Torizawa is general manager of the Protein Science Research Department. He is currently in charge of the early stages of drug discovery to uncover molecules that could be candidates for new drugs. Chugai Pharmaceutical was the first domestic pharmaceutical company to introduce cryo-electron microscopy (cryo-EM), which has recently been garnering attention as an innovative technology. The company was able to implement the technology in just a short period of time. While looking back at the processes that have helped to streamline the drug discovery process, in this article Torizawa tells us about his thoughts and outlook for new drug development.

(Interviewee: Torizawa)

*Reproduced from Chugai Pharmaceutical’s official Talentbook page (https://www.talent-book.jp/chugai-pharm) Article details and employee positions are current as of October 2024

Attempting to Reform the Drug Discovery Process with Cryo-EM

Torizawa is general manager of the Protein Science Research Department (ProS Department) within the Research Division. Chugai Pharmaceutical’s three core drug discovery technologies are small-molecule, antibody, and now mid-size molecule drug discovery. Expectations are high for mid-size molecule drugs to become a new therapeutic modality (method of treatment), and this is the area in which Torizawa and his team are active.

 

“Many of the biomolecules targeted by diseases are proteins. At the ProS Department, we are in charge of the early stages of drug discovery, preparing and analyzing these proteins to discover molecules that could be candidates for new drugs.

Screening is a process that involves identifying these candidates from a vast library of different types of molecules. Our role is to prepare conditions suited to target proteins for this screening process. In some cases we might oversee a part of this screening process, and in others we take candidates that have been screened by other departments to eliminate false-positives and identify true positive molecules.

Moreover, once the candidates have been finalized, we also collect and analyze information that is required to develop the candidates into medicine, such as the three-dimensional structure of the molecules, the strength of the interactions between the molecules, and other characteristics,” says Torizawa.

 

One essential element in streamlining the process for selecting and developing these candidates into drugs is three-dimensional structural analysis. Obtaining and visually analyzing the three-dimensional structure when proteins bind to these candidate molecules enables the design of elaborate candidates.

Cryo-EM is a new method for obtaining images of this three-dimensional structure. The core technology for cryo-EM was awarded the Nobel Prize in Chemistry in 2017 and since then has been attracting attention as an innovative technology.

 

“Previously, a method known as x-ray crystallography was used to determine three-dimensional structures. With this method, however, the candidate protein had to be bound to the protein for crystallization.

But crystallizing large protein complexes or intracellular or cell membrane proteins was incredibly difficult, and obtaining images of these three-dimensional structures was a real challenge. As a result, developing the candidate molecule into a drug without a proper understanding of the three-dimensional structure required significant time and manpower.

On the other hand, cryo-EM allows for analysis without crystallization, enabling the early acquisition of a three-dimensional structure with high probability,” says Torizawa.

 

There are huge expectations for the streamlining of processes using cryo-EM.

 

Torizawa continues, “Previously, this crystallization process hindered the acquisition of three-dimensional structures, meaning that some projects spent years assessing candidate molecules. Cryo-EM has already started to have a huge impact on the drug discovery process, with projects that previously would have been been suspended due to the lack of a three-dimensional image now moving forward thanks to the new technology.

Using analytical information of three-dimensional structures makes it easier to understand how candidate molecules bind to and act on the target molecules. In turn, this enables the quick and efficient selection of multiple candidates with promising mechanisms that align with specific needs.

To date, there was no shortage of cases where after a long process to develop candidate molecules into something akin to a drug, it turned out that there were certain limitations.

Using cryo-EM, we are looking at ways to contribute further upstream in the drug discovery process by preparing several candidate molecules with positive modes of action.”

Background to Becoming the First Domestic Pharmaceutical Company to Adopt Cryo-EM

Torizawa says, “Around 2015 and 2016 we conducted a benchmark survey of other similar areas of research, and we learned the extent to which cryo-EM was contributing to technological innovation. Visualizing the details in three-dimensional structural analysis is incredibly important. At the time, however, structural images of how proteins and pharmaceutical candidate molecules bound together were not of a high enough resolution to actually be used in the drug discovery process, and we expected it to be many years before we could use these images for proper observations.

However, there was an instantaneous improvement in resolution which led to a huge step forward for practical use. In 2017, the biophysicists who developed the single particle analysis methods used in cryo-EM were awarded the Nobel Prize in Chemistry, and the technology went on to receive global acclaim.

Later, in 2018, Chugai Pharmaceutical began joint research with an institution with detailed knowledge of cryo-EM. In the UK at the time, consortiums were being formed by several pharmaceutical companies to share use of cryo-electron microscopes, and mega global pharmaceutical companies were beginning to introduce the equipment.

After carefully assessing the technological developments involving cryo-EM, and with a desire to introduce the equipment at the ideal timing, we submitted a report to research division management outlining the results we gleaned from joint research and the technology’s future potential. We proposed the introduction of cryo-EM equipment in 2020 and were given approval in the summer.”

 

Torizawa was group manager when the company first began considering the introduction of the cryo-EM technology. He knew that the technology was a unique opportunity to drive growth in his organization and contribute to the improvement of the drug discovery process.

 

He says, “In our research activities, x-ray crystallography was the base of our method for determining the three-dimensional structure. The handling of target molecules was becoming increasingly difficult year on year, and even though we assigned large numbers of researchers to the task, we were struggling to find effective ways to determine the three-dimensional structures of target proteins that did not crystallize.

It was precisely at this timing that we looked at the speed of development of cryo-EM technology and determined it would be an excellent alternative to x-ray crystallography. I remember thinking that as a tool for determining three-dimensional structures, it would be a breakthrough that would allow us to take drug discovery one step further, helping us overcome the difficulties surrounding difficult clusters of target molecules.”

 

In April 2021, Chugai Pharmaceutical became the first domestic pharmaceutical company to introduce cryo-EM technology. Key to this outcome was the company’s proactive approach to incorporating state-of-the-art technologies.

 

Torizawa recalls, “When we proposed the introduction of cryo-EM technology at a meeting attended by company management, both the president and other executives were very positive about the idea. The president even said he wished that we’d put forward the idea earlier.

In addition to management, our researchers also supported the technology’s introduction. This flexible mindset was a key factor to our proposal’s success. Despite being busy with x-ray crystallography and other work, it was great to have everyone so proactive about adapting to and building this new technology.”

Rapid Implementation of Cryo-EM. A Fresh Approach in the Drug Discovery Process

The critical steps for cryo-EM technology come after the equipment has been installed. It requires personnel with expert knowledge on how to use the technology, an IT infrastructure to process a huge amount of data, and numerous other challenges. Torizawa and his team addressed this seemingly never-ending list of tasks in just two years, ultimately bringing it to a level at which it could be used for drug discovery.

 

Torizawa says, “It is not as simple as installing the equipment and using it. We first had to prepare samples that were suited to cryo-EM.

The technology flash-freezes the sample on a grid that is 3 mm in diameter, but this requires expertise on how to handle samples in this environment. We also needed a technology to judge the quality of the samples based on images from the cryo-EM equipment, as well as a technology to analyze and process the data.

While working closely with our joint research partner, we hired specialists from outside the company and trained in-house researchers who previously worked on x-ray crystallography and other tasks from the ground up. In doing so, we were able to create an environment that gave us the confidence to say that we were using cryo-EM to design candidate molecules.”

 

As manager, Torizawa also had to look after his team members, and he paid close attention to team building.

 

“While some members of the team spent a huge amount of time learning the new technologies, others didn’t have the time. I therefore focused on building an awareness that we were all one team and that we were working together and supporting one another to improve our capabilities. We all had to learn while working on our existing tasks, and I knew that the team would become unbalanced if the new technologies were only used by those who had learned them first. I was aware that this imbalance would hinder our ability to maximize our capabilities.

In any case, the whole team was incredibly cooperative. I think another reason why the team functioned so well was because many of our employees had experience with x-ray crystallography, knew its limits, and were on the same wavelength in terms of wanting to be able to do more.

Moreover, Chugai Pharmaceutical’s researchers have no reservations and are very proactive about incorporating new technologies, and each and every employee is equipped with the mindset to be bold and try new things.”

 

Torizawa says that since the implementation of cryo-EM, there has been a definite reform in the drug discovery process.

 

“Particularly with projects involving target proteins that are difficult to crystallize, whereas previously the early stages of the drug discovery process would have taken around four years, use of this new technology has drastically shortened these early stages to just less than a year.

Drug discovery projects in which three-dimensional structural images cannot be obtained can hold back the entire research center. In fact, there have previously been projects in which we focused so many of our resources on the crystallization of a challenging target molecule that it impacted the progression of our other projects. Now, however, this issue has been eliminated, and overall the speed of the drug discovery process has improved.”

 

These initiatives were also highly acclaimed in-house.

 

“In 2022 we received the gold prize in the research division director’s awards. It shows how our reform of the drug discovery process through the establishment of cryo-EM technology was so well-received.

Meanwhile, equipment using the latest technologies can quickly become dated, and so installing the equipment at the wrong timing can mean it instantly becomes outdated. We set out to introduce the technology at the perfect timing, quickly installing the equipment so that it could be used in the drug discovery process. It was this approach that ultimately ensured that the initiative was a success.”

High-level Collaboration Between Internal and External Functions to Create an Important Drug Discovery Platform

The ProS Department was newly established in April 2021. As the department works on the discovery of new drugs, there are certain things that Torizawa is placing the utmost importance on.

 

“The ProS Department is a rarity among global pharmaceutical companies in that it focuses on target proteins while bringing together other associated functions. While there is no doubt that we have plugged a significant hole in the drug discovery process using cryo-EM technology, three-dimensional structural analysis using this equipment only accounts for a small part of our overall workflow at the department.

As drug discovery research becomes increasingly difficult, across various modalities it is our role to oversee all the early stages of the drug discovery process involving target molecules. It is essential that we quickly obtain the right information and work to revitalize the company’s unique drug discovery process.”

 

The aim of the ProS Department is to become an irreplaceable research organization that generates reform in drug discovery. As general manager of the department, Torizawa sees its future in the following way:

 

“In this project, we installed an innovative technology in cryo-EM and successfully introduced a series of processes. Our efforts have shown that we are an organization with the capabilities to quickly introduce a state-of-the-art technology in a short space of time and apply it to the drug discovery process.

Whether we bring in external technologies or develop them in-house, while carefully looking at the emergence and growth of new science our aim is to introduce the optimal technologies at the optimal timing for Chugai Pharmaceutical’s drug discovery research.

Moreover, at the ProS Department we are aiming to make all core functions world-class. For us to contribute to the enhancement of the company’s drug discovery, it is paramount that we work to reinforce these functions and have them work together to address the scientific challenges facing the drug discovery process.

We have termed the high-level collaboration between these functions and the integration and examination of related drug discovery information as ‘integrated protein science.’ Our current mission is to create a system in which we can efficiently and effectively work on this integrated protein science.

While working alongside other departments engaged in drug discovery projects, we will do everything in our power to deliver medicines to patients as quickly as possible.”