While scientists have long dreamt of co-opting the process by which microorganisms naturally produce antibiotics and other biologically active compounds, successful bioengineering of nature’s molecular assembly processes has been out of our reach. It’s as though we have been watching steel, plastic and rubber go in one end of an automotive manufacturing plant, and seeing completed cars emerge from the other, but with little knowledge of the steps between start and the finish. Perhaps we’d like to make some changes to produce a Porsche instead of a Volkswagen? No such luck—unless we could get our hands on a blueprint that explains the assembly process. And that’s precisely what three faculty members from the Life Sciences Institute have made possible with recent findings published in Nature: They’ve developed a blueprint for the assembly of complex macromolecules in bacteria.
As a scientist, I’m amazed and thrilled by this beautiful work and its potential for improving human health. And as the director of the LSI, I know firsthand that our non-traditional organization and culture made this work possible.
These three individuals had not worked together before they came here, and probably never would have if they had followed the course of traditional scientific careers.
David Sherman, who has been a faculty member in the LSI since 2003, explores the biochemical pathways of marine microorganisms with the goal of finding new drug candidates for infectious diseases and cancers. He collects samples from marine and terrestrial sources around the world to build an extensive library of natural chemical compounds with disease-fighting potential, and conducts molecular genetic analysis of the biosynthesis of natural products.
One of the most vexing questions that he and others in the field have faced, has been, “How do these microorganisms make these drugs?” Answering that question—getting our hands on the blueprint of the molecular factory—would mean having the ability to modify the assembly process to create more powerful drugs and really impact human health.
Janet Smith, a structural biologist who uses X-ray crystallography to determine the structures in detail and thus functions of proteins, joined the LSI a year after Sherman. Smith figured out the forms of individual parts of the factory. But even after combining knowledge from their areas of specialty, Sherman and Smith still couldn’t fully see the whole assembly line or determine how the pieces fit together
Proteins like the ones Smith and Sherman were studying are relatively large, yet delicate. To see them in a microscope without damaging them is difficult—they quickly disintegrate when extracted from their native environment. And Smith’s crystallization work can’t quite elucidate structures of macromolecules that have moving parts. But in order to understand how the molecular factory was making chemical compounds, they needed to see the machine in action—and observe it moving.
And so they recruited the third member of this extraordinary team to take the analysis to another level: Georgios Skiniotis, an expert in a technique called cryogenic electron microscopy, or “cryo-EM”, who joined the LSI in 2009. By quick-freezing the proteins studied by Smith and Sherman, Skiniotis was able to fix the molecules in place without damaging them, and then use high-resolution electron microscopy to take photographs of the molecules in different positions. Seeing the complex in its native state, and in various positions as it executes its functions, ensures the physiological relevance of the findings.
It’s fantastic work, maximizing scientific creativity and technological capabilities, and it could only have happened in a place like the LSI. The three researchers and their collaborators harmonized to create an understanding of a key biological process that is far beyond what any of the individuals could have reached. Their finding represents a quantum leap in how we think about making new medicines, and will have an indisputable impact on science and human health.
This story also illustrates that deep collaboration requires more than scientists in complementary disciplines sitting next to each other in a building. Driven to understand more than what their individual disciplines could deliver, all three of these investigators aggressively sought to connect with others outside their field. Each knew that their goals required them to take risks, and to step outside their “comfort zone” to challenge their usual way of looking at problems. The result was a deep dive into the meaning of this basic biological and chemical process common to thousands of organisms on earth that has eluded researchers for years.
Understanding the structure of the assembly process that creates polyketides, a broad class of diverse and bioactive chemical compounds that comprises some of the most important antibiotics, antifungal agents, cancer chemotherapeutics, and immunomodulators in wide clinical use gives investigators a solid blueprint for redesigning the microbial assembly line to produce a new generation of novel drugs.
So now, with this work, we can see the factory that makes these powerful medicines. We are no longer speculating about how the assembly line works. Instead, we can begin to imagine the other drugs we can make using this remarkable machine—next-generation antibiotics that evade resistance, more effective cancer treatments, safer anticholesterol therapeutics—and continue to follow the science until we realize the full potential for impact of this discovery on human health.