When you hear about the potential of a rapidly evolving technology, it might spark awe and excitement about the type of world it will enable — your imagination momentarily captured by the fantasy of homes grown from a single seed, wooly mammoths wandering the Earth again, or genetics that you chose for yourself.
Or, you might feel an immediate knot in your gut; some part of you screams for hesitance and caution as your mind plays a montage of humanity’s greatest acts of hubris: diseases that devastated entire ethnicities in the name of exploration and crops engineered to tolerate toxic, cancer-causing herbicides in the name of profit.
If you find yourself doing the former, you’re a wizard. If you do the latter, you are a prophet. These two archetypes were first pitted against each other by science journalist Charles C. Mann, who used them to characterize the dueling perspectives of two visionaries: Norman Borlaug, the wizard, and William Vogt, the prophet.
Both Borlaug and Vogt witnessed extreme poverty and came to different conclusions about how humanity might survive. Borlaug, an agronomist, believed that humanity could overcome overpopulation and the food scarcity that follows by innovating and “expanding the pie.” He developed the high-yield, rust-resilient wheat that launched the “Green Revolution” — the widespread adoption of new crop varieties and agricultural techniques in developing countries. Borlaug and the Green Revolution are often credited with saving a billion lives from starvation.
William Vogt, an ecologist, saw the effects of overpopulation, resource depletion, and environmental collapse, and concluded that humanity must live within the Earth’s natural limits by following sustainable resource management practices, population control, and conservation. His book “Road to Survival” set the stage for the very beginnings of the environmental movement.
The Wizard encourages ingenuity and experimentation even if risky, believing that science and technological advancement will solve humanity’s problems.
The Prophet warns us about the unintended consequences or misuse of new technologies, advocating for careful oversight, and arguing that restraint and ethical considerations are paramount.
This foil between the Wizard and the Prophet applies to more than just Borlaug and Vogt, illustrating a fundamental dichotomy in any fast-moving, high-impact field. Some examples of this tension are obviously seen in the news: AI accelerationism pushes for rapid development and integration of AI into our daily lives, whereas AI safety emphasizes caution and risk mitigation. SpaceX and Blue Origin are pushing to make space travel more accessible, but opponents argue that we should focus on preserving the planet we have. There are obvious cases of such archetypes in biology, as well.
Wizards include:
- Drew Endy — a pioneer of synthetic biology — who is most known for applying the principles of engineering to biology by creating kits of standardized DNA parts, which significantly accelerates workflows, and he advocates for Open Source Biology.
- Ellen Jorgenson is a molecular biologist and evangelist for Do-It-Yourself biology. In her 2012 TED Talk on biohacking she posited that, “the press had a tendency to consistently overestimate our capabilities and underestimate our ethics.”
- He Jiankui — a wizard who pushed the limits of societal comfort and ethics too far — when first applied CRISPR gene editing to human babies and was immediately condemned by the scientific community. Jiankui was later fined and sentenced to three years in prison.
Prophets include:
- Mary Warnock who was a champion of the UK’s policies on “strictly regulated but highly permissive” embryo research and assisted reproduction; she helped establish the fourteen-day rule, which legally limits gene-edited embryos from developing past fourteen days, in the UK which prompted widespread international adoption.
- Marcy Darnovsky is the executive director of the watchdog group Center for Genetics and Society, which is dedicated to the social justice and human rights issues surrounding new biotechnologies.
- Henry Greely, a professor of law and a bioethics expert, is known for anticipating the legal and ethical impacts of new biotechnologies. Greely prescribes finding the balance between public interest and scientific progress.
But when we look for these archetypes in a foundational subfield of modern biology — synthetic DNA production — we see some obvious Wizards, but no clear Prophets. Rather, we see the would-be Prophets repeatedly morph into a third archetype: one which hears prophetic fears yet adopts a wizardly mindset to fiercely innovate protective technology — I’ve dubbed these individuals the Paladins. As DNA printing becomes increasingly more accessible, we will need Paladins who concoct clever technologies that preserve our ability to boldly innovate while also mitigating risk.
Synthetic DNA production, or DNA printing, is the backbone of modern biological research. It is the process of chemically creating DNA outside of a cell. Prior to our ability to print DNA, researchers would have to use restriction enzymes to chop up genomes, construct large DNA libraries of these fragments, laboriously search for the desired gene (often with complex screens), and then sequence that gene to confirm its identity. Nowadays, a gene or genetic element of interest can be simply ordered from a company such as Twist or IDT, printed, and mailed to the scientist’s lab bench. Every new vaccine, cancer cure, antibody, potential CRISPR therapeutic, or engineered organism uses synthetic DNA. Biologists likely universally agree that advocating against the use of synthetic DNA is like advocating to dial back biological research progress half a century.
The Wizards
The Wizards of DNA printing hope for cheap, decentralized, benchtop machines. In this vision, the barrier to access is low and the pace of innovation is fast. Groups like Open Insulin and biologists like Sebastian Cocioba could purchase a printer and engineer yeast to produce insulin or create novel and exotic flowers. Even further, anyone could be a synthetic biologist: high school students, brewers, gardeners, chefs, interior designers — engineering biology would be as ubiquitous as any hobby.
Few scientists capture the spirit of synthetic DNA wizardry as well as Emily Leproust and Keoni Gandall. Leproust is co-founder and CEO of Twist Biosciences. She helped launch the market for synthetic DNA to new heights of scale, efficiency, and low costs by utilizing semiconductor technology to miniaturize the synthesis reactions. In a 2023 end-of-the-year reflection, Leproust touts that Twist’s brand new Factory of the Future will enable the company to cut turnaround times for synthesized genes in half, from ten days to just five — speed the field has not seen before.
Gandall (whose name is conveniently reminiscent of a famous fictional wizard), embodies radical advocacy for access to synthetic DNA. His fiery writing rallies for individual autonomy in innovation, accessibility and empowerment, “Everyone deserves the opportunity to engineer life to make the world a better place. Biotechnology does not belong to those in power, it belongs to us all.” Gandall ran the Free Genes Project — which aimed to be a publicly accessible repository for DNA parts — and is now focused on a stealth DNA assembly startup.
The (would-be) Prophets
The would-be Prophets of DNA printing warn against the risk of nefarious actors creating bioweapons and emphasize the need for strict rules and regulations about who can access what DNA. They might shudder at the thought of affordable DNA printers on every bench, and would tell cautionary tales, like that of Seiichi Endo — a member of the doomsday cult Aum Shinrikyo who helped carry out a 1995 poison gas attack in Tokyo that killed 13 people and sickened thousands of others. Endo reportedly had graduate-level training in virology, and he led the cult’s biological weapons program. Given the current accessibility of synthetic DNA, it is not difficult to imagine a scenario in which a terrorist could create a viral-based bioweapon.
In 2018, a group of researchers triggered the Prophets’ alarms by recreating Horsepox, a once-extinct virus closely related to smallpox. These researchers revived the virus by ordering ten synthesized DNA fragments of its (roughly) 200,000 base pair genome, stitching these fragments together — adding terminal sequences from vaccinia virus — and introducing this new, chimeric genome to cells cultured with a helper virus, thus creating an infectious virus. They conducted the controversial work with the goal of creating an improved vaccine and hoped it would spur “new and informed public health discussions relating to synthetic biology”.
In 2020, more alarms went off (about the lack of alarm) when Tonix Pharmaceuticals — which funded the previously mentioned study — quietly announced results from a preclinical study utilizing this chimeric horsepox virus as a vaccine for smallpox and monkeypox prevention. Smallpox killed somewhere between 300 and 500 million people in the twentieth century, and its eradication is one of humanity’s greatest triumphs, so the revival of its close relative served as proof that the same could be done for the much deadlier smallpox. This fear has only become more prominent in the wake of COVID-19; the catastrophic effects of viral disease are tangibly felt everywhere, making the Prophets’ perspective all the more compelling.
The Paladins
But when it comes to DNA printing, the Prophets consistently transfigure into a third, new archetype, the Paladin. In popular lexicon, paladins are holy knights dedicated to a code of ethics and fight to protect their values. In the context of our Wizard and Prophet archetypes, the Paladin listens to the Prophet whispering warnings on their shoulder but also embraces the Wizard’s spirit of innovation to create advanced safeguarding technologies.
Kevin Esvelt is perhaps the premier Wizard-turned-Prophet-turned-Paladin. He invented the CRISPR-based gene drive — a powerful tool with the potential to end malaria or lyme disease, or wipe out entire species. Esvelt reactionarily became a champion of bio-risk innovation, especially for synthetic DNA screening. To assess and prevent potential danger from a synthetic DNA order, Paladins develop DNA screens — algorithms that query a database for a certain gene sequence to see if it could produce a toxin or pathogen.
In 2020, Esvelt’s group at the MIT Media Lab published a method to identify the lab-of-origin for engineered DNA with 70% accuracy across 1,300 labs. Their machine learning toolkit utilizes “clues” or decisions that biologists make when designing and assembling synthetic DNA: each country, institute, and lab tends to prefer certain strategies and genetic elements. From these preferences, Esvelt and his colleagues could deduce the lab-of-origin. They dubbed this method deteRNNT, and while the authors acknowledge that the current method is not exhaustive, they hope that it can deter nefarious actors and set the stage for future improvements in “genetic engineering forensics”.
Currently, 80% of the global DNA synthesis market share adheres to the voluntary screening protocols of the International Gene Synthesis Consortium, or IGSC. Members of IGSC screen DNA orders — and all six potential reading frames of the order — against a Regulated Pathogen Database. If a sequence is flagged, the orders are reviewed by a human expert with more intense screening criteria and is either edited to meet additional requirements or rejected.
IGSC also has a customer screening protocol that simply requires identification data, including a shipping address, institution name, country, telephone number, and email address. This often manifests as an email asking “does your company have a website?” along with the shipping address being checked for non-residential zoning. A simple landing page and office address will satisfy this customer screening step.
Esvelt and his colleagues claim these current screening strategies are insecure, as they rely on public databases, and inaccurate, often causing false alarms that increase operational costs because follow-up screens require human experts. Esvelt and a team of biologists, cryptographers and policy analysts founded SecureDNA, a project aimed to address these issues.
While the project’s site reads prophetically, citing that over 20 million lives were lost to COVID, ten times more than if a nuclear warhead hit a major city, and goes on to warn that engineered bioweapons could be even more destructive. However, the project doesn’t stop there. It identifies and tries to solve several key issues with status quo bioweapon screening protocols used by synthetic DNA providers.
Their proposed solution is a new screening protocol that compares fragments of ordered DNA against a cryptographically secure database of critical regions of potential bioweapons. The protocol can also screen for functionally equivalent variants and keeps the database up-to-date with new and emerging threats. SecureDNA is accurate enough to be fully automated and is offered for free.
Challenges on the Horizon
The Paladins of DNA printing face three main challenges: achieving international consensus on a screening protocol, regulating benchtop DNA printers, and de novo designed proteins
The International Biosecurity and Biosafety Initiative for Science (IBBIS), a project launched by the Nuclear Threat Initiative, emphasizes that bio-risks transcend borders — a gap or oversight anywhere jeopardizes everyone. This initiative is developing another DNA screening system, called the Common Mechanism, with particular emphasis placed on ensuring that every synthetic DNA provider has access to screening tools.
While the US currently has no laws (only recommendations) that regulate who can order what DNA, on October 30th 2023, President Biden issued an Executive Order on the Safe, Secure, and Trustworthy Development and Use of Artificial Intelligence, which, while focused on AI, decreed what will be the first regulations on DNA synthesis in the US. The executive order initiates development of a DNA screening framework and requires that any federally funded research may only source synthetic DNA from companies that perform screening.
With SecureDNA, The Common Mechanism, IGSC, and the recent executive order, it is unclear how or if all these efforts are working in collaboration with one another. These screening protocols also seem to rely on the belief that synthetic DNA production will remain a service, something that is outsourced to an oligopoly of regulated synthesis companies and not done locally in labs.
Benchtop DNA printers are currently not widely used; I have yet to meet an academic or industry scientist who uses one in house as the cost of purchasing and operating one does not compete with ordering from a synthetic DNA provider. They do exist however.
Kilobaser’s benchtop DNA printer boasts being “the most affordable synthesizer on the market”, with the basic edition going for $35,000. The machine is based on a kit (which is not publicly priced) and produces 1 oligo per run, with each run requiring a one-time-use chip, the run time is two and a half minutes per base and has a maximum recommended length of 50 nucleotides.
To add context, an oligo is a short piece of single stranded DNA, while oligos are versatile and essential to research, they are equivalent to a 1×1 lego brick in a puzzle containing thousands of bricks. When I worked at UC Berkeley, I could order one oligo (often in sets of tens) from IDT for just a couple dollars and receive it the very next day.
DNA Script’s SYNTAX System prints oligos up to 120 nucleotides. The benchtop printer takes about 23 hours to print ninety-six 120 nucleotide oligos. So, to synthesize the aforementioned Horsepox genome (212,633 base pairs) in oligos of 120 nucleotides, in 96 well-plates, you need nineteen SYNTAX kits, nineteen days to print it, and a robust oligo-assembly-based cloning protocol to stitch them all together. This is cause for alarm.
A 2023 report by NTI recommends that companies selling benchtop DNA printers ensure their customers are legitimate researchers and implement screening software. However even if such measures were implemented, the potential of hacking similar devices has already been shown: the FDA recently issued a recall for Illumina’s DNA Sequencing Device for a software security flaw that could have been exploited to reveal patient data. As benchtop DNA printers will undoubtedly continue to improve in ability and fall in price, we will need innovative Paladins.
Recently, George Church and David Baker proposed a (high level) Paladin’s approach to protecting against a new threat: de novo designed proteins. Such proteins would seemingly slip through the cracks of the previously mentioned screening protocols because they are unlikely to have any sequence similarity to the natural proteins in the screening databases. Church and Baker propose that all synthesized sequences should be logged into a central database and encrypted to protect customer trade secrets. This way, they write, “if a new biological threat emerges anywhere in the world, the associated DNA sequences could be traced to their origins.”
Hopefully, the Paladins can offer some comfort that scientists are not universally barreling toward unrestrained innovation — careful and creative innovation is limiting who can get their hands on synthetic DNA. That being said, the Paladins do face several hurdles. DNA screening protocols only go as far as their reach, if just 80% of the synthetic DNA market share screens their orders, a malicious actor would still have plenty of ability to obtain sequences capable of causing harm. Furthermore, these screening protocols are designed to be enforced by a company, but most Wizards hope for benchtop DNA printers. While this technology is not currently widespread, the security of such a device is cause for concern and will likely take a tour-de-force of Paladin ingenuity to resolve.
In a talk on his book, The Wizard and The Prophet, Charles C. Mann propounded: “What you are doing here is trying to make a vision of the future that is consonant with your values… what kind of world do you want to live in and create?”
Personally, I want us to bravely innovate technology that will both: hurdle us into a beautiful biopunk future — sooner than anyone could have imagined — and protect humanity (plus the creatures we cohabitate with) from self-inflicted catastrophe. Renee Wegrzyn, a great Paladin of biology explained, “you don’t put brakes on the car because you want to stop, you put them on so that you can go fast.” This dream can only happen if Wizards channel their creative efforts towards integrating preventative and defensive measures into their technology, and if Prophets steer such efforts with informed regulations, international consensus, and adoption.
