Podcast Summary
From Science Fiction to Reality: The Evolution of Synthetic Biology: Synthetic biology emerged as an interdisciplinary field to understand complex biological networks using engineering principles, leading to significant advancements in therapeutics and manufacturing.
The field of synthetic biology has evolved significantly over the past 20 years, moving from science fiction to reality, with applications ranging from therapeutics to manufacturing. This episode features a conversation between Vijay Pandey, general partner on the BioHealth Fund at a16z, Hannah Winarsky, editorial partner, and Professor James J. Collins of MIT, one of the pioneers in the field. They discuss the origins of synthetic biology, the differences between how biologists and engineers approach problems, and the impact of synthetic biology on education. The field emerged as a response to the limitations of the genome effort, which could identify genes but not the underlying networks that make up living cells. Engineers and physicists were brought in to help understand these networks and reverse engineer large-scale biological systems, using engineering concepts like reverse engineering a network, which involves understanding how interconnected parts function together. This interdisciplinary approach has led to significant advancements in the field and continues to shape the way we approach biological problems.
Designing synthetic biological networks: In the late 1990s, scientists turned to designing their own biological networks instead of reverse engineering them, leading to the field of synthetic biology and the creation of a genetic toggle switch as an example of designed functionality.
Just as you might reverse engineer the circuitry of your home to understand how different systems are connected, scientists faced a similar challenge in understanding complex biological networks. In the late 1990s, they lacked the necessary data and technology to reverse engineer large-scale biological networks, so they turned to a tinkerer's approach. Instead of figuring out how the networks were wired together naturally, they began designing and building their own circuits with intent. This approach, known as synthetic biology, allowed them to create desired architectures and functions. After much thought, they decided to build a genetic toggle switch, inspired by electrical engineering's memory elements. By designing a mutually inhibitory network, they created a bistable system that could exist in two stable states. This shift from reverse engineering to design marked a significant turning point in the field of systems biology.
Creating a Genetic Toggle Switch: Perseverance and Interdisciplinary Collaboration: Researchers at MIT and Princeton independently developed genetic toggle switches, demonstrating the power of interdisciplinary collaboration and perseverance in scientific discoveries.
A team of researchers, led by Tom Knight at MIT, aimed to create a genetic toggle switch using mathematical modeling and persistence. Despite skepticism from molecular biologists, who believed it was impossible due to the complexity of the cellular environment, a graduate student named Tim Gardner successfully built a functioning toggle switch in just nine months. Simultaneously, two physicists, Michael Elowitz and Stan Leibler, were working on a similar approach at Princeton, leading to the creation of a repressilator or ring oscillator. Both teams published their findings in the journal Nature back-to-back in late January 2000, marking a significant milestone in the intersection of physics and molecular biology. This story illustrates the importance of perseverance, interdisciplinary collaboration, and the power of engineering principles in advancing scientific discoveries.
Science and Engineering: Overcoming Culture Clash for Interdisciplinary Success: Science and engineering's distinct perspectives can lead to criticisms and misunderstandings, but interdisciplinary collaboration is crucial for progress. Engineers and scientists can benefit from each other's discoveries and technologies, enabling new avenues for research and applications.
The fields of science and engineering, particularly in the context of biology and chemistry, often face criticisms and misunderstandings due to tribalism and differing modes of knowledge. Biologists and engineers approach problems from distinct perspectives: scientists are driven by curiosity and discovery, while engineers are more purpose-driven and focused on applications. This culture clash can lead to valid criticisms, but it also overlooks the value of interdisciplinary approaches and the synergy between science and engineering. For instance, engineering can benefit from scientific discoveries and open up new avenues for research, while science can benefit from engineering technologies that enable the exploration of new questions. The use of E. coli as a workhorse in molecular biology is a testament to the importance of interdisciplinary collaboration and the value of different perspectives in advancing scientific and engineering knowledge. Despite the differences, the synergy between science and engineering is essential for making meaningful progress in understanding complex systems.
Engineering Bacteria: From Sensors to Therapeutics: Engineers have applied traditional principles to bioengineer bacteria as sensors, diagnostics, and therapeutics, leading to successful companies like Synlogic.
The field of engineering bacteria as living technologies began with the assumption that most of the genes in E. Coli were already understood, but this turned out to be far from the truth. Despite this surprise, engineers continued to push the boundaries, initially focusing on creating bacteria as sensors for detecting environmental threats. As the concept of the microbiome gained prominence, the potential for engineering bacteria as living diagnostics and therapeutics became increasingly exciting. This led to the founding of Synlogic, which now has multiple clinical trials and is using E. Coli to treat various conditions, including rare genetic metabolic disorders, inflammatory bowel disease, and cancer. The success of Synlogic demonstrates that engineers can apply existing engineering principles and techniques to the bioengineering space, but new approaches are also continually being developed.
Engineers vs Researchers Approaches in Synthetic Biology: Engineers adopt parallel approach, focusing on making things work, while researchers prefer serial approach, delving deep into one design. Bridging this gap could lead to more efficient progress in synthetic biology.
While both synthetic biology researchers and engineers share the common goal of creating functional prototypes, they approach the process from different perspectives. Engineers tend to adopt a parallel engineering approach, exploring multiple possibilities simultaneously and iteratively improving upon the closest fit. In contrast, researchers often prefer a serial approach, drilling down deeply into one design before moving on to the next. This cultural divide arises from the differing priorities: scientists are driven by a curiosity to understand, while engineers prioritize making things work. However, there is a lack of significant buy-in from engineers for using techniques like directed evolution, which could help improve prototypes to desired levels. The challenge lies in establishing design principles in synthetic biology, as we don't yet have a solid understanding of the relationships between variables, leading to a trial-and-error process. Ultimately, bridging this gap between engineering and scientific approaches could lead to more efficient and effective progress in the field.
Advancements in Synthetic Biology through the Intersection of Engineering, Biology, and Machine Learning: Nobel Prize-winning work in directed evolution optimizes biological systems, machine learning predicts and optimizes these systems, and their intersection allows for the exploration of genotype-phenotype spaces, leading to significant advancements in synthetic biology.
The intersection of engineering, biology, and machine learning is leading to significant advancements in the field of synthetic biology. Frances Arnold's Nobel Prize-winning work in directed evolution, which optimizes biological systems, is challenging traditional engineering approaches. Machine learning, in turn, is enabling the prediction and optimization of these systems, making it a promising frontier in synthetic biology. However, generating enough data for machine learning models remains a challenge. The combination of directed evolution and synthetic biology, which allows for the exploration of genotype-phenotype spaces that would be difficult to reach through evolution alone, is key to making significant progress in this field. The blurring of lines between traditional scientific disciplines and the rise of interdisciplinary research are driving these advancements. While some researchers will continue to focus on their specific areas of expertise, the interdisciplinary approach is leading to new discoveries and innovations.
The intersection of synthetic biology and data analytics: Synthetic biology's potential is significant but faces economic viability challenges, with recent success in biomedicine and high-value molecule production.
The intersection of quantitative approaches in science, particularly in the field of synthetic biology, and data analytics, including machine learning and computer-based modeling, is becoming increasingly dominant as we strive to make sense of the vast amounts of data we can now collect. However, synthetic biology has faced challenges due to excessive hype and unrealistic expectations, which have led to disappointing results and a collapse of investment in the field. This hype was fueled by the romantic notion of engineering life to solve global problems and the belief that synthetic biology could produce bioenergy at a large scale, but the technology was not yet ready for that level of commercialization. The field has since refocused on building out tools, constructs, and platforms, and has found success in areas such as biomedicine and the production of high-value molecules. The potential of synthetic biology is significant, but the jury is still out on whether it can be economically viable for many companies.
Deciding Between Platform and Product Companies in Synthetic Biology: Platform companies focus on internal capabilities for engineering organisms and producing multiple products, while product companies engineer organisms for specific diseases and bring products to market. The choice depends on company goals and resources.
When it comes to building a company in the synthetic biology space, there are distinct differences compared to traditional bio companies. A key decision that needs to be made is whether to build a platform company or a product company. Platform companies focus on developing internal capabilities to engineer organisms and produce multiple products, while product companies focus on engineering organisms to address specific diseases and bring products to market. The choice between the two models depends on the company's goals and resources. Synlogic is an example of a product company, while Ginkgo Bioworks is a platform company. Platform companies typically attract technology investors, while product companies appeal to traditional biotech investors. Historically, there have been cycles of focus on platforms and products, and currently, there is a shift towards interest in platforms from biotech investors. However, there is a risk of becoming a single asset company if too much focus is placed on one asset, so it's important for companies to also invest in building long-term internal capabilities, such as design and manufacturing, to increase their value.
Deciding the go-to-market strategy for synthetic bio products: Early synthetic bio companies face challenges in choosing between partnerships and independent product development, deciding which application to focus on, and navigating education opportunities while addressing safety concerns.
The go-to-market strategy for synthetic bio products or platforms involves significant considerations, especially for early companies. The decision to partner or develop a product independently comes with challenges such as timing, value for investors, and market opportunities. Synthetic biology's potential to tackle various issues also brings the challenge of deciding which application to focus on. Education is one area where synthetic biology is percolating down, with the introduction of BioBits kits. These kits, inspired by chemistry sets, allow users to experiment with cell-free extracts outside a living cell, making synthetic biology more accessible for education purposes. However, safety concerns remain, as these experiments should not be conducted at home. Overall, the synthetic biology landscape requires teams with the flexibility to adapt to changing markets and opportunities.
Learning Synthetic Biology: The Future of Science and Technology: Synthetic biology offers potential solutions to global challenges like world hunger, climate change, and environmental degradation by designing and engineering proteins and circuits. Inspire the next generation to tackle these complex issues and create a sustainable future.
The future of science and technology lies in the field of synthetic biology, and it's crucial to introduce this concept to young minds at an early age. Comparing it to an owl pellet kit for cells, synthetic biology offers the potential to design and engineer proteins and circuits, addressing global challenges such as world hunger, climate change, and environmental degradation. Synthetic biology is expected to provide solutions in areas like carbon capture, coral reef preservation, and creating synthetic ecosystems. The next decade will see significant progress in these areas, and it's essential to cultivate talent and comfort with these technologies. While it's challenging to predict the full extent of what synthetic biology will achieve in 50 years, the potential is immense. By introducing the concepts and principles to young people, we can inspire the next generation of scientists and engineers to tackle these complex issues and create a sustainable future.
