navy Seals? And can we eliminate dying?

Dont think we humans will go there? Comedian and futurist Jon Stewart told Stephen Colbert he sees it going this way: The world ends. The last words man utters are somewhere in a lab. A guy goes, Huh-huh. It worked!

Scientists disagree on whether Stewart was joking but recommend further research.

Relevant reading

When Winter Came

Dr. Pierre Sartor wrote an inspiring first-person account of how he treated more than 1,000 patients and by his reckoning, lost only five which lay forgotten in a lockbox of family artifacts until it was discovered decades later by his granddaughter, Beth Obermeyer, a journalist and author of

Read the original here:
Messing with the blueprints: Gene therapy has arrived - Mayo Clinic Press

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