Are we dreaming big enough?

CRISPR-Cas9 has given us tools to rewrite life. The discovery on how to edit our genes is said to be the holy grail of science with possibility to fix gene disorders and improve people’s lives. Yet, not that many treatments or applications has been developed. How come?

A few years ago, American biochemist and Nobel prize winner Jennifer Doudna was working on her laptop in an airport lounge in New Jersey, when a couple walking by with their two boys caught her attention. The younger boy made his way on crutches, displaying signs of a hereditary disease called muscular dystrophy.

“Generally manifesting in childhood, the disease steadily robs those who have it of their ability to walk. Eventually, I knew, the crutches would no longer be enough,” she recalled in an article in The Atlantic.

Doudna had just come from a meeting where a cure for the boy’s disease appeared possible, using CRISPR technology to rewrite the DNA of kids just like him.

“Imagining how the technology I’d helped create could change this boy’s life, I was overwhelmed with emotion. Beyond hope and wonder, I was filled with a sense of fierce urgency to expand CRISPR’s impact to the people around the world who need it most,” she wrote.

In 2020, Jennifer Doudna and Emmanuelle Charpentier received the 2020 Nobel Prize in Chemistry “for the development of a method for genome editing”, known as CRISPR-Cas9. As with many great scientific achievements, scientists before them had made ground-breaking discoveries that paved the way for their work.

The potential of their discovery seems endless.

In 1987, Japanese molecular biologist Yoshizumi Ishino and his colleagues discovered a protein named Cas9 found in the Streptococcus bacterial “CRISPR” immune system that co-operates with guide RNA and works like scissors. The protein slices up the DNA of viruses, preventing them from infecting the bacterium. This natural defence system was later characterised by the Spanish molecular biologist and microbiologist Francisco Mojica. However, it was Doudna and Charpentier who showed, in 2012, that they could use different RNAs to program the protein to cut and edit different DNA. The potential of their discovery seems endless.

The blueprint of our lives

“It’s a little scary, quite honestly,” Doudna told The New York Times about the possibilities of our CRISPR future. “But it’s also quite exciting.”

Our DNA is called the blueprint of life. It contains the genetic code, which is essentially the instructions for creating an organism. By altering our DNA, we can, in a sense, rewrite the rules of life. Our eye colour, hair colour, height and the size of our noses – it’s all determined by our genes. Unfortunately, errors in our DNA can cause severe diseases. Sickle cell disease, Cystic fibrosis, Down syndrome and Huntington’s disease are examples of genetic disorders.

“If we could go in and fix these mistakes, we could save many, many lives and get rid of these diseases,” philanthropist Bill Gates has explained. Editing DNA with precision has, as he puts it, been the holy grail for scientists for decades. His foundation is funding work to see if CRISPR can be used to knock out mosquito populations dramatically, as well as to make better seeds, help with very accurate diagnostics, and lead to cure for HIV and things like sickle cell. CRISPR has also been used to enable T-cells (a part of the immune system that focuses on specific foreign particles) to find and destroy cancer cells.

As Gates points out, using the CRISPR gene editing tool for curing diseases isn’t very controversial. The idea of changing the DNA that determines your baby’s eye colour or skin tone, however, is another story. Most scientists agree that this is something we should not do. But where should we draw the line? And how do we make sure we don’t cross it?

It needs a push

In her article, Jennifer Doudna writes that the advances made so far – and those still to come in preventive medicine, diagnostics, agriculture, biomanufacturing and synthetic biology – promise to improve the lives of millions of people. They’ve also launched companies and helped existing ones break new ground. This growing CRISPR economy was estimated at USD 5.2 billion in 2020. Venture capitalists poured more than USD 1 billion into the growing ecosystem of genome-editing companies in 2021 alone.

“Sometimes, when I think about my part in all this, I am overcome,” Doudna writes. At the same time, she asks: Are we dreaming big enough? Moving quickly enough?

Her answer is “no”. She compares it with cell phones, which went from a niche luxury technology to outnumbering the human population, creating new economies and changing the way we live. For the CRISPR technology to be widely adopted, it needs a push, just like mobile phones did, Doudna argues.

“Realizing CRISPR’s full potential will require many more of us to come together. (…) Academic scientists, industry researchers, investors, policymakers and members of the public each have a role to play,” she concludes.

Positive reactions

After reading Doudna’s article, I couldn’t help but wonder why more wasn’t being done to make sure we seize this possibility to improve the lives of so many people. Here we have a pioneer of her field, waving her incredible tool, urging the world to see its potential and use it. I was curious to know if she had received any reactions to the article. Had it been the wake-up call she might have hoped?

In an e-mail, Doudna’s Lab Coordinator Keana Lucas assured me that the reactions to The Atlantic op-ed were positive.

“At this 10th-anniversary mark, it’s clear that CRISPR tech has made remarkable progress. Winning the Nobel has only brightened the spotlight and amount of investment and engagement in a technology that promises to positively change our health and the health of our world,” she told me.

A Swiss army knife

What about Emmanuelle Charpentier? Where does she stand on all this? Emmanuelle Charpentier is a French professor and researcher in microbiology, genetics and biochemistry. As of 2015, she has been a director at the Max Planck Institute for Infection Biology in Berlin. Between 2009 and 2017, she worked as a research director and guest researcher at Umeå University in Sweden. In a video clip on the University’s website from 2015 – five years before she received the Nobel prize – Charpentier explained her discovery as “a Swiss army knife that allows repairing genes”.

“If you want to discover something important, you need to ask maybe crazy questions. It is when I came to Umeå that I developed a project that was to somehow bring together two different mechanisms that became the CRISPR-Cas9 mechanism,” she says, adding that her ultimate wish is that the technology be used to treat serious genetic disorders.

She believes that one of the greatest dangers we face is that the basic sciences are no longer attractive to young people.

In 2019, Charpentier founded a company called CRISPR Therapeutics. In 2022, the company published preliminary results from a clinical trial showing that 15 patients with beta thalassemia – a severe type of anaemia that requires lifelong reliance on blood transfusions – had gone months without needing transfusions after receiving a drug that edited the gene that caused the disease. In an interview with El País, she explained that she is focused on looking for new forms of gene editing to combat antibiotic-resistant infections. She also said she believes that one of the greatest dangers we face is that the basic sciences are no longer attractive to young people, people who will need to invent new treatments and medicines in the future.

“I think we all – and especially young people – need to ask ourselves what kind of world we want to live in,” she told the Spanish newspaper.

Marcus Jarås is a Swedish associate professor at the Department of Clinical Genetics at Lund University. His work focuses on using CRISPR to find new targets for cancer treatments. Using CRISPR to better understand the biology behind different diseases is the most common way of using the technology today, he explains. Swedish scientists were quick to start using the CRISPR technology, but as far as Jarås knows, it hasn’t led to any new treatments yet. That isn’t surprising, however, considering that it normally takes ten years from discovery to approval of a new treatment.

Use of CRISPR as a gene therapeutic treatment is further complicated by the fact that there are patents in the field that require licenses for technical commercial services, Jarås adds. In part, he shares Doudna’s analysis that CRISPR needs a nudge.

“More can always be done, but I still think that CRISPR has very quickly established itself as a powerful new tool for gene editing, not least in biomedical research. On the other hand, things are slow with CRISPR in plant breeding due to the GMO debate that led to EU legislation that makes it difficult to use this technology. In this area, CRISPR could really use a push,” he says.

Needs to be handle with caution

But if CRISPR can fix errors in our DNA code, could it also accidentally cause them harm? According to Swedish researchers at Uppsala University, who’ve experimented with editing the DNA of zebrafish using the tool, the answer is “yes”. Their studies show that there were several types of unexpected changes to the fish DNA.

Sometimes, larger parts of the DNA than intended were changed. Other times, the edits were made in the wrong part of the genetic material. The researchers also saw that the mutations could be passed on to future generations of zebrafish since they had occurred in fertilized egg cells. The techniques currently being developed for humans, however, are not using reproductive cells. There is, in other words, no risk that the changes – good or bad – can be passed on to the offspring.

The point of the research, according to the scientists, is not to suggest that gene scissors are an unfit tool for treatment. Only, that it needs to be handled with caution. The Uppsala University team is now focusing on improving the safety of CRISPR-
Cas9 therapies, where cells from a patient are genetically enhanced outside of the body and reinjected as a treatment.

“Such treatments are now being developed for a wide range of diseases. Our aim is to develop efficient methods to screen for unwanted mutations in the genetically modified cells,” says Adam Ameur, Associate Professor at the Science for Life Laboratory at Uppsala University.

So, the question remains – are we using this tool to its full potential – and if not, what possible advancements are we missing out on when it comes to decreasing pain and suffering? Is it the idea of rewriting the rules for life that is holding us back, or is it simply the time it takes to make sure we get it right? Not even the inventors of the technology seem to know the answer.