COVID-19 anti-vaxxers and skeptics alike have their (not so good) reasons for opposing or questioning vaccines.  The speed at which certain vaccines were developed though should definitely not be one of them.  In Walter Isaacson’s recent book, The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race,he details in part how research on vaccines used to fight COVID-19 were years in the making.  The book, which had been recommended on our summer reading list, also covers a number of other fascinating topics, including designer babies and of course, the story of the gene editing star herself, Jennifer Doudna.  What I appreciated most though was Isaacson’s telling of how we were prepared to fast-track a COVID-19 vaccine because of significant research that had recently been done on the molecular superstar, RNA.

What is RNA?

It stands for Ribonucleic Acid, which is “a nucleic acid present in all living cells.  Its principal role is to act as a messenger carrying instructions from DNA for controlling the synthesis of proteins, although in some viruses RNA rather than DNA carries the genetic information.”

The genetic material in a Coronavirus is RNA, a molecule which happens to be Doudna’s speciality.  RNA had been at the center of her research long before the pandemic.  

Why is RNA Important For the COVID-19 Vaccines?

Both the Moderna and Pfizer-BioNTech vaccines were developed with RNA given the Coronavirus genetic makeup.  The vaccines utilized the most basic function of RNA, performing as messenger RNA (mRNA) that carries genetic instructions from DNA (which is barricaded in a cell’s nucleus) to the manufacturing region of the cell.  The mRNA instructs what protein to make.  In the cases of these two COVID-19 vaccines, mRNA instructs cells to make part of the spike protein that is on the surface of a Coronavirus. 

RNA vaccines have notable advantages over DNA vaccines.  RNA does not need to enter the nucleus of a cell unlike a DNA vaccine.  The RNA operates on the outer region of cells (the cytoplasm), which is where proteins are constructed.  These types of vaccines deliver their payloads inside tiny oily capsules known as lipid nanoparticles.  

The invention of easily replicable COVID-19 RNA vaccines was a feat of blazing-fast human ingenuity.  Their development was based on a foundation of research – decades in the making – by scientists like Doudna who were simply curious about fundamental life science principles.  Human understanding of RNA and its role in viruses and vaccines did not miraculously appear overnight. 

Scientists for years had researched – in an oftentimes intensely competitive race – how genes encoded by DNA are transcribed into snippets of RNA that tell cells what proteins to assemble.  CRISPR gene-editing technology in particular came from understanding the way that bacteria use snippets of RNA to guide enzymes to chop up dangerous viruses.  It goes to show: ingenious inventions often derive from basic science.

CRISPR Gene-Editing Technology and Its Role In Vaccines

CRISPR technology comes from reprogramming a system that scientists discovered in bacteria.  For centuries, bacteria have defended themselves against viruses using various “Cas” proteins.  In the context of fighting viruses, CRISPR technology often employs the Cas9 protein, which “can be easily programmed to bind to almost any desired target sequence, simply by giving it a piece of RNA to guide it in its search.”  

From there, the molecule surveys strands of DNA packed into our cells until it finds and binds to a 20-DNA-letter long sequence that matches the RNA sequence.  Keep in mind, our DNA sequences are over 6 billion letters each, so this technology is impressive to say the least. 

The Cas9 protein then cuts the DNA at the target location.  This often disables the gene by introducing mutations, rendering a virus like COVID-19 ineffective. 

Humanity can thank Jennifer Doudna and her partner in crime, Emmanuel Charpentier, for their seminal June 2012 paper on CRISPR, which paved the way for editing of human genes.  For her part, Charpentier should have played more of a starring role in Isaacson’s book.

Both superstar biochemists galvanized an entirely new field of biotechnology, but they did not do it without competition.  Once the pair’s June 2012 paper was published – which mainly focused on test tube research – the race was on to see who could prove its effectiveness in human cells.  Doudna and Charpentier were beaten to this by Feng Zhang and George Church, rival scientists who proved ruthless competitors, but also invaluable cooperators in the fight against COVID-19.

“The idea of using an easily programmed RNA molecule to target specific genes and change them was for humanity a momentous step into a new age.”

– Walter Isaacson

Five papers were published within 6 months of the Doudna-Charpentier paper.  This reinforced Doudna’s argument in later patent battles that CRISPRs use and effectiveness in humans was “obvious” and inevitable after it had been shown it could work in a test tube. 

Cooperation In Fighting COVID-19

The fierce biotechnology competition that initially started in 2012 and 2013 set the groundwork in the world’s fight against COVID-19.  The first officially certified death caused by the virus was reported in January 2020.  In that same month, Chinese researchers publicly posted the full genetic sequence of the COVID-19.

With the genetic sequence in hand, structural biologists around the world went to work on modeling the virus, atom by atom and helix by helix.  The goal of molecular biologists was to find treatments and vaccines that would block the ability of the virus to latch onto human cells. 

Prior to COVID-19, nobody considered using CRISPR as a diagnostic tool, but the world needed a quick and easy way to detect the virus.  Other tests at the time involved various mixing and temperature cycles.  So scientists started exploring how to deploy RNA-guided enzymes programmed to detect the genetic material in COVID-19.  They would adapt the CRISPR system originally developed by Doudna and Charpentier.

It should have surprised no one that Doudna’s Berkeley Lab had formed a company to use CRISPR as a detection tool.  A similar company was organized by none other than Feng Zhang.  The two found themselves in competition once again.  This time, however, the stakes were higher and the prize was not patents, but saving humanity from COVID-19.  Both companies shared their discoveries with the scientific community for free.

Thankfully they did.  In the early days of the Coronavirus, the FDA put up roadblocks to developing working tests and the Trump administration falsely criticized the World Health Organization tests as “bad.”  It wasn’t until Anthony Fauci pressed the FDA to allow universities, hospitals, and private testing services to start using their own tests while waiting for emergency authorization that people across the United States finally started to get tested in mass.  As Isaacson put it, “With the failure of the Trump Administration to carry out widespread testing, university research labs began taking on a role that has normally been performed by the government.”

The same was true for vaccine development.  Where the Trump Administration recklessly dropped the ball – predicting at times that the virus would miraculously disappear – universities and private companies stepped up.  Using Doudna’s research as a solid footing, companies like Moderna and ventures like Pfizer-BioNTech were able to develop safe and effective RNA vaccines in record time. 

Molecules Are the New Microchips

The CRISPR technologies developed in 2012 and at the onset of the pandemic in 2020 have fast-tracked humanity’s entrance into a life science era.  Molecules are the new microchips.  Humanity now has gene editing technology to fight gruesome diseases like sickle cell anemia, while preparing us to stave off the next pandemic.

Of course, CRISPR technology does not come without risks.  From reprogenetics, which has the risk of exacerbating inequality and creating future Frankensteins, to the ability of average people to purchase Cas9 protein and guide RNA kits online, the technology is simultaneously extraordinary and terrifying.  More regulation and international standards are required for germline editing.  More oversight is needed for people who buy the Cas9 RNA kits online and for fertility clinics who might supply them with embryos.      

If anything, these issues demand a greater appreciation and understanding by everyone in the humanities.  The need for moral guideposts is more critical than ever, in addition to what’s considered right and wrong in terms of treatments versus pure genetic enhancements.  Hopefully we do a better job at policing the development of CRISPR and its related technologies than what we did with the microchip and the social media companies it spawned. 

One thing we did prepare well for was developing diagnostic tests and vaccines for COVID-19.  Scientists like Douda, Charpentier, Zhang, and others may not have realized it at the time, but their CRISPR technology gave us a running start in battling one of the worst outbreaks to plague the human race.

In conclusion, here’s one of my favorite quotes from Doudna.  Hopefully it inspires all of us to stay curious and keep searching for answers.  You never know what your discovery might prepare us for. 

“I have always loved mystery stories.  Maybe that explains my fascination with science, which is humanity’s attempt to understand the longest-running mystery we know: the origin and function of the natural world and our place in it.”

– Jennifer Doudna