The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race by Walter Isaacson.
This book of over 500 pages certainly has the most sweeping title of any that I have written about over the past year or so. Referencing the future of the human race seemed a tad much to me before I read the book. After finishing it, the title really works. The code breaker referenced in the title is Dr. Jennifer Doudna, a central figure in the relatively new field of genetic engineering. While she is prominent in Isaacson’s writing, the book takes the reader on a tour of the world of the researchers who advanced genetic science and how they put aside their rivalries to develop the vaccines in use today.
The book begins on March 13, 2020, when some people were realizing that this coronavirus posed a major threat to our world. The best way to beat it would be to develop an effective vaccine as soon as possible. Dr. Doudna convened a Zoom meeting involving the network of fifty research universities that she had worked with over the decades. Her message was a simple one: “This is not something that academics typically do. We need to step up.”
Isaacson starts off by talking about the three great revolutions of modern times.
One of Isaacson’s main points is that basic science is the key to effective applied science. Curiosity motivates the scientist (or people in other fields) to develop an in-depth understanding of how things work. After you understand the theory - what’s under the hood - you can develop practical applications.
Jennifer Doudna grew up in Hilo, Hawaii, where her father was a university professor. She was blond and tall and did not fit in with most of the kids who were native Hawaiians. She was ostracized to some extent, and frozen out of many activities. As she got older and hit high school, she made friends with another Anglo who taught her to stand up against bullies. It worked and Jennifer’s high school days got better. Encouraged by her father and some teachers, she also blossomed as a student, excelling in science and math.
Jennifer spent a lot of time in the woods and climbing mountains and walking beaches trying to understand the world around her. She was very curious about how things worked. In sixth grade she read a tattered copy of James Watson’s classic book on early genetic research, <em>The Double Helix</em>, which was about the race to discover the structure of DNA, the building block of all life. She was hooked.
DNA James Watson and Francis Crick built on the work of Charles Darwin and Gregor Mendel who had done some rudimentary research on heredity. Darwin developed the theory of natural selection. Mendel’s experiments produced different peas by cross-breeding various types. Darwin’s “natural selection” held that nature tended to automatically alter the species in order to survive new challenges. A bird with a soft beak that ate fruit would have a problem cracking nuts if the fruit crops went away and nuts were the only available food. Over time, the beak would get harder and become an effective nutcracker. As he played with his peas, Mendel found that some traits were dominant and some were recessive.
In the 1950s, scientists knew that DNA transmitted inheritable transformations. That’s about all they knew. Watson and Crick were trying to figure out what DNA looked like, which would help them understand it better. They, and other genetic scientists, used cardboard trying to develop a model that would explain how DNA worked. Watson and Crick collaborated with other researchers but eventually they went off on their own. However, there is some controversy around the fact that Watson and Crick used some research from a prominent woman scientist, Rosalind Franklin, in their work without crediting her.
They came up with the famous double helix to describe how DNA worked. They also discovered that it would be possible to copy genetic material for various purposes, including altering how genes worked. The possibilities for research and medicine were endless. In 1962, they received the Nobel Prize.
Jennifer Doudna went to Pomona College in California, wanting to study chemistry. At first, she wasn’t very good at it and almost switched her major to French. When she talked to a French professor about doing that, she was told that French majors had a lot fewer opportunities in life than chemistry majors. Jennifer stuck with science, tried harder, and became an outstanding student.
In the mid-1980s, she went to Harvard for her doctorate and was quickly impressed with the fact that faculty and students came from all over the world. She excelled as a student, as did just about everyone else in her program. She was studying the science of genetics just as the world was developing ways to map genes.
In the late 1990’s, the Human Genome Project spent billions of dollars to refine gene sequencing and crack the genetic code. In 2000, President Bill Clinton proudly announced that scientists had “cracked the code of human life.” Many observers were confident that it would be easier to apply the new knowledge to curing and preventing disease that it was to map DNA.
They were wrong.
While most of the research action at the end of the 20th Century was focused on DNA, Doudna was more interested in the ignored little sibling, RNA. DNA resides in the nuclei of cells and basically protects the information it contains, information that literally is the basis of life. RNA is a messenger; it runs information here and there and helps DNA do its thing. (Is that a great technical explanation or what!)
Jack Szostak, Jennifer Doudna’s mentor at Harvard, saw that all of the focus in genetics was on DNA so he decided to study RNA, much of which was a mystery. Doudna and Szostak developed a way to reproduce and stitch together RNA, which opened up endless possibilities for studying it and seeing if RNA could be useful in treating and preventing diseases. After Jennifer received her PhD in 1989, she moved on to the University of Colorado at Boulder, home of Thomas Cech, who was using something called X-ray crystallography to supplement the traditional chemical experiments that genetic scientists generally utilized.
In 1993, she took a position at Yale, where researchers had refined the process of studying the structure of RNA. Doudna and her colleagues meticulously mapped the RNA molecule, an essential step in harnessing RNA to treat people with genetic defects and also to find effective cures for disease. That set up her next move, to the University of California at Berkeley where people were studying RNA interference, which could be used to regulate genes which would open the door to harnessing the power of genetic engineering to do good things. Some researchers theorized that RNA interference might one day be used to treat and prevent viral infections, including coronaviruses.
They were right.
In the early 2000’s, researchers found that bacteria with certain repetitive genetic characteristics were good at fighting off viruses. These were called CRISPR, for “clustered regularly interspaced short palindromic repeats.” For years, this was test tube stuff, with no practical application, but the CRISPR system would turn out to be of great benefit to humans.
CRISPR works with enzymes, a type of protein found within a cell that creates chemical reactions in the body which usually do good things. When the target DNA is found, Cas9 – one of the enzymes produced by the CRISPR system – binds to the DNA and cuts it, shutting the targeted gene off. Using modified versions of Cas9, researchers can activate gene expression instead of cutting the DNA. These techniques allow researchers to study the gene's function and ultimately change it to eliminate a bad characteristic or add a good one.
In 2008, Jennifer tried a brief stint in the genetics business sector and hated it so she returned to Berkeley after a few weeks. She pulled together a talented team to learn how to work with CRISPR RNA to develop tools that would be useful in medicine. She started a company, Caribou, to develop and market CRISPR products.
In 2009, Jennifer Doudna worked with her colleagues to build an atomic model of CRISPR RNA (CrRNA) which helped them understand how to use CrRNA to combat and prevent disease. Emmanuelle Charpentier was a French scientist who figured out that in order for RNA to be useful, it had to be easier to make. RNA also be able to latch onto a virus in order to alter it. She was a lone wolf who bounced from lab to lab around the world. She had met Doudna at a conference and the two hit it off. In 2011, Jennifer arranged for one of her colleagues to do the lab work needed to fully develop what would become known as tracer RNA (trcrRNA) which was a key to harnessing the power of CRISPR for medical uses. The trcrRNA was the scaffolding that held everything in place as cells were being genetically edited. In 2012, Doudna and Charpentier published a paper in a journal that described how trcrRNA worked to actually attack and change viruses. That paper essentially moved genetic engineering from a theoretical construct into a practical application.
The Race Three research groups were working to show how CRISPR could edit the genes of humans: Feng Zhang of the Broad Institute of MIT and Harvard; George Church of Harvard; and Jennifer Doudna at Berkeley. The race was on.
Fred Zhang was born in China to an academic family. His first toys were robot kits. The family emigrated to the US when Fred was 10 in 1991. After seeing the movie <em>Jurassic Park</em>, he became interested in biotechnology. As a 12-year old he thought it would be cool to create dinosaurs. His high school in Iowa happened to have an advanced work program in molecular biology. (Didn't your high schools have that?) Zhang was a prodigy. He went to Harvard and then Stanford for his doctoral work.
George Church looks like a crazed scientist, bushy beard and all. He went to Duke for his undergraduate work and then flunked out of their doctoral program. He talked his way into Harvard and the rest is history. He is known for his advanced work with DNA. He’s been exploring the idea of creating woolly mammoths, an extinct species, from DNA, as in Jurassic Park.
Jennifer Doudna worked with George Church in her doctoral program at Harvard. One of the major points of the book is that high-end researchers know each other pretty well. It is a rarified community, but over the decades different people come to work together on various projects.
The three competitors were each trying to use CRISPR to develop practical human gene editing tools and techniques. Fred Zhang was probably the most competitive. He claimed that a paper he published a few months before the Doudna-Charpentier 2012 piece beat them in describing how to do gene editing. He had published, but his work wasn’t as comprehensive as the women’s, and he left a few key things out. George Church had periodic tiffs with Fred. They worked together on many projects over the years and Zhang would sometimes overstate his role in the research.
In late 2012, Zhang and Church published papers within a few days of each other that set out how CRISPR could be used to edit human genes. Doudna’s team was still working on her approach, but she called and congratulated her former mentor, George Church. He encouraged her to finish the work and she did, publishing her team’s findings in January of 2013. Each of the papers ended up in about the same place on how to actually do gene editing. Isaacson points out that the invention of the microchip had a similar trajectory, with two labs coming up with the how-to at about the same time.
Fred invited Jennifer to join him in starting their own company. At first, she was interested, but the more she talked to Fred the less she trusted him. It seemed that he wanted her name associated with his company, but didn’t want her to have much of a voice in what went on. She and Fred went their separate ways. Eventually Church and Zhang started a company in Cambridge that had an impressive roster of world-class researchers and lots of start-up money. Jennifer was asked to join and she did, but it didn't work out. She sensed that Fred was up to his old tricks of freezing her out of decision-making and not living near the company was a problem. She also realized that these were all Boston men, and she didn't quite fit into their network. Her base was Berkeley. After a few months, she resigned. She went home and started her own company with people she had worked with and trusted over the years: Intellia Therapeutics.
After publishing their seminal article in 2012, Charpentier and Doudna drifted apart. Emmanuelle never stayed in one place very long, and her research interests were different from Doudna’s. They did keep in touch enough to win three major scientific competitions and pocket about $4 million each between 2014 and 2018.
Eric Lander was the founder and head of the Broad Institute in Cambridge, perhaps the world’s leading biotech think tank with 3,000 affiliated researchers. He was an uber-alpha, pushing and shoving his way through life and usually winning. He was close to Fred Zhang, no surprise since Fred was at Broad. Lander tended to minimize the work of Doudna while highlighting anything Fred did. In January of 2016, he published a major article on “The Heroes of CRISPR” in which he pretty much ignored Doudna’s contributions to the business. At the time, the Broad Institute was in competition with Jennifer’s company to get gene-editing patents, something Eric neglected to reveal.
There was a huge blowback against Lander after the article hit. Besides diminishing Doudna, he greatly exaggerated Fred’s role in developing gene editing technology. There were other factual problems with the piece. Women scientists spoke out against Lander’s sexism, and even MIT faculty members and Broad Institute staff took him to task. A writer in Scientific American called it “the most entertaining food fight in science in years.” Lander went off to Antarctica during the brouhaha.
Doudna and Zhang filed patent applications for various gene editing tools and techniques. Fred got his approval before Doudna did. That upset her a little, but what really ticked her off was that Fred had used a lot of her research in his application. They sued each other and each ended up getting patents. The lawyers did well. Isaacson notes that Intel and Texas Instruments had a similar squabble over microchip patents but negotiated with each other to work things out. That would have made sense in this case.
Biohacking Josiah Zayner got his doctorate in molecular biophysics at the University of Chicago. Instead of working at a prestigious lab, he is a biohacker. He believes that everyone should be able to do genetic editing and he sells kits to do just that. You can buy a “Do-it-yourself CRISPR kit” for $169 or a “Genetic engineering home lab” for $1,999. While this may seem crazy at first, Zayner may be on to something. Open source computer code - not owned by anyone - was developed by hackers and now is mainstream. It may come to be that serious people make use of readily available tools to expand the horizons of genetic engineering.
Walter Isaacson had the opportunity to do gene editing in Jennifer Doudna’s lab. There are many steps involved but it’s not too difficult, especially when you have equipment in a laboratory. Editing DNA in a test tube is relatively easy. Editing a human cell, which the author also did, is more complicated, but Isaacson actually changed a gene in the human cell he was working with.
Bioethics Many people have thought about the ethical implications of gene editing. What is OK to do? Most agree that curing or preventing maladies such as Huntington’s or Parkinson’s disease or cerebral palsy makes sense. What about gene editing of babies to make them smarter or taller or stronger? That’s a lot shakier. There seems to be a rough consensus that going beyond treating diseases to enhancing human capabilities is crossing a line. Most researchers believe that using gene editing to ameliorate suffering by curing or preventing disease is good. That is called somatic editing. Using genetic engineering to create heritable traits - known as germline editing - in an embryo or an egg or sperm is not good. Given that <em>in vitro </em>fertilization is an option for many today, it would be easy to modify an egg before insertion.
A major goal of people involved in genetics research is to keep the government out of strictly regulating the business. They also don’t want there to be a moratorium on research until we figure out all of the ethical angles. Once scientists start playing God, the government is more likely to step in.
Jennifer Doudna is often asked about genetic ethics. She is still thinking about this, but is leaning towards using genetic engineering to fix defective embryos. She was moved to consider the issue because of all the emails she received from parents raising children who had serious birth defects. Her view is that gene editing would be allowed in “medically necessary” situations.
Designer babies He Jiankui is a Chinese scientist who used gene editing to make babies less receptive to the HIV virus that causes AIDS. He edited the genes of twins in the womb who were born in November of 2018. He didn’t bother to talk to any people about the morality or wisdom of doing this work to produce designer babies. He also didn't clear it with the Chinese government. He was condemned by most of the scientific world. In December of 2019, Jiankui was sentenced to three years in a Chinese prison for “illegal medical practice.”
One criticism was based on the fact that you can “wash” an embryo to ensure that HIV is not present without having to do any gene editing. Doudna, whose work paved the way for what Jiankui did, was appalled at what he had done in producing genetically engineered babies.
James Watson literally wrote the book, The Double Helix, that inspired Jennifer Doudna to become a genetic scientist. He is an interesting person who has created a lot of controversy over his 93 years on earth. Watson has always been outspoken and postulated unconventional ideas on race, genetics and intelligence. In 2007 he was featured in an article in the Sunday Times of London. He told the interviewer that black employees were harder to work with than those of other races. In 2018 PBS did a feature on him in which he said that Blacks have lower IQs than whites and that genetics is the reason. That comment cost him his affiliation with the Cold Spring Harbor Laboratory on Long Island, a leading biomedical research center that is a gathering place for all serious genetic scientists.
He and Jennifer Doudna were colleagues, despite his beliefs. At a recent meeting with her, Watson said, “The reason that CRISPR is the most important discovery since DNA’s structure is that it not only describes the world, as we did with the double helix, but makes it easy to change the world.” That is high praise indeed, even coming from a curmudgeon.
In February of 2020, Jennifer was worried about the new coronavirus that was in China. She was the director of the Innovative Genomics Institute (IGI) at Berkeley, which was one-stop shopping for genetic research. On March 13, 2020, she called the Zoom meeting of 50 research universities that was referenced earlier. The first job was to develop accurate tests. The US Centers for Disease Control (CDC) had botched its rollout of Covid tests and there were very few test kits available in this country. Universities and hospitals across the land developed Covid tests but they needed approval by the US Food and Drug Administration which, you will not be shocked to learn, was being very bureaucratic and demanding things that made no sense. Finally, at the end of February the FDA approvals came through.
Jennifer’s IGI group had built a lab and assembled a team that had developed accurate, quick turn-around tests by April 6 and began to distribute them around San Francisco. In Cambridge, Fred Zhang and his Broad Institute team also developed good tests and began distribution. Jennifer and Fred were again in a competition but this was a friendly one. Doudna’s team named the testing protocol Mammoth while Fred’s group called theirs Sherlock. Each team developed biotechnology that would enable them to quickly program the test kits to detect any virus that may come down the road. Both groups chose not to patent their products but rather leave them in the public domain so that anyone could use them. These tests, that analyzed a person’s RNA, could detect the virus as soon as someone was infected. Other approaches needed the anti-virus antigen to develop in the body in order to be detected. That could take several days.
Vaccines 101
Vaccines work by stimulating the body’s immune system.
The challenge in using genetic vaccines is that you have to develop a delivery system to get the genetic material to hook up with the person’s cells to create immunity. CRISPR is the delivery system. In 2014, a researcher at Oxford developed a genetic vaccine for the MERS virus but the disease fizzled out so people didn’t need to be immunized. The good news here is that all of the prep work needed for a Covid vaccine had already been done for MERS. Once the Chinese published the genetic sequence of the new coronavirus in January, 2020, it was relatively easy to come up with an effective vaccine, which is why so many were developed.
RNA is a little messenger for the big fella, DNA, which resides in our cells. With CRISPR, you can genetically engineer the RNA - the messenger - with the instructions to teach the body’s cells to fight off the virus.
As we know, Moderna in Cambridge (with a lot of graduates from Jennifer Doudna’s doctoral program) and Pfizer were the first to develop the shots, followed by AstraZeneca and Johnson & Johnson. Moderna was a new, relatively small, company without the financial resources of the others. The company’s board reached out to Dr. Anthony Fauci and asked for help. He told them to go for it, and the US government would pay for it. Ten days later, Moderna had the vaccine ready for testing.
These vaccines are much more effective than traditional ones. In the late fall, when the president of Pfizer was informed of the vaccine trial results in a conference call, he thought he had heard “over 19%” effective rather than the “over 90%” that was the real number. When Moderna's chairman, Noubar Afayan, saw the results from the clinical trials, he said, “It was a bad day for viruses. There was a sudden shift in the evolutionary balance between what human technology can do and what viruses can do. We may never have a pandemic again.”
In the future, researchers should be able to use CRISPR to guide enzymes to chop up the genetic material of viruses instead of having to rely on our immune system to fight them. That is much more efficient and safer than beefing up your immune system, which is problematic for some people. There are two research teams, including Jennifer Doudna’s Berkeley group, that are making good progress on this.
Jennifer Doudna and Emmanuelle Charpentier wrote and published the seminal paper of CRISPR in 2012. While they had worked together to win scientific competitions they had drifted apart. Over the summer of 2020, Walter Isaacson put them together on a Zoom call that he organized. The two caught up and promised to work together on a major project once the pandemic was over.
The Nobel Prize
On October 9, 2020, Jennifer Doudna was in a hotel in Palo Alto, CA, where she was having a series of small meetings with colleagues to work on Covid issues. At 2:51 AM, the phone rang. She learned that she and Emmanuelle Charpentier had won the 2020 Nobel Prize for Chemistry for their 2012 paper that described how trcrRNA worked to actually attack and change viruses. Emmanuelle was in Berlin at the Max Planck Institute when she got the word.
This award was significant in several ways. It went to two women, which was rare. It only went to two people. The prize is usually given to teams of three. And they were recognized only eight years after they published the paper, lighting speed for the Nobel Prize, which is often awarded decades after the research was done.
Bob’s Take
This is complicated stuff. These people are wicked smaht. Most of the research was done by people who already had their terminal degree, a doctorate, but they kept on researching. Many scientists would go from one postdoc opportunity to another and spend years there to work on their specialty.
There is lots of money in the field of genetics. During the course of the book, researchers could always get what they needed, including personnel, relatively quickly. Someone - probably a university or a bio-corporation - had the money to pay for it.
Jennifer and Emmanuelle brought in close to $4 million each by winning scientific competitions, and the Nobel Prize paid each of them over $1 million. <strong>Most researchers in the book were foreign-born</strong>. China constantly reinforces the science-is-very-important mantra and many of the scientists in the story were Chinese.
Egos are huge. Male and female scientists each had opportunities for ego-tripping. The high-end science research business has lots of prizes and awards and financial incentives available to produce the next great thing. In order to win, people get very competitive very quickly.
Whatever you think of President Trump, Project Warp Speed worked. The vaccine was produced in record time.
- The main thing the US government did was provide money - to Moderna, which was a relatively new, small company that didn’t have the cash to do the research. For the bigger companies, the feds promised to buy lots of vaccines.
- The other thing the government did was to get out of the way and let the genetic research companies apply the lessons of the past 20 years to develop very effective messenger RNA vaccines.
The future looks good. Genetic engineering has become mainstream. Down the road, we should be able to rely on CRISPR solutions for a lot of medical problems - sickle cell anemia, cancer, some blindness, eliminating high cholesterol and associated heart problems, and Alzheimer’s, Parkinson’s and Huntington’s Diseases.
There also is work being done to treat serious mental illness genetically by literally rewiring harmful genes. James Watson’s son has serious schizophrenia and Josiah Zayner, the zany gene hacker, has major bipolar disorder. Each of them believes that gene editing can become the mechanism to effectively treat these devastating conditions.
A silver lining. Isaacson and many of the hundreds of people he interviewed for the book believe that the Covid crisis has changed scientific research for the better.
- To fight the virus, labs and universities put aside their insatiable desire for recognition and money which caused them to work in secret and not share anything. Collaboration and sharing everything became the new normal.
- Because of the need to quickly develop and produce a vaccine, many scientists began publishing their papers on-line as opposed to in traditional publications. These e-journals could quickly disseminate the papers. The trade-off was less peer review; but, in practice if you publish something silly, people will call you on it right away.
Tomorrow. The next pandemic will show up at our door, probably sooner than later. With the work that Jennifer Doudna and her colleagues around the world are doing, we will beat the virus in short order.
