A snip in time

Somewhere in West Africa around 7,000 years ago, a child was born with a gift. A genetic mutation had caused a change in the child’s haemoglobin protein — responsible for carrying oxygen in red blood cells. It caused no problems. On the contrary, it gave the child a huge advantage, protection from malaria.

Because of this, the child survived, and so did its children and their children, and we know this because we still see this genetic mutation around today. Anyone with one copy of the mutant gene (we all have two pairs of genes, one from each parent) is protected from the deadly malaria.

It was evolution at play, but there was a problem. When two of the descendants of the child got together and had children, some of them inherited two copies of the mutant gene. It caused these children to lose their ability to produce normal haemoglobin.

Today, we know this condition as sickle cell anaemia, in which a person’s red blood cells lose their frisbee-like shape and become crescent moon-shaped, or sickle-like. And soon, humanity will wield its own molecular scissors that can undo the mutation triggered by evolution thousands of years ago.

“Sickle cell is an illness that has extreme variation between individuals,” says Dr Terry Jackson, 49, a geneticist who has the condition. “One single little change (in genetic code) has all kinds of downstream effects because of the molecule that is mutated — haemoglobin.”

While Dr Jackson experiences damage to his bones due to the condition, causing him chronic pain, others can have ulcers on their legs. Some may have kidney problems while others, vision related issues. The condition also triggers complications such as stroke, hypertension, organ damage, and chronic pain.

All this happens due to the red blood cell’s decreased ability to carry oxygen to different parts of the body (anaemia), causing cell death. And the condition affects numerous people. In the US, there are over 100,000 individuals with sickle cell disease. In India, estimates put the number at 1.4 million.

We know about the saga of sickle cell disease thanks to research done by Daniel Shriner and Charles N Rotimi from the US-government’s Center for Research on Genomics and Global Health, who analysed the genomes of nearly 3,000 individuals to trace the genetic roots of the condition.

This story gains significance now because we are incredibly close to a therapy (that could soon be approved by the US Food and Drug Administration) to alter the DNA of red blood cells of individuals with sickle cell anaemia and undo what evolution did all those millennia ago.

Gene therapies, which introduce a new or corrected gene into a person’s cells to replace or supplement a defective gene, are showing promise in treating conditions such as Huntington’s disease, cystic fibrosis, and other genetic disorders. What is even more impressive is that the technology these therapies are built on is no older than a decade — clustered regularly interspaced short palindromic repeats (CRISPR).

THE CRISPR STORY

“CRISPR is like a courier system that can be loaded with whatever we want. Its main aim is to find a specific position and, in that position, load whatever we would like to,” says Dr Ajinkya Sase, senior research investigator at the University of Pennsylvania, Philadelphia, USA.

Like many tools developed by humanity, CRISPR too was inspired by what we saw in nature — specifically a defence mechanism employed by certain bacteria against attacking viruses. Researchers found that a portion of the bacterial immune system could cut the DNA of invading viruses (phages) and with the help of a guide molecule move the cut DNA strand to a particular region of its own DNA and implant it there. This gave the bacterial cell immunity against future attacks.

What the scientists had created was a pair of molecular scissors that, when programmed, can cut a segment of DNA precisely. It allowed them to rewrite the genetic code of any living organism, something that won Dr Emmanuelle Charpentier and Dr Jennifer Doudna the Nobel Prize in Chemistry in 2020. Not only is the CRISPR/Cas9 duo more accessible and cost-effective than older technologies, it is also faster and safer. “Before CRISPR also we were trying different ways to edit genes, we were trying to modify DNA, but those techniques were very lengthy and very expensive,” adds Sase.

The discovery of the gene editing method has spurred the development of therapies, 20 of which have already been approved by the US FDA so far, with trials being conducted on treatments for rare genetic disorders including sickle cell anaemia, cystic fibrosis, haemophilia, muscular dystrophy, and even some cancers.

It has also spurred innovation in genetically modified crops and organ transplantation. Like in 2022, when the first genetically modified pig heart was transplanted into a human. The researchers used CRISPR to make 10 genetic modifications to the heart of the pig—knocking out genes related to immune-rejection and inserting human genes. The heart was then transplanted into the individual, who survived for two whole months, longer than anyone else who had undergone a similar treatment.

This is part of the promise that CRISPR offers. It is an extremely effective way to treat diseases caused by a single mutation. Diseases involving multiple genetic mutations are still more challenging, but that is what is driving innovation in the space.

WILD APPLICATIONS

“Gene, cell, organ therapies will not only replace missing components, but will provide enhanced versions—specifically resistance to pathogens, immunity, senescence—to help prevent recurrence (or even primary occurrence of disease),” says George Church, Professor at MIT and Harvard, who is considered one of the founding fathers of modern genomics. Church and his group have been pushing the boundaries of CRISPR technologies to simultaneously activate and deactivate multiple genes, transplant organs grown in animals or the lab into humans and bring back extinct species to solve environmental challenges of today.

In 2021, Church launched Colossal, a venture to de-extinct the woolly mammoth by editing elephant genes (the woolly mammoth’s closest genetic relative) using CRISPR. The team has already identified 60 genes that confer mammoth-like features and hope to reach a point of actually growing the genetically modified animals in the next six years.

Similarly, the US National Aeronautics and Space Administration, better known as NASA, has funded several studies exploring the use of CRISPR and other gene editing technologies to modify the DNA of plants and bacteria to make them more resilient to the harsh conditions of space. Some teams are researching the use of gene editing to protect astronauts from the effects of radiation exposure in space.

Others, like those at the Imperial College London, used CRISPR to introduce a gene into a population of malaria-causing mosquitos, which if possessed by both parents would stop the females from laying eggs. They reported that within seven generations, the entire population of mosquitos had been wiped out.

While all these examples stem out of good intentions, they push the boundaries of ethics. Most of the criticism is against those who look at CRISPR as a tool to enhance humans, for instance altering genes that regulate intelligence, skin colour or height. The major problem is we do not yet know the consequences of such drastic changes to the human genome.

Like when Chinese scientist He Jiankui shocked the world by modifying the genomes of the embryos of twin girls born in 2018 using CRISPR/ Cas9. He stated that the goal of the experiment was to make the girls immune to infection by HIV, the virus that causes AIDS.

“Gene editing in blood cells and bone marrow is common, where genetic changes cannot pass to the next generation” says Dr Nootan Pandey, a postdoc researcher from University of Pennsylvania. But gene editing reproductive cells (such as sperm and egg cells) raises significant ethical concerns, she adds.

Church too sides with good reason for what should and what should not be done with gene editing. “As the name itself suggests, lifestyle disorders can be managed by making easy and simple modifications in our dietary habits. One need not approach or target gene therapy-based solutions for such health conditions,” Church told Happiest Health.

CHALLENGES BEYOND…

But while some say they want to enhance human babies to better fight disease or be smarter, others talk of reversing the process of ageing using genetic editing. However, given where the CRISPR-Cas9 technology is currently, some of these solutions are still in the realm of science fiction.

“It’s a bit of a fad at the moment to think about ways in which you can reverse ageing,” said Dr Jyoti Nangalia, clinician scientist and consultant haematologist at the Sanger Institute in the UK. “There is not one rogue cell that if you get rid of or redirect, that you’ll be fine.”

Speaking at the Happiest Health Future of Medicine summit held in Bengaluru on 9 March 2023, Dr Nangalia explained that her research shows that (just in blood) ageing induces widespread mutations in the DNA of cells to the point where the structure of tissues in our bodies changes completely.

Others like Dr Sase say that future cures will require the development of new technologies. He likens CRISPR and gene therapies to antibiotics, the field of which made massive strides in the previous century but is causing several issues today.

“These technologies [gene editing] show promising results in helping management of even complex diseases, but there will be a check point for these as well,” says Dr Sase said. “Even with antibiotics, we have some side effects, but we still take them because we know those side effects can be tolerated. The same needs to be figured out for gene editing tools.”

Another aspect that can hold up adoption of gene therapies is a human one. Dr Jackson says he is still on the fence about taking the gene therapy for sickle cell disease as and when it becomes available. While he worries about its cost, the time it would take, and the roadblocks insurance companies may put up for receiving the therapy, he is also anxious about what life will be like without the condition he has had since birth.

“I don’t think I have scepticism of the actual procedure. I’ve looked at the science and it’s pretty good,” says Dr Jackson. “It’s more an issue of access to everyone as there are many people who need this more than me. I’ve already surpassed the average age of people with sickle cell.”

This article was first published in the April 2023 issue of the Happiest Health magazine. To read more such stories subscribe to the magazine, please click here.