The particular Gene-Synthesis Revolution

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Ten years ago, when Emily Leproust was a director of research at the life-sciences giant Agilent, a pair of scientist-engineers in their 50s — Bill Banyai and Bill Peck — came to her having an idea for an organization. The Bills, while they were later dubbed, were biotech veterans. Peck was a mechanical engineer by training with a specialty in fluid mechanics; Banyai was a semiconductor expert who had worked in genomics because the mid-2000s, facilitating the transition from old-school Sanger sequencing, which processes a single DNA fragment at a time, to next-generation sequencing, which works through an incredible number of fragments simultaneously. If the chemistry was miniaturized and put on a silicon chip, reading DNA became fast, cheap and widespread. The Bills, who met when Banyai hired Peck to work on a genomics project, realized that there was an opportunity to make a move analogous for writing DNA — to really make the process of making synthetic genes more scalable and cost-effective.

At the time, DNA synthesis was a slow and difficult process. The reagents — those famous bases (A’s, T’s, C’s and G’s) that define DNA — were pipetted onto a plastic plate with 96 pits, or wells, each of which held roughly 50 microliters, equivalent to one eyedropper drop of liquid. “In a 96-well plate, conceptually what you have to do is you put liquid in, you mix, you wait, perhaps you apply some heat and then take the liquid out, ” Leproust says. The Bills proposed to place this same process on a silicon chip that, with the same footprint as a 96-well plate, would be able to hold a million tiny wells, each with a volume of 10 picoliters, or less than one-millionth the size of a 50-microliter well.

Since the wells were so small, they couldn’t simply pipette liquids into them. As an alternative, they used that which was essentially an inkjet printer to fill them, distributing A’s, T’s, C’s and G’s rather than pigmented inks. A catalyst called tetrazole was added to bind bases into a single-strand sequence of DNA; higher level optics made perfect alignment possible. The upshot was that instead of producing 96 pieces of DNA at exactly the same time, they could now print millions.

The concept was simple, but, Leproust says, “the engineering was hard. ” Whenever you synthesize DNA, she explains, the yield, or success rate, goes down with every base added. A’s and T’s bond together more weakly than G’s and C’s, so DNA sequences with more and more consecutive A’s and T’s are often unstable. In general, the longer your strand of DNA, the greater the probability of errors. Twist Bioscience, the company that Leproust and the Bills founded, currently synthesizes the longest DNA snippets in the industry, around 300 base pairs. Called oligos, they are able to then be joined together to form genes.

Today Twist charges nine cents a base pair for DNA, a nearly tenfold decrease from the industry standard a decade ago. As an individual, you can visit the Twist website, upload a spreadsheet with the DNA sequence that you would like, select a quantity and pay for it with a charge card. After a few days, the DNA is brought to your laboratory door. At that point, you can insert the synthetic DNA into cells and obtain them to begin making — hopefully — the target molecules that the DNA is coded to produce. These molecules eventually end up being the basis for new drugs, food flavorings, fake meat, next-gen fertilizers, industrial products and services for the petroleum industry. Twist is one of a number of organizations selling synthetic genes, betting on the next filled with bioengineered services and products with DNA as their building blocks.

In a way, that future has arrived. Gene synthesis is behind two of the biggest “products” of the past year: the mRNA vaccines from Pfizer and Moderna. Very nearly as soon as the Chinese C. D. C. first released the genomic sequence of SARS-CoV-2 to public databases in January 2020, the two pharmaceutical companies were able to synthesize the DNA that corresponds to a specific antigen on herpes, called the spike protein. This meant that their vaccines — unlike conventional analogues, which teach the immune system to identify a virus by introducing a weakened version of it — could deliver genetic instructions prompting the body to create just the spike protein, so it will be recognized and attacked throughout an actual viral illness.

As recently as 10 years ago, this would have been scarcely feasible. It would have now been challenging for researchers to synthesize a DNA sequence long enough to encode the full spike protein. But technical advances in the last few years allowed the vaccine developers to synthesize considerably longer pieces of DNA and RNA at reduced cost, more rapidly. We’d vaccine prototypes within weeks and shots in arms within the year.

Now companies and boffins look toward a post-Covid future when gene synthesis is going to be deployed to tackle a variety of other dilemmas. If the first phase of the genomics revolution focused on reading genes through gene sequencing, the second phase is about writing genes. Crispr, the gene-editing technology whose inventors won a Nobel Prize last year, has received much more attention, but the rise of gene synthesis promises to be an equally powerful development. Crispr is similar to editing an article, allowing us to make precise changes to the writing at specific spots; gene synthesis is similar to writing the article from scratch.

Like many technologies in their infancy, gene synthesis (along with the field it has enabled, synthetic biology) has sparked a good deal of speculation and start-up activity. All of the companies — excepting those working on the coronavirus — come in experimental phases; their applications have yet to return conclusive results. Still, the possibilities captivate both investors and scientists, whether they are fabricating microorganisms to create industrial chemicals or engineering human cells to treat medical disorders. If even a small percentage of these efforts succeed, they could cause trillion-dollar markets. The analogy frequently used by biotech venture capitalists is that we have been in the Apple II days of synthetic biology, with roughly the same as iMacs and iPhones still to come. It’s a grandiose claim — but not implausible, especially now that Covid has battle-tested a number of the underlying technologies. Personal computing created our digital lives; reading and writing DNA could mean get a handle on over our physical ones.

Illustration by Jaedoo Lee

One of the aphorisms of synthetic biology is this: Nature is the best innovator . For example , CaS-9, the “cutting” enzyme used in Crispr, was originally a defense that bacteria evolved to fight off viruses. But the aphorism glides over the proven fact that for most of history, nature has also been opaque, requiring that humanity stumble upon its inventions entirely by chance. Penicillin, quinine — many of our medicine-cabinet staples have been discovered from leaving food out for a long time or by locating the active ingredients in herbal solutions. Only since the advent of modern chemistry have we had the oppertunity to write down the sort of formulas that are common in physics and math.

Then came the genomics revolution. The first phase, marked by milestones like the sequencing of the human genome and by the emergence of businesses like 23andMe, centered on reading genes. The next phase, just underway, is about writing genes. It is now possible to take our understanding of molecular biology — how DNA specifies the sequence of RNA, which specifies the production of proteins — and use Crispr and DNA synthesis to devise genetic recipes that produce the outputs we would like. So what does this look like in practice?

Among Twist’s biggest customers is Ginkgo Bioworks, a cell-engineering company that went public to much fanfare in September and by mid-November was valued at $25 billion. Ginkgo’s main offices occupy a converted warehouse in Boston’s seaport district. When I visited a few months ago, Patrick Boyle, a Ginkgo executive, walked me through their five “foundries” — so named after microchip fabrication plants. We passed one machine that uses microfluidics technology to mix reagents and cells and another that uses mass spectrometry to rapidly analyze the chemical composition of liquids.

For many years, the fundamental labor unit of biological research has been the lowly grad student, who toils away pipetting liquids, taking measurements, looking through results and, if lucky, maybe owning a few experiments per month. Ginkgo, in contrast, has had an assembly line’s efficiency to the lab, utilizing machines that can pipette, mix and assay with far more precision than any human ever could, therefore to be able to run thousands of different experiments at the same time.

Ginkgo is a “platform” company — as opposed to producing end products and services for itself, it engineers cells because of its clients. The process goes roughly like this: A customer calls up Ginkgo and says, “We’re looking to produce a rose scent for our perfumes that’s cheaper than distilling it from flowers. ” Ginkgo’s designers comb by way of a library of genes and pick out the ones that are known from previous observation or sequencing to produce the characteristics of rose oil. After these sequences are organized on a computer, Ginkgo orders the DNA from Twist or other providers, who do much of the synthesizing of the bottom pairs.

At Ginkgo, the synthesized DNA is then inserted in to a host cell, perhaps yeast, which starts producing enzymes and peptides. Trial and error follow. Maybe the outputs from the first gene sequence are too floral, not spicy enough; maybe those from the second gene sequence have the best scent, but the cells don’t produce enough of it. Once an effective prototype is available, Ginkgo increases its production by growing the yeast in large vats and streamlining a process for extracting the desired molecules from the soup. What Ginkgo delivers is a recipe and ingredients — the winning genetic code, the host cell and the conditions in which the cells need to be nurtured — that the client can then use on its own.

Ginkgo’s platform first attracted customers in the fragrance industry, in the last two years it’s been partnering with pharmaceutical companies to search for new therapeutics. One such project is seeking to uncover the next generation of antibiotics, in order to counter antibiotic resistance. Lucy Foulston, whose back ground is in molecular microbiology, is leading the effort; Tom Keating, a chemist, is working with her. Together, they highlighted for me personally a beautiful, twisted paradox — most antibiotics, and most antibiotic resistance, come from bacteria themselves. Bacteria carry genetic snippets with directions to produce antimicrobial molecules that kill other bacteria. Typically there is also a capacity for self-resistance, so that the bacteria building a particular antibiotic avoid killing themselves, but this resistance may be transferred among bacteria, so that it becomes widespread.

Historically, two paths have been taken fully to come up with new antibiotics. The first, celebrated in stories of Alexander Fleming and moldy bread, is to seek them in the natural world: Boffins go out, obtain a little soil from a geyser or coral reef, put what they find in a petri dish and see whether it kills any interesting bacteria. The second approach is to comb through chemical libraries looking for molecules that show antibacterial activity. Together, these two approaches gave us a steady method of getting new antibiotics up to the 1980s and ’90s, when discoveries began to dry up.

“There was plenty of speculation, ” Keating says. “Did we find all the of good use ones? Did we find everything that was easy to find? Did we run into bacteria which can be now so difficult to kill that the newest ones we find don’t really work in it? ” Whatever the reason, the reality is that we’ve been running out of new antibiotics in the face of growing antibiotic resistance.

‘I think what we’re just scratching the surface of is, can we program biology to complete what chemists have traditionally done. ’

The antibiotics project at Ginkgo is looking through bacterial genomes for segments encoded to generate novel antimicrobials. The sequencing efforts of the ’90s and 2000s yielded large databases of bacterial genomes, both public and private, that have given boffins an increasingly sophisticated comprehension of which genes produce which molecules. And scientists have also developed the necessary techniques to, as Foulston says, “take these genes out, put them in another bacterial strain” — one they know how to work with — “and then coax that particular strain to create the molecule of interest. ”

Keating continues: “We don’t need the organism anymore. We don’t need it to be growing on a plate. We don’t need it to be killing whatever else. All we need may be the code. ”

No matter how many programming metaphors you utilize, DNA is messier than code. In the event that you type “print ‘hello world, ’” you anticipate the computer to come back “hello world. ” If you synthesize a DNA sequence, ACTCAG, and put it in a cell, you might be able to predict with some confidence what comes out of the cell, however, you never really know.

Nevertheless, biotech is here at a singular new moment — one in which software, hardware, data science and lab science are typical finally mature enough to work together and reinforce one another. mRNA vaccines, which was not approved by the foodstuff and Drug Administration before the pandemic, really are a prime example; Ginkgo’s antibiotics project is another. And further advances in machine learning and computer modeling will only multiply the options. The same goes for semiconductors: As small as one of Twist’s 10-picoliter wells may appear, Leproust points out that from the perspective of the 21st-century semiconductor industry, it’s “a Grand Canyon, almost like being in the Stone Age. ” Already, the company is tinkering with chips whose wells are more than 300 times smaller, with diameters of 150 nanometers. (For reference, Intel is now fabricating seven-nanometer silicon chips for computers. ) It’s a progression that promises to reduce the cost of gene synthesis a millionfold and make it accessible to ever more researchers and useful in a lot more experiments and applications.

For synthetic biology, the next frontier is to go where even nature hasn’t gone. Instead of wanting to replicate the scent of a rose, can we combine genes to produce much more intoxicating aromas? Can we turn DNA into circuits that enable cells to behave as living computers? “So far, we’re just taking what nature has already invented, copying it, maybe optimizing it, ” Keating says. But he aspires to the sort of command and creative power now enjoyed by chemists, who can synthesize whatever can be diagrammed. “I think what we’re just scratching the surface of is, can we program biology to do what chemists have traditionally done, ” that he says. “If you are able to draw a molecule on a piece of paper, can we engineer an organism to create that molecule, even when it’s something that nature has never seen before? We’re nowhere near that — but, you know, baby steps. ”

Yiren Lu is a writer and software engineer based in New York. She last wrote for the magazine about start-ups trying to fix virtual meetings.

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