The Genesis Machine: Our Quest to Rewrite Life in the Age of Synthetic Biology
By Amy Webb, Andrew Hessel | 2021

This book is a wonderful primer on Synthetic Biology. Amy Webb has a gift for storytelling which makes this a compelling read.

Preface

In 2010, Craig Venter (the eccentric genious who pretty much single-handedley decoded the Human Genome) successfully synthesized “life” – a self-replicating bacteria to be precise – in the lab. He called this bacteria JCVI-syn1.0 or Synthia (scientific name: Mycoplasma laboratorium).

Venter had hypothesized (and he eventually proved it) that a minimally viable genome might act as a basic chassis, the scaffolding upon which other genes could be added for new functionality.

In 2017, Venter’s company Synthetic Genomics demonstrated a sort of biological printer, which he called a digital-to-biological converter, or a DBC. It consisted of a robotic DNA/RNA synthesizer-assembler system about the size of a sofa. Researchers can send various genetic programs to the DBC and print out DNA for manufacturing a protein, an RNA vaccine, and even a bacteriophage (a virus designed to infect bacterial cells).

This development has enormous implications for our species – it has the unparalleled potential to do both great good and existential harm.

So what is Synthetic Biology?

Researchers working in the synthetic biology struggle to define its contours, but it is an umbrella for chemistry, biology, computer science, engineering, and design united for a single goal: to gain access to the cellular factory and to life’s operating system in order to write new—and possibly better—biological code.

Synthetic biology digitizes the DNA manipulation process. DNA sequences are loaded into software tools—imagine a text editor for DNA code—making edits as simple as using a word processor. After the DNA is written or edited to the researcher’s satisfaction, a new DNA molecule is printed from scratch using something akin to a 3D printer. The technology for DNA synthesis (transforming digital genetic code to molecular DNA) has been improving exponentially. Today’s technologies routinely print out DNA chains several thousand base pairs long that can be assembled to create new metabolic pathways for a cell, or even a cell’s complete genome. We can now program biological systems like we program computers.

It’s expected that Synthetic biology will transform three key areas of life: medicine, the global supply of food, and the environment.

Why should you care as an investor?

Synthetic biology’s value network is just starting to form. So far there are just a few players in each segment. But that’s changing quickly. Investors poured $8 billion into synthetic biology startups in 2020.

The rate of investment growth in synthetic biology has doubled every year since 2018. BlackRock launched an ETF for synthetic biology in October 2020, following ARK Capital Management and Franklin Templeton, whose ETFs were performing better than expected. ARK’s made a 44 percent return on investment in 2019, and a staggering 210 percent return in 2020. The median size of synthetic biology IPO deals is rising, too: in 2020, the average IPO was valued twice as much as it was in 2019.

Notes from the book

• Genentech to developed the world’s first biotechnology product: Humulin (biosynthetic human insulin) which won US FDA approval in 1982. It is synthesized in a lab where a genetically altered E coli bacteria with recombinant DNA produces biosynthetic human insulin.

• Although there are more than five hundred known amino acids, just twenty routinely show up in biological systems

• Insulin, which an estimated 10 percent of Americans require every day, is only made by three companies—Sanofi, Novo Nordisk, and Eli Lilly—and its price has skyrocketed. Between 2012 and 2016, the cost per month doubled, from $234 to $450.34 Today, one vial of insulin can cost $250.

• Biological equivalent of the “start” button is a three-letter sequence (in the DNA) called a codon.

• AlphaFold was used to predict the structure of more than 350,000 proteins from humans and 20 model organisms. The dataset is expected to surpass 130 million structures by 2022. This will allow scientists to develop drugs to treat diseases far more quickly than the trial-and-error methods.

• The language of DNA uses A-C-T-G, and DNA’s version of a byte is a codon, which uses three, rather than eight, positions. For example, ATG corresponds to the amino acid methionine. When the cell sees that very first ATG, it knows to begin producing protein there. ATG is biology’s “hello world.”

• A protein is a chain of amino acids connected together. You can think of this like a beaded necklace. The beads (amino acids) are connected together by a string (bond), which forms a long chain (protein).

• SBOL (Synthetic Biology Open Language) makes the biological data machine readable and easily integrated into different software tools.

• Artemisinin (for treatment of malaria) is hailed as synthetic biology’s first successful product, even though the business created to manufacture and sell it was a failure (developed by Amyris biotech)

• Harvard’s George Church and his team genetically reprogrammed microbes so they would eat sugar and excrete polyhydroxybutyrate, a strong and biodegradable material that could hold liquids for a short period of time. In 2009, they made “plastic made 100% from plants.”

• A keystone species is a species which has a disproportionately large effect on its natural environment relative to its abundance, a concept introduced in 1969 by the zoologist Robert T. Paine.

• Our planet’s biodiversity has plummeted. The total biomass of the human race accounts for less than 0.01 percent of all life on Earth but we’ve wiped out 83 percent of the animal species.

• GenBank is essentially a biological version of Wikipedia. There, researchers submit genetic sequences they’ve decoded along with notes about them. Community moderators review the sequences, and if they’re approved, publish them.

• Moderna gets its name from combination of words “modified” and “RNA”—referring to the idea that messenger RNA could be re-engineered using synthetic biology techniques to develop personalized cancer treatments.

• Using synthetic RNA would be far more effective and adaptable than long-standing vaccine protocols, like making use of weakened viruses. In effect, Moderna was crafting genetic instructions that could be written like software and packaged into the equivalents of nanoscopic USB drives. Once these biological USB drives were inserted into the cells, those cells would dutifully download the mRNA instructions and follow them. Such vaccines would also be safer and easier to control.

• Decoding the first human genome took thirteen years, and the total cost of the Human Genome Project—which also included nontrivial expenses unrelated to genome sequencing—cost $3.2 billion.

• Roswell Biotechnologies, headquartered in San Diego, is developing molecular electronic sequencing technologies that fuse DNA enzymes directly to semiconductor chips. Such chips will be able to record what individual enzymes are doing electronically; by doing so, they effectively wiretap their activities. The hope is that in the next year or two, a portable device will be able to sequence an entire genome in under an hour for less than $100.

• UK-based Oxford Nanopore Technologies makes a sequencing machine that’s both the price of an iPhone and half its size.

• The first DNA synthesizer was introduced in 1980, when Vega Biotechnologies brought to market a machine the size of a microwave oven that could automate DNA production. It cost $50,000—around $160,000 in today’s dollars—and could make one DNA fragment (called an oligonucleotide, or oligo) per day, so long as it was only fifteen bases long. Since then, the cost of making oligos has come down dramatically, to pennies per base or less. Millions can now be synthesized at once.

• In 2019, Microsoft launched a platform called Station B, with the idea of creating end-to-end interconnected applications and services for synthetic biology. It’s partnering with startups to develop the open-source programming language used for biological experiments, and other startups that automate the work of lab machines made by different manufacturers. For example, the platform is used to replace first-generation synthetic biology instructions, like “shake a test tube vigorously,” with precise digital commands for lab robots.

• DNA is already nature’s hard drive. In 2019 Twist Bioscience and Microsoft researchers prototyped the first fully automated read-write DNA storage system, using it to first write and then read the word “Hello” in just five bytes of data. All of the world’s digital information could potentially be stored in DNA molecules suspended in about nine liters of solution!

• Advances in DNA synthesis have eliminated what used to be one of the highest barriers in genetic engineering: translating digital DNA code into code that a cell can run. But most synthesized DNA today is just a few thousand bases long, which is only about enough for a single protein. Building anything more complex, such as writing the complete genome of a microbe, requires tedious rounds of assembling fragments and precision sequencing before the biological design can be booted up, tested, and debugged. Biofoundries will simplify or automate this drudge work.

• In 2019, sixteen organizations banded together to form the Global Biofoundry Alliance to cooperate on these issues and address common challenges, such as locating the best prices for DNA synthesis, sourcing talent, and finding sustainable business models.

• There is a Moore’s Law analog in synthetic biology, and it’s named for a physicist Rob Carlson. He made the case that as technology improved, the cost of sequencing and synthesis would sharply decline. So far, his calculations—which have come to be known as the Carlson Curves—are holding true. The cost to sequence a high-quality draft of a human genome in 2006 was $14 million, and a finished sequence cost between $20 million and $25 million. By mid-2015, the cost for a finished sequence had dropped to $4,000. Today, BGI, a Chinese company, can sequence a genome for $100.

• In the next two decades, synthetic biology technologies will be harnessed to eradicate life-threatening disease and to develop personalized medicines for individual people and their specific genetic circumstances. Researchers will genetically engineer viruses to treat cancer, and they will grow human tissue in a lab for organ transplantation and to test new therapeutic treatments. New technologies will monitor us continuously, eliminating traditional doctor’s exams. Most importantly, we will engineer healthier people: predicting and eliminating genetic disorders, and potentially making enhancements, to babies before they are born.

• In 2021, geneticists at the Imperial College of London used CRISPR to modify the sexual development and other traits of female mosquitoes. Females born with the edited genes had different mouths, so they can’t bite, and they also can’t lay eggs, which means they can’t spread the malaria parasite.

• New mosquitoes with different genetic modifications are being developed and tested at scale in a high-security facility in Terni, Italy. In 2021, millions of other genetically engineered mosquitoes were scheduled for release in the Florida Keys to curb the spread of Zika.

• Long before they were making COVID-19 vaccines, both Moderna and BioNTech were researching immunotherapies for cancer. After analyzing a tissue sample from a cancerous tumor, the companies ran genetic analyses to develop custom mRNA vaccines, which encode protein-containing mutations unique to the patient’s tumor. The immune system uses those instructions to search and destroy similar cells all throughout the body, which is similar to how the companies’ COVID-19 vaccines work.

• BioNTech is currently in clinical trials for personalized vaccines for many cancers, including ovarian cancer, breast cancer, and melanoma. Moderna is developing similar cancer vaccines. Both companies understand that the world’s most powerful drug manufacturing factory on Earth may already be inside you. We just need to figure out all the ways we can harness it.

• Synthetic biology is being used to engineer and grow organoids—tiny blobs of tissue grown from human stem cells. Lab-grown lung and brain tissues are being used to research the lasting effects of SARS-CoV-2. Miniature guts and livers are also being grown, and infected with the virus, in high-security labs. With it, researchers can poison a mock respiratory system with new viruses, lethal chemicals, or other toxins to see how the body would react, and then test potential treatments on living human tissue without harming humans or other animals.

• Toto’s “Wellness Toilet” was announced at the Consumer Electronics Show (CES) in 2021. This is a real device intended for everyday use: the high-tech toilet uses a similar array of sensors to analyze “key outputs” and provide users with insights on hydration and their diets.

• At-home test startup Healthy.io has developed a urinary tract infection test kit that uses a mobile app to connect patients who have positive results with an online doctor and sends a prescription to a nearby pharmacy if needed. Healthy.io also partnered with the National Kidney Foundation to offer an annual kidney test kit to detect early signs of disease.

• Researchers at MIT have developed an ingestible-based bacterial-electronic system to monitor gut health. Other ingestibles can detect bleeding or tissue abnormalities, or even check to make sure a patient is taking prescribed medication.

• IVG (in vitro gametogenesis) is an emerging tech that will soon allow same-sex couples to create a baby using their own genetic material without requiring donor eggs or sperm. A Japanese scientist, Shinya Yamanaka, won the Nobel Prize in 2012 for his remarkable discovery: a method to turn any cell in the human body into induced pluripotent stem cells (iPSCs for short), which can be reprogrammed with the functions of any other cell.

• Roughly one-third of the food produced every year for human consumption—1.3 billion tons—is wasted or lost. In the United States, there is more food waste in landfills than any other material. In total, more than 40 percent of food waste happens at the retail and consumer levels in the industrialized world.

• Around 14 percent of all cotton grown worldwide is genetically modified, and nearly half of all soybeans are modified, too.

• Scientists in China are developing “super-pigs,” which not only resist the virus but are stronger and mature more quickly than other pigs. They are also fortified with a gene that regulates body heat, which enables them to stay outdoors during northern China’s extreme winters.

• The startup KnipBio engineers fish feed from a microbe found on leaves, editing its genome to increase carotenoids important to fish health and using fermentation to stimulate its growth. The microbes are then pasteurized, dried, and milled.

• Other agricultural projects underway include synthetic organisms that can produce vast quantities of vegetable oil, and nut trees that can grow indoors using a fraction of the water these thirsty trees normally require, while also producing twice as many nuts.

• CRISPR has increased the level of omega-3s in plants and aided the creation of non-browning apples, drought-resistant rice, and mushrooms that can withstand jostling during transportation. (In a nod to some consumers’ sentiments, in most countries product labels identify such products as genetically modified.)

• Vertical farming projects are now scattered across the globe, mostly in urban centers such as Berlin and Chicago. But Japan leads the world when it comes to indoor farming. The Kansai Science City Microfarm, near Kyoto, uses artificial intelligence and collaborative robots to raise seedlings, replant, water, adjust lighting, and harvest fresh produce.

• Microsoft operates FarmBeats, a sort of Internet of Things for farms, on its Azure Marketplace. The company is testing the technology on two US farms as part of a multiyear plan to modernize agriculture with data analytics. The system uses unlicensed, long-range TV frequencies to connect with and capture data from solar-powered sensors, while drones gather aerial footage of crops. Machine learning algorithms mine and refine the data before sending analyses back to farmers with recommendations on which variables to tweak.

• By 2030, you could be shopping at a grocery store full of fresh, nutritious, CRISPR-edited foods.

• In 2013 the first lab-grown hamburger made its debut. It was grown from bovine stem cells in the lab of Dutch stem cell researcher Mark Post at Maastricht University. The price to produce a single patty was $375,000. But by 2015, the cost to produce a lab-grown hamburger had plummeted to $11.43

• Late in 2020, Singapore approved a local competitor to the slaughterhouse: a bioreactor, a high-tech vat for growing organisms, run by US-based Eat Just, which produces cultured chicken nuggets. In Eat Just’s bioreactors, cells taken from live chickens are mixed with a plant-based serum and grown into an edible product. Chicken nuggets produced this way are already being sold in Singapore, a highly regulated country.

• An Israel-based company, Supermeat, has developed what it calls a “crispy cultured chicken,” while Finless Foods, based in California, is developing cultured bluefin tuna meat, from the sought-after species now threatened by long-standing overfishing.

• Mosa Meat (in the Netherlands), Upside Foods (in California, formerly known as Memphis Meats), and Aleph Farms (in Israel), are developing textured meats, such as steaks, that are cultivated in factory-scale labs.

• Two other California companies are also offering innovative products: Clara Foods serves creamy, lab-grown eggs, fish that never swam in water, and cow’s milk brewed from yeast.

• Perfect Day makes lab-grown “dairy” products—yogurt, cheese, and ice cream.

• Investors in cultured meat and dairy products include the likes of Bill Gates and Richard Branson, as well as Cargill and Tyson, two of the world’s largest conventional meat producers.

• Lab-grown meat remains expensive today, but the costs are expected to continue to drop as the technology matures. Until they do, some companies are creating hybrid animal-plant proteins. Startups in the United Kingdom are developing blended pork products, including bacon created from 70 percent cultured pork cells mixed with plant proteins. Even Kentucky Fried Chicken is exploring the feasibility of selling hybrid chicken nuggets, which would consist of 20 percent cultured chicken cells and 80 percent plants.

• Shifting away from traditional farming would deliver an enormous positive environmental impact. Scientists at the University of Oxford and the University of Amsterdam estimated that cultured meat would require between 35 and 60 percent less energy, occupy 98 percent less land, and produce 80 to 95 percent fewer greenhouse gases than conventional animals farmed for consumption.

• A synthetic-biology-centered agriculture also promises to shrink the distance between essential operators in the supply chain. In the future, large bioreactors will be situated just outside major cities, where they will produce the cultured meat required by institutions such as schools, government buildings and hospitals, and perhaps even local restaurants and grocery stores.

• In the mid-2010s, there was a rash of fake extra virgin olive oil on the market. As a solution, the Functional Materials Laboratory at ETH Zurich developed DNA barcodes that revealed the producer and other key data about the oil.

• Transforming cotton into fibers and textiles contributes 10 percent of global carbon emissions. Producing clothing requires a tremendous amount of water, and washing clothes made from polyester releases 500,000 tons of microfibers into the oceans each year. That’s the equivalent of 50 billion plastic bottles. Roughly 85 percent of textiles ends up in landfills every year.

• Bolt Threads developed a synthetic “microsilk” fabric, engineered from spider DNA. A Japanese startup, Spiber, synthesized enough fibers to manufacture a limited-edition parka.

• Synthetic biology processes can transform mycelium—the fuzzy, fibrous structures that help fungi grow—into rugged material resembling leather. Hermès, famous for its highly coveted leather handbags, partnered with startup MycoWorks in 2021 to develop sustainable textiles made out of mycelium.

• Nylon is cheap to produce and durable, so it shows up everywhere. Its production generates more than 60 million tons of greenhouse gases annually. But it’s now possible to produce nylon using engineered microorganisms. Two startups, Aquafil and Genomatica, are doing that.

• Several companies are developing bio-based, ultra-durable hard biofilms and coatings so that chipped nails, scratched paint, and cracked screens become yesterday’s problem. Zymergen developed a transparent biofilm that is thin, flexible, and durable enough to be used to transmit touch on a variety of surfaces, including smartphones, TV screens, and skin. Other possible applications include nearly invisible printed electronics that flex and move as needed.

• Synthetic biology also points to a future in which our packaging and shipping materials could be far more sustainable than they are today. The insides of soda cans could be coated with a fully biodegradable film rather than plastic, as they are now. New bio-packaging could be designed to withstand heat or cold, revolutionizing the logistically complex, energy-intensive, environmentally damaging cold chain we use today to transport perishables.

• Scientists at Columbia University are developing plastic trees that passively soak up carbon dioxide from the air and store it on a honeycomb-shaped “leaf” made of sodium carbonate—baking soda. So far, these fake trees are proving to be a thousand times more efficient at soaking up CO2 than real trees.

• Chemists at George Washington University are experimenting with what they call “diamonds from the sky.” They bathe carbon dioxide in molten carbonates at 750°C (1,380°F), then introduce atmospheric air and an electrical current on nickel and steel electrodes. The carbon dioxide dissolves, and carbon nanofibers—the diamonds—form on the steel electrode. Carbon nanofibers that can be used for consumer and industrial products, including wind turbine blades or airplanes.

• The startup Blue Planet developed a way to convert CO2 into a synthetic limestone that can be used as an industrial coating or mixed in with concrete. The company’s bicarbonate rocks were included in the reconstruction of San Francisco International Airport.

• White button mushrooms commonly used in omelets, pizzas, and spaghetti sauce start turning brown just after they’re cut. That happens because of the oxidation that occurs when the mushroom is exposed to air, and specifically, because of a gene that codes for an enzyme called polyphenol oxidase. In 2015, Yinong Yang used CRISPR to edit six mushroom genes, which reduced that enzyme’s activity by 30 percent. The result: mushrooms that stayed white longer in the package, didn’t brown as easily when sliced, and could withstand being handled by automated harvesting robots.

• In 2011 Ron Fouchier, a virologist at the Erasmus Medical Center in Rotterdam, successfully augmented the H5N1 bird flu virus so that it could be transmitted from birds to humans, and then between people, as a new strain of deadly flu. H5N1 had a high mortality rate: 59 percent of those who’d been infected died. Fouchier had taken one of the most dangerous naturally occurring flu viruses we had ever encountered and made it even more lethal. He told fellow scientists that he’d “mutated the hell” out of H5N1 to make it airborne, and therefore significantly more contagious.

• In December 2019, a mysterious and anonymous organization called the Earnest Project announced that it had surreptitiously collected DNA from used breakfast forks, wine glasses, and paper coffee cups used at the World Economic Forum’s annual meeting in Davos. The Earnest Project launched a website and auction catalog and announced plans to sell the genetic data of many world leaders and celebrities.

• As of April 2021, there were more than five thousand general patents for CRISPR and more than one thousand for CRISPR-Cas9 in the United States alone. There were thirty-one thousand CRISPR patents and applications listed in the World Intellectual Property Organization’s database. Hundreds of new CRISPR patents are being filed every month. Now here’s the rub: CRISPR is certainly the most famous technology within synthetic biology, but it’s hardly the only one. CRISPR represents just a tiny fraction of R&D activity within the broader synthetic biology ecosystem.

• Genomic Prediction (company) offers a polygenic score, measuring DNA at several hundred thousand positions in order to predict the likelihood of a future person having, say, low intelligence, or being among the shortest 2 percent of the population. It uses genetic profiles of NFL quarterbacks to determine how closely the embryo matches those profiles for athletic ability.

• Within the decade CRISPR and other genetic tools will be developed to manage viruses, repair tissue, combat mutations, and lengthen our lifespans.

• China’s BGI Group, one of the world’s largest sequencing companies, already says that it can boost the IQ of children by up to twenty points through genetic selection. BGI Group is actually making a measured bet: as it sequences more people, the data will reveal patterns among those who are smartest. Then, it’s just a matter of identifying genetic markers and selecting for them before implantation.

• Over the past decade, China has quietly created a scaled, national DNA drive to collect, sequence, and store its citizens’ genetic data. DNA repositories are part of a wider panopticon, aided by the Chinese Communist Party’s ambitions for artificial intelligence, to allow the government to continually surveil its constituents.

• More than half the world’s population relies on rice as a primary daily staple. But the most popular variety, white, is stripped of its whole grain, which contains fiber, minerals, vitamins, and antioxidants. So rice, for much of the world, is filling, but not very nutritious.

• All grains today have been modified through cisgenic breeding, in which genes from the same or a closely related species are inserted to improve yield, confer greater tolerance to drought and heat, and increase nutritional value.

• The rice plant species most commonly consumed is Oryza sativa, which only has 12 chromosomes and a total of 430 megabases, which is a nucleotide length of 1 million base pairs. This makes it an excellent candidate for plant genomics.