The Self-Synthesizing Ribosome
This cellular factory-on-a-chip could be used to design, produce, and test drugs against antibiotic resistant bacteria
REHOVOT, ISRAEL—April 20, 2020—As the cell’s protein factory, the ribosome is the only natural machine that manufactures its own parts. That’s why understanding how the machine itself is made could unlock the door to everything from understanding how life develops to designing new methods of drug production. An intensive research effort at the Weizmann Institute of Science has now demonstrated the self-synthesis and assembly of the small subunit of a ribosome – 30S – on a surface of a chip. The findings were published in Science Advances.
Prof. Roy Bar-Ziv and Dr. Shirley Shulman Daube of the Institute’s Department of Chemical and Biological Physics have been working on this project for around seven years. One of the main challenges in such an effort is the sheer number of different molecules the cell must produce to make the subunit, the core of which is a long strand of RNA with 20 different proteins attached. These get organized by the weak chemical forces between the protein molecules and the RNA – repelling at some points and attracting in others – and the whole structure thus relies on the proper manufacture and organization of each component. Add to that another six proteins that are not part of the structure, but which act as chaperones to assist in the assembly. That makes at total of a least 27 different genes – one to encode each component or chaperone – that must work together to make subunit 30S.
Together with postdoctoral fellow Dr. Michael Levy, who led the current study, and research student Reuven Falkovich, the team produced the subunits on tailored chips developed by Prof. Bar-Ziv. Ultimately, the scientists succeeded in mimicking the natural process of synthesizing the parts and assembling them into the ribosome subunits. The tiny chips in Prof. Bar-Ziv’s lab are based on densely packed DNA strands attached at one end to the surface. The team initially used all 27 genes needed to reproduce 30S from an E. coli bacterium. The components were caught in “molecular traps” placed near their genes, which improved the efficiency of the process and enabled the scientists to observe the production process in real time. They then took a step back, allowing the various parts to autonomously assemble themselves into the ribosomal units without outside direction or interference.
In the beginning, Prof. Bar-Ziv and Dr. Shulman Daube found that while they could make the components, getting them to self-assemble, as the natural structures do, was a challenging hurdle. Over the course of the next seven years and hundreds of trials, the scientists tracked down the proper placement of the genes on the chips. Similar to the organization of genes in the chromosome, the genes on the chip had to be positioned in the right locations, and in the proper relative quantities. This, it turned out, was crucial to the overall orchestration of the complex assembly process. Each time, the scientists would attach a different constellation of genes to the chips, narrowing down the possibilities until they had a composition that could mimic that natural process of subunit production as well as self-assembly.
In nature, subunit assembly is a hierarchal process. In the course of their experiments, the scientists were able to break down the assembly to the individual steps to prove that the end result was a self-assembled subunit, and to observe the roles of the chaperones in this process.
Prof. Bar-Ziv and Dr. Shulman Daube believe that this new insight into producing complex, multi-component structures could pave the way to creating all sorts of other complex molecular structures – existing ones as well as those not yet found in nature. Thus, for example, structures found in disease-causing bacteria might be produced for the purpose of safely testing and manufacturing drugs, vaccines, or diagnostics without using whole, infectious bacteria.
In the future, the self-assembly method could lead to the development of novel types of vaccines, as well as assembly lines for various complex molecules for a range of industries.
Prof. Roy Bar Ziv’s research is supported by the Clore Center for Biological Physics.
The Weizmann Institute of Science in Rehovot, Israel, is one of the world’s top-ranking multidisciplinary research institutions. The Institute’s 3,800-strong scientific community engages in research addressing crucial problems in medicine and health, energy, technology, agriculture, and the environment. Outstanding young scientists from around the world pursue advanced degrees at the Weizmann Institute’s Feinberg Graduate School. The discoveries and theories of Weizmann Institute scientists have had a major impact on the wider scientific community, as well as on the quality of life of millions of people worldwide.