If the 20th century was the era of molecular biology, the 21st century may well be the time of structural biology, an exciting field of study where basic research is directly linked to real-world applications.
Structural Biology is Overturning Conventional Wisdom in Biology
“To be honest, half of today's biology textbooks now contain errors.”
After creating a stir with this remark during our interview, Professor Osamu Nureki expanded on his meaning.
“More precisely, much of what is written in today's textbooks is already obsolete in terms of structural biology, which seeks to understand life with resolution at the atomic level. Our job as researchers is to correct those errors and create new knowledge in biology.”
Structural biology aims to elucidate the functions of biopolymers such as proteins and nucleic acids (DNA or RNA) that are composed of amino acids, from their three-dimensional structures. A protein is a macromolecule created by a gene with DNA as its blueprint. In accordance with the intent of molecular biology, which made great strides in the life sciences in the 20th century, we should be able to explain all the mechanisms of life phenomena by reading sequences of DNA, the so-called design drawings for proteins. However, the Human Genome Project, which started in the late 20th century and had deciphered all human DNA sequences by 2003, showed that this knowledge alone cannot fully explain the functions of proteins. So now, humankind faces new mysteries about life to explore.
In structural biology, we focus on the three-dimensional structures of proteins in order to solve these new mysteries. It is gradually becoming clear that proteins are not simply one-dimensional sequences of amino acids, but rather that they function by folding into three-dimensional structures. The keys to observing the three-dimensional structures of such proteins are technological innovations such as X-ray crystallography (*1), cryogenic electron microscopy (*2), and X-ray free electron lasers (*3). Thanks to these technologies, we can now visualize the three-dimensional structures of proteins at atom-level resolution.
It is in the battlefield of structural biology where Professor Nureki wields these new weapons. He is attempting to elucidate the mechanisms by which genes drive life phenomena that cannot be explained by conventional molecular biological approaches.
*1. X-ray crystallography: When a substance is irradiated with X-rays, some of the X-rays are scattered by electrons located around the atomic nuclei. Observing the scattered X-rays allows us to obtain data on this distribution of electrons in a substance and thus ascertain the three-dimensional structure of molecules and atoms. The BL32XU and BL41XU beamlines in Japan's large-scale radiation facility SPring-8 in Hyogo Prefecture, and the Swiss Light Source beamline in Switzerland are used for three-dimensional structural analysis of proteins.
*2. Cryogenic Electron Microscopy (Cryo-EM): A microscopy technique in which the image of a sample cooled to a low temperature is magnified and visualized using electrons. As the wavelength of an electron beam is shorter than that of visible light, it is possible to observe a sample at atom-level resolution, something that cannot be done with an optical microscope. As X-ray crystallography requires samples to be crystallized beforehand, cryogenic electron microscopy is more effective for the structural analysis of proteins that are difficult to crystallize.
*3. X-ray free-electron laser (XFEL): An X-ray laser that uses the light emitted from free electrons stripped from atoms in a synchrotron to allow the instantaneous movement of atoms and molecules to be observed. The SACLA XFEL source at SPring-8 in Japan and the Linac Coherent Light Source at SLAC in the United States are examples of XFEL systems in operation around the world.
Transforming Scientific Discoveries into Useful Tools for Society
Structural biology is a basic science that seeks to visualize the three-dimensional structure of biopolymers such as proteins and nucleic acids. However, it also generates direct links to practical applications.
In 2014, Professor Nureki determined the three-dimensional structure of a protein called CRISPR-Cas9 and published his findings in the scientific journal Cell. You might remember CRISPR-Cas9 as the name of the revolutionary genome editing technology for which the Nobel Prize in Chemistry was awarded in 2020. Genome editing is a technology that can modify genes with overwhelmingly higher accuracy than conventional gene recombination technology by inserting “scissors” into genes at targeted locations. The technology was made possible by Professor Nureki's determination of the three-dimensional structure of CRISPR-Cas9 at atom-level resolution. In other words, Professor Nureki made no small contribution to the 2020 Nobel Prize in Chemistry.
In December 2020, Professor Nureki ascertained the three-dimensional structure of CRISPR-Cas12f, which may yield a technology that is more convenient than that of CRISPR-Cas9 (his work was reported in the journal Molecular Cell). More advanced applications of genome editing technology are expected to be forthcoming.
“We have also founded a company to make the tools created from such basic research into applications that can be used in the real world,” says Professor Nureki.
Away from his research, Professor Nureki also serves as external director of the bio-venture Modalis Therapeutics, which was listed on the Mothers market of the Tokyo Stock Exchange in August 2020. One of the company's core technologies is an application of CRISPR Cas9 called CRISPR-GNDM, the purpose of which is to treat various genetic diseases while keeping patients alive.
“Scientific discoveries in themselves cannot be used as is. The fundamental science of structural biology transforms scientific discoveries into tools and innovations for society by seeking to understand the structure of discoveries revealed by science at atom-level resolution.”
Explaining Everything, from the Origin of Life to the Nature of Humans
Structural biology rewrites the biology textbooks with a dynamic approach that has been unthinkable until now. For example, it attempts to understand both the origin of life and how advanced eukaryotes such as humans are formed, by determining the structures of certain proteins.
“The origin of life can be thought of as the birth of cells capable of self-propagation. The formation of a cell requires a cell membrane, a structure that isolates the cell from the outside world. This is where membrane proteins come into play,” says Professor Nureki.
In the nucleus of the cell we find DNA, the blueprint of life that enables the self-propagation of life. Professor Nureki says that the proteins that make up about one-third of the genes in this DNA are the membrane proteins found in the cell membrane. Membrane proteins are involved in exchanging information between the interior and exterior of cells, and this function allows all cells in the human body to communicate with each other, a crucial and fundamental role in life phenomena.
The 2012 Nobel Prize in Chemistry saw the name of a family of membrane proteins called G protein-coupled receptors (GPCR) burst onto the scene. GPCRs are membrane proteins that are heavily involved in the transmission of information across the cell membrane, controlling information from that related to the five senses such as light, smell, and taste, to the transmission of hormones.
“The largest neuronal network regulated by GPCRs is the brain, the organ that makes us human,” says Professor Nureki. The brain is a high-density integrated circuit of GPCRs and membrane proteins known as channel transporters.
At present, one of Professor Nureki's main interests is to “see” these GPCRs at atom-level resolution. In other words, he hopes to ascertain the functions of GPCRs and channels from their three-dimensional structures, and to explain everything from life itself to the function of the brain, the essence of human beings. This research will also lead to the rewriting of biology textbooks.
This is the vision of atom-level resolution, a dynamic perspective that structural biology offers that was previously absent from conventional biology. Professor Nureki's laboratory is already conducting research on the brain and is currently focusing on the five senses and sensory reception.
The Basics of the Basics Lead to Applications
Professor Nureki has also launched a company called Curreio, Inc. that aims to develop technology to link structural analysis to drug discovery through the application of cryogenic electron microscopy, one of the key tools of structural biology. In December 2020, the company was developing RNA polymerase inhibitors specific to the novel coronavirus, an RNA virus, in a bid to provide a useful technology for society.
“Structural biology is an emerging discipline that combines physics, chemistry, and biology. Nowadays, cutting-edge research and advanced applied research often arise from such interdisciplinary fields, and one of the great attractions of the School of Science at the University of Tokyo is that it brings together all fields of natural science,” says Professor Nureki.
The School of Science is often thought of as a venue for basic research, but in Professor Nureki's view, the reality is much different. The expression that Professor Nureki likes to use is “the basics of the basics are applications.” This is a phrase that only Professor Nureki can use, as his research in structural biology, the very “basics of the basics” for determining the three-dimensional structures of proteins and nucleic acids, has led to advanced applications, drug discovery, and entrepreneurship.
“We seek to create knowledge that has lain hidden to date, using that knowledge to update our textbooks and advance science. By implementing that knowledge in society, we can change the world. I would urge anyone who wants to be active in such an exciting field to knock on the door of the School of Science.”
That's right. Science is a genuinely exciting and adventurous activity that is worthy of betting your life on.
Interview and text: Masatsugu Kayahara
Photography: Junichi Kaizuka