At the most fundamental level, we are all code. The typical human body is an assembly of some 37 trillion cells, and each holds all the information needed to make a complete human being.
Our DNA, the double-stranded helix responsible for heredity, contains 3 billion letters that dictate everything from hair and skin color to blood type. In fact, DNA is the most important identity document we will ever carry. Besides random mutations and damage, it doesn’t change from the day we’re born.
But that paradigm may soon start to shift. Scientists around the world have been experimenting with a powerful new tool called the CRISPR-Cas9 system, which has begun to open up the possibility of rewriting faulty or unwanted human, animal and plant DNA.
“We now have a way of easily making changes directly to the genome,” says Anja Smith, the research and development director at Dharmacon, a unit of GE Healthcare Life Sciences developing technologies for gene expression and editing, including CRISPR-Cas9. “You can now go directly into the cell itself and make changes to genes.”
A Revolution in the making
Genetic engineering has advanced rapidly since the 1970s, when scientists first combined snips of DNA from one bacterium or virus with another. The genetic blueprints for life are almost entirely written in a seemingly simple language whose alphabet has just four letters, which stand for four different molecules called nucleic acids: A for adenine, C for cytosine, G for guanine and T for thymine.
Sequences of these letters spell out what we call genes, the basic units for inherited traits like blue eyes or the blood disorder hemophilia.
The ability to start reading that code, called DNA sequencing, took off in the 1970s and began accelerating in the 1980s. By 2003, scientists from the U.S. National Institutes of Health and the private firm Celera Genomics announced they had sequenced the first essentially complete human genome.
If genetic engineering were a race, everything that preceded decoding the human genome was only a trip to the starting line.
After that, the tempo picked up quickly. There was the phenomenal discovery that allowed scientists to effectively stop genes from working, a process called RNA interference. This allowed researchers to start silencing targeted genes, turning them off to see what would happen and learn what they do. That led to a torrent of findings that started to reveal exactly which genes are associated with disorders ranging from cancers to neurodegenerative diseases. The technique won its discoverers, Andrew Fire and Craig Mello, a Nobel Prize in 2006.
Along the way, researchers also began refining the difficult technique of inserting foreign DNA sequences into host genomes, getting the host cell to follow the foreign instructions and produce entirely foreign proteins. The finding allowed biopharmaceutical companies to create bacteria that could mass-produce the hormone insulin outside the human body.
In 2012, Emmanuelle Charpentier and Jennifer Doudna revealed the CRISPR-CAS9 system, which allows researchers to go deeper and precisely edit and fix individual genes. Their groundbreaking work has triggered the next revolution in genetic engineering.
A tailor with a pair of scissors, sewing needle and thread
In the early 2000s, biologists realized that bacteria and their microscopic cousins, archaea, had short sequences of letters that showed up over and over again in their own DNA. These came to be known as “clustered regularly interspaced short palindromic repeats,” or CRISPRs.
It turned out that the sequence of letters between these CRISPRs were actually parts of foreign DNA from viruses, which had previously attacked the bacterium. After defeating the virus, the bacterium incorporated a piece of the invading DNA into its own to recognize the next time it was under attack.
This bacterial acquired immunity defense system was a clever cut-and-paste job. The scissors were the bacterium’s DNA-cutting protein called Cas9. The pasted bit included DNA information identifying the virus.
Scientists figured they could use this same system to target specific parts of any DNA to cut and splice in new sequences at precise locations. They’ve also learned how to use the system to silence genes, activate silenced genes, and to add in sequences for whole new functions.
So far, CRISPR-Cas9 has proven to be extremely versatile, effectively targeting, cutting and editing DNA in human cancer and stem cells, yeast, fish, rabbits, wheat, and other organisms. “If you design an RNA sequence that’s 20 letters long that corresponds to the part of the DNA you want to edit, you can direct the CRISPR-Cas9 system to make a double-strand break anywhere in DNA,” Smith says. “It’s an easy way to knock out genes to help understand what they do, but it also allows an easy way to create insertions that are very precise and could be used to treat disease. This discovery has totally reinvigorated the potential of gene therapy, and somebody is going to win a Nobel Prize for it.”
The gene-editing technology is still being developed and businesses like Dharmacon are helping speed up the research process. The GE unit has recently released a product called Edit-R – editor, get it? – which drops from weeks to days the time it takes to build the genetic sequence the system uses to guide the Cas9 cutting protein to the exact spot along the target DNA. “We’re removing the steps that are required to save researchers time,” Smith says. “Edit-R is also more amenable to higher-throughput testing, which can be used to screen hundreds or thousands of genes at a time for biomedical research.”
Smith says rapid and accurate editing of genes opens up all sorts of research opportunities, from creating disease mutations for study to routes for new therapies against cancers, immune diseases and other ailments.
This gene-editing tool isn’t just expected to be useful against human disease; researchers plan to use it for improving crops and livestock and potentially even for projects like mosquito control. Revolutionary though CRISPR-Cas9 may be, such a powerful instrument to delete, insert or edit genes also comes with big ethical questions that are still being argued.
In April, Chinese scientists announced they had used the system to genetically alter human embryos for the first time. The revelation set off vigorous debate in scientific circles and among the general public. Should such powerful scientific tools be used to alter the DNA of a human before they are even born? If so, should that engineering be limited to fixing genetic mistakes that will lead to serious or fatal disorder, or can it be also used to augment people to have preferred traits?
Such concerns are still a ways off, but the case of the Chinese research is just the first in what will surely be more difficult questions now that genetic engineering is starting to look more like programming computer code.
“People are being very cautious about this,” Smith says. “It’s warranted. This is very new technology and we aren’t necessarily sure what editing one part of the DNA will do in another part of the cell. You’re targeting gene X, but are you accidentally also targeting gene Y and Z? The answer to this is still unknown.”