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March 28 - April 28, 2025
The gene-editing tool that Doudna and others developed in 2012 is based on a virus-fighting trick used by bacteria, which have been battling viruses for more than a billion years. In their DNA, bacteria develop clustered repeated sequences, known as CRISPRs, that can remember and then destroy viruses that attack them.
She led by listening.
Our newfound ability to make edits to our genes raises some fascinating questions.
What might that do to the diversity of our societies? If we are no longer subject to a random natural lottery when it comes to our endowments, will it weaken our feelings of empathy and acceptance? If these offerings at the genetic supermarket aren’t free (and they won’t be), will that greatly increase inequality—and indeed encode it permanently in the human race?
The invention of CRISPR and the plague of COVID will hasten our transition to the third great revolution of modern times. These revolutions arose from the discovery, beginning just over a century ago, of the three fundamental kernels of our existence: the atom, the bit, and the gene.
Now we have entered a third and even more momentous era, a life-science revolution. Children who study digital coding will be joined by those who study genetic code.
RNA. It’s the molecule that actually does the work in a cell by copying some of the instructions coded by the DNA and using them to build proteins.
We all see nature’s wonders every day, whether it be a plant that moves or a sunset that reaches with pink fingers into a sky of deep blue. The key to true curiosity is pausing to ponder the causes. What makes a sky blue or a sunset pink or a leaf of sleeping grass curl?
Doudna’s career would be shaped by the insight that is at the core of The Double Helix: the shape and structure of a chemical molecule determine what biological role it can play.
Darwin and Wallace had a key trait that is a catalyst for creativity: they had wide-ranging interests and were able to make connections between different disciplines.
Malthus argued that the human population was likely to grow faster than the food supply. The resulting overpopulation would lead to famine that would weed out the weaker and poorer people. Darwin and Wallace realized this could be applied to all species and thus lead to a theory of evolution driven by the survival of the fittest.
“Hypocrisy in search of social acceptance erodes your self-respect.”
The easiest of these viruses to study are the ones that attack bacteria, and they were dubbed (remember the term, for it will reappear when we discuss the discovery of CRISPR) “phages,” which was short for “bacteriophages,” meaning bacteria-eaters.
The project began as a collaboration, but as with many tales of discovery and innovation it also became a competition.
Having a map of DNA did not, it turned out, lead to most of the grand medical breakthroughs that had been predicted. More than four thousand disease-causing DNA mutations were found. But no cure sprang forth for even the most simple of single-gene disorders, such as Tay-Sachs, sickle cell, or Huntington’s. The men who had sequenced DNA taught us how to read the code of life, but the more important step would be learning how to write that code. This would require a different set of tools, ones that would involve the worker-bee molecule that Doudna found more interesting than DNA.
DNA doesn’t do much work. It mainly stays at home in the nucleus of our cells, not venturing forth. Its primary activity is protecting the information it encodes and occasionally replicating itself. RNA, on the other hand, actually goes out and does real work. Instead of just sitting at home curating information, it makes real products, such as proteins.
enzymes. They serve as catalysts. They spark and accelerate and modulate the chemical reactions in all living things. Almost every action that takes place in a cell needs to be catalyzed by an enzyme.
they found that some RNA molecules can split themselves by sparking a chemical reaction. They dubbed these catalytic RNAs “ribozymes,” a word conjured up by combining “ribonucleic acid” with “enzyme.”2
Szostak and Doudna pursued the subject out of pure curiosity about how nature works. Szostak had a guiding principle: Never do something that a thousand other people are doing.
“I learned from Jack that there was more of a risk but also more of a reward if you ventured into a new area.”
second big lesson, in addition to taking risks by moving into new fields: Ask big questions.
Crick’s hypothesis was that, early on in the history of earth, RNA was able to replicate itself. That leaves the question of where the first RNA came from.
But the simpler answer may be that the early earth contained the chemical building blocks of RNA, and it didn’t require anything other than natural random mixing to jostle them together. The year that Doudna joined Szostak’s lab, biochemist Walter Gilbert dubbed this hypothesis “the RNA world.”
An essential quality of living things is that they have a method for creating more organisms akin to themselves: they can reproduce. Therefore, if you want to make the argument that RNA might be the precursor molecule leading to the origin of life, it would help to show how it can replicate itself. This was the project that Szostak and Doudna embarked upon.7
As a young PhD student, Doudna mastered the special combination of skills that distinguished Szostak and other great scientists: she was good at doing hands-on experiments and also at asking the big questions.
that RNA is made up of very few chemicals, so it accomplishes complex tasks based on the different ways it is folded. One of the challenges with RNA is that it’s a molecule made of only four chemical building blocks, unlike proteins, which have twenty. “Because there is a lot less chemical complexity to RNA,” she says, “the challenge is to think about how does it fold into a unique shape.”
“We have now been able to see how an RNA molecule can form itself into a complicated three-dimensional structure.” Asked what the implications could be, she again pointed to what would be her future work: “One possibility is that we might be able to cure or treat people who have genetic defects.”5
she was interested in how the RNA in some viruses, such as coronaviruses, allow them to hijack the protein-making machinery of cells. During her first semester at Berkeley, in the fall of 2002, there was an outbreak in China of a virus that caused a severe acute respiratory syndrome (SARS). Many viruses are composed of DNA, but SARS was a coronavirus that instead contained RNA.
Doudna also became interested in a phenomenon known as RNA interference. Normally, the genes encoded by the DNA in cells dispatch messenger RNAs to direct the building of a protein. RNA interference does just what the name implies: small molecules find a way to mess with these messenger RNAs.
RNA interference operates by deploying an enzyme known as “Dicer.” Dicer snips a long piece of RNA into short fragments. These little fragments can then embark on a search-and-destroy mission: they seek out a messenger RNA molecule that has matching letters, then they use a scissors-like enzyme to chop it up. The genetic information carried by that messenger RNA is thus silenced.
Enzymes are a type of protein. Their main function is to act as a catalyst that sparks chemical reactions in the cells of living organisms, from bacteria to humans. There are more than five thousand biochemical reactions that are catalyzed by enzymes. These include breaking down starches and proteins in the digestive system, causing muscles to contract, sending signals between cells, regulating metabolism, and (most important for this discussion) cutting and splicing DNA and RNA.
Basic research is the pacemaker of technological progress.”1 Based on this report, President Harry Truman launched the National Science Foundation, a government agency that provides funding for basic research, mainly at universities.
Genentech became the model for commercializing biotech discoveries: scientists and venture capitalists raised capital by divvying up equity stakes, then they entered into agreements with major pharmaceutical companies to license, manufacture, and market some of their discoveries.
With prodding from its provost Frederick Terman, Stanford professors were encouraged to turn their discoveries into startups. The companies that sprang out of Stanford included Litton Industries, Varian Associates, and Hewlett-Packard, followed by Sun Microsystems and Google. The process helped turn a valley of apricot orchards into Silicon Valley.
The idea was that the company, which moved into a low-slung space in a nearby strip mall, would commercialize the patents related to the Cas6 structure and eventually other discoveries to come out of Doudna’s lab. Their initial aim was to turn Cas6 into a diagnostic tool that clinics could use to detect the presence of viruses in humans.
In the case of Caribou, that came as a grant from the Bill and Melinda Gates Foundation, which provided $100,000 to fund work on using Cas6 as a tool to diagnose viral infections. “We plan on creating a suite of enzymes that specifically recognize RNA sequences characteristic of viruses including HIV, hepatitis C and influenza,” Doudna wrote in her proposal to the foundation. It was a prelude to the funding Doudna would receive from Gates in 2020 to use CRISPR systems to detect coronaviruses.7
It turns out that tracrRNA performs two important tasks. First, it facilitates the making of the crRNA, the sequence that carries the memory of a virus that previously attacked the bacteria. Then it serves as a handle to latch on to the invading virus so that the crRNA can target the right spot for the Cas9 enzyme to chop.
found this protein, an enzyme called Cas9,” she explained. “It can be programmed to find viruses and cut them up. It’s so incredible.” Andy kept asking how it worked. Over billions of years, she explained, bacteria evolved this totally weird and astonishing way to protect themselves against viruses. And it was adaptable; every time a new virus emerged, it learned how to recognize it and beat it back.
It took another fifteen years before scientists began to deliver engineered DNA into the cells of humans. The goal was similar to creating a drug. There was no attempt to change the DNA of the patient; it was not gene editing. Instead, gene therapy involved delivering into the patient’s cells some DNA that had been engineered to counteract the faulty gene that caused the disease.
Instead of treating genetic problems through gene therapy, some medical researchers began looking for ways to fix the problems at their source. The goal was to edit the flawed sequences of DNA in the relevant cells of the patient. Thus was born the endeavor called gene editing.
The invention of gene editing required two steps. First, researchers had to find the right enzyme that could cut a double-strand break in DNA. Then they had to find a guide that would navigate the enzyme to the precise target in the cell’s DNA where they wanted to make the cut.
The enzymes that can cut DNA or RNA are called “nucleases.” In order to build a system for gene editing, researchers needed a nuclease that could be instructed to cut any sequence that the researchers chose to target. By 2000, they had found a tool to do this. The FokI enzyme, which is found in some soil and pond bacteria, has two domains: one that serves as scissors that can cut DNA and another that serves as a guide telling it where to go. These domains can be separated, and the first can be reprogrammed to go anywhere the researchers want.1
Competition drives discovery.
“Healthy rivalries,” she later wrote, “have fueled many of humankind’s greatest discoveries.”
Competition gets a bad rap.2 It’s blamed for discouraging collaboration, constricting the sharing of data, and encouraging people to keep intellectual property proprietary rather than allowing it to be free and open for common use. But the benefits of competition are great. If it hastens the discovery of a way to fix muscular dystrophy, prevent AIDS, or detect cancer, fewer people will die early deaths.
Most sickle-cell patients in the world are Africans or African Americans. These are populations that have been historically underserved by the medical community.
Even though the genetic cause of sickle-cell disease has been understood for longer than any similar disorder, new treatments have lagged behind. For example, the fight against cystic fibrosis, which affects primarily white Americans and Europeans, has received eight times more funding from government, charities, and foundations. The great promise of gene editing is that it will transform medicine. The peril is that it will widen the healthcare divide between rich and poor. Doudna’s sickle-cell initiative is designed to find ways to avoid that.
In addition to treating blood disorders, such as sickle-cell anemia, CRISPR has been used to fight cancer. China has been the pioneer in this field, and it is two or three years ahead of the United States in devising treatments and getting them into clinical trials.
The third use of CRISPR editing that was underway by 2020 was to cure a form of congenital blindness.
