How Constructive Bio is building beyond nature with Benchling

Over the last two decades, the Chin Lab has redefined what’s possible at the intersection of biology and chemistry, advancing the field of synthetic biology. Seeing an opportunity to advance synthetic biology, Constructive Bio emerged as a leader in the field, pioneering genome writing and genetic code reprogramming.

Built on twenty years of academic innovation, combined with advanced technology and AI, Constructive Bio is expanding the toolkit available to biology. By reprogramming cells to function as sustainable biofactories, the company is shaping the future of synthetic biology and creating the next generation of biologic drugs.

Reprogramming the genetic code

Constructive is revolutionizing biotechnology with a two-pronged approach: whole genome writing and engineered protein translation. By assembling small DNA segments into large and complex (megabase-scale) fragments, the team can replace natural genomes with synthetic ones. These synthetic genomes allow for extensive genetic reprogramming, equipping cells with a toolkit to create biomolecules using an extended set of building blocks beyond the 20 amino acids typically found in nature.

By programming cells to incorporate these new building blocks (new-to-nature monomers), Constructive can discover and produce polypeptides with enhanced properties, such as increased stability, binding ability, and resistance to degradation, at scale. Where natural peptides may lack the stability needed for practical applications, this expanded chemistry provides new options for improved functionality.

Through the addition of valuable molecular properties, Constructive is not only developing better drug candidates, but is doing so in a sustainable and scalable way. “What we're particularly excited about is the ability to convert conventional chemical-based synthesis into a process which is dictated by biology,” shares CEO Ola Wlodek. Rather than using harmful solvents in large quantities as with chemical synthesis, Constructive can engineer cells to directly synthesize the target molecule with techniques that are readily scaled and built on decades of innovation.

“We think there are a lot of applications within therapeutics, as well as other types of biomaterials which hopefully one day could include things like programmable bioplastics,” Wlodek explains. With applications across pharma, agritech, and industrial biotech, the possibilities abound.

The next generation of therapeutics

Harnessing their science and technology, Constructive is employing synthetic genomes and non-canonical amino acids to unlock a vast array of applications. One of the biggest opportunities lies in the development of next-generation therapeutics, with transformative molecules already gaining recognition for their significant impact on diabetes and weight loss worldwide.

For example, semaglutide — an active ingredient in drugs such as Ozempic and Wegovy — incorporates a non-canonical amino acid to improve drug stability. By incorporating these new chemistries, one can add beneficial properties like stability or resistance to certain proteases, enabling the druggable target to be acted upon.

Constructive’s technology also enables the production of other therapeutic peptides and proteins comprising designer, site-specific intermolecular linkages. This innovation paves the way to the discovery and development of entirely novel therapeutic modalities that combine functionalities of multiple drugs to address shortcomings of existing treatments.

Another opportunity for impact lies in antibody-drug conjugates. Currently, the conjugation of drugs to antibodies is nonspecific, introducing various issues regarding stability, therapeutic index, and more.

“With our technology, you can introduce these non-canonical amino acids, which means you can precisely determine where the cytotoxic payload is going to be conjugated,” explains Wlodek. With Constructive’s ability to design molecules with unprecedented specificity and fidelity, the potential to bring new biologics into the clinic, and then manufacture them in a sustainable manner, is at the forefront of the company’s mission.

Scaling efficiently with technology

To achieve the degree of scale needed to reach such outcomes, the team naturally sought the right technology, with a focus on accelerating the design and creation of synthetic genomes for target applications.

“Biology has evolved genome sequences to be perfected over billions of years, and we make profound changes to those sequences. Predicting what genome designs yield the optimal cells for our purposes is no easy task, but we are trying to accelerate our ability to predictively design and construct those genomes in the scale of weeks,” explains Wlodek. Foundational to this process is a vast amount of genomics data, as well as subsequent analyses of how changes to the genetic code impact everything from cell growth to transcription and translation at the molecular level.

Constructing optimally designed genomes depends on choosing the right platform. For Constructive, Benchling was the obvious solution. “We needed something that was going to be reliable and scalable as the company grows, so to some extent it felt like the natural choice,” expresses Daniel de la Torre, Head of R&D. “From the early stages, we identified that it was going to be really important to set up that system.”

As their ground source of truth, Benchling enables Constructive to centralize raw experimental data while linking it to strain inventory, analysis, and reporting. With a platform that produces thousands of different bacterial strains and plasmids, in multiple formats and for various purposes, Benchling allows the team to organize and track materials across teams and projects.

“We can create our entities and notebook entries, tailoring them to the type and granularity of information that we want to record,” explains de la Torre. “This has been very helpful in standardizing and streamlining the input of data by scientists.” As one of the first solutions put in place by the R&D team, Benchling has been foundational to Constructive’s growth from early stages, setting the company up for success now and in the future.

Developing, expanding, and growing at Constructive

Building on decades of academic innovation, Constructive is continuing to pioneer advancements in the field of synthetic biology. Harnessing the power of machine learning, the ability to predict a biological output based on modifications made on a molecular level, has the potential for far reaching influence, expanding the toolkit available to biology across industries.

As the ability to design and create new genomes grows, so does the company. Constructive is focusing on hiring new talent this year and invites you to join their team of experts to explore the future of drug discovery and biomanufacturing.