November 8, 2023
Professor Nobuhiro Kosugi
Director
Institute of Materials Structure Science
High Energy Accelerator Research Organization
Tsukuba, JapanRe: Evaluation of the Structural Biology Research Center, IMSS, KEK

Dear Professor Kosugi,Upon invitation of the IMSS management, I had a privilege to participate in a two-day
presentation and discussion of the activities of the Structural Biology Research Center, IMSS.
The meeting took place on October 16 and 19, 2023. Based on the presentations by staff
members of the SBRC, as well as on the written activity report covering the years 2020-2023, Iwould like to provide my assessment of the progress achieved by SBRC during the last 3½ years
since the previous evaluation.
As already discussed in the previous report, SBRC is principally responsible for the structural
biology portfolio of KEK. SBRC plays a double role – it is responsible for the management of thestructural biology pipeline for the university-based and company-based scientific community, as
well as conducting its own research projects. With the scientific staff of ~45, supported by 5administrative personnel, SBRC is tasked with providing access to the state-of-the-art protein
expression, purification, and characterization facility, operation of five Photon Factory (PF)synchrotron beamlines devoted to protein crystallography (MX), as well as two beamlines forbiological small-angle scattering (SAXS). Additionally, SBRC is in charge of the operation of anelectron microscopy facility that utilizes two high-performance instruments.
The main change of the scope of operation of SBRC since the last site visit was the vast
expansion of its abilities to conduct research using the methods of single-molecule cryo-EM.
This was accomplished by construction of a new research building that now houses twoinstruments, a 200 kV Talos Arctica and 300 kV Titan Krios. The former machine has been inoperation since 2018 and has now been moved into its new location, whereas the latter one wasinstalled only in 2022. Nevertheless, access to these instruments for both the SBRC staff andfor researchers elsewhere in Japan has already resulted in more than 20 scientific publications
during the review period. Some of them were published in top journals, such as Nature, NatureCommunications, Molecular Cell, or PNAS. This is quite a remarkable achievement.
Only minor modifications and improvements have been made to the biochemical laboratories
and the crystallographic facilities of the SBRC. The protein expression, purification, andcharacterization laboratories found an additional home in the recently constructed building that
also houses the cryo-EM facility. These laboratories are equipped with a variety of instruments
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for protein purification and characterization, and I do not see any important gaps in thatinstrumentation. The cryo-AM facility has also all the tools needed to prepare samples, including
some home-made instruments such as a small plunger for rapidly freezing grids in an anaerobicchamber.
Major instruments for crystallographic and SAXS studies have undergone some improvement.
A dedicated goniometer for in-situ data collection has been installed on beamline BL-17A and arobot for automatically changing plates is being installed. Software capabilities for evaluating
diffraction in crystallization plates, as well as for room temperature crystallography, are beingupgraded. These are important developments for keeping the facility on a competitive level.
Bio-SAXS facilities have also undergone significant improvements, both in the area of hardware,
as well as in extending the capabilities of software. It is now possible to conduct time-resolved
SAXS studies using a prototype microfluidic cell. Software packages such as SAngler andMOLASS, developed at SBRC, are used both in-house and in other laboratories.
Ever since its establishment over 20 years ago, the SBRC has been playing a dual role by, first,providing unique facilities for researchers from a number of institutions within Japan and also
from other countries, as well as by conducting high-quality in-house research. Research efforts
by the SBRC staff have been very successful, leading to around 100 publications in Japaneseand international journals (mostly the latter ones) during the review period. Many of thesepublications appeared in the top journals in the field of structural biology, testifying to the highquality of the underlying science.
Support for the research activities of SBRC has been provided mainly by the Ministry ofEducation, Culture, Sports, Science and Technology (MEXT), largely through the BINDS
program. This support allows no-cost utilization of the facilities by academic users in Japan, as
well as some foreign visitors. An important component of the funding is support from industrial
entities that gain paid access to SBRC facilities. It is important to note that some of thedevelopment projects use the latter funding mode. An example is development of new types ofcrystallization plates with very thin window that would enhance the capabilities for in-situ datacollection on a PX beamline.
Although SBRC can be, in general, considered as being very successful, some potential future
problems have been identified during the review. One of them is staffing that is not fully adequate
for the number of facilities that need to be supported. For example, only three scientists areresponsible for operation of five PX beamlines – even with the very high level of automation thisis not a sustainable model. For comparison, each sector of the APS synchrotron at the Argonne
National Laboratory, providing X-rays to two or three beamlines, is supported by between 10and 12 scientists. With the current switch to cryo-EM as the preferred technique in investigationof macromolecular structures cutting the number of beamlines to 4 or even 3 might still provide
sufficient support for the users without undue pressure on the beamline staff.
It needs to be stressed that Photon Factory is one of the oldest operating PX facilities in theworld that has not undergone extensive modifications. Such modifications are probably overdue,
although the problem affects not only SBRC, but also other uses of this synchrotron. However,proposals for increasing the flux and brilliance of the radiation source are beyond the scope of
this review. Another problem that is becoming clear is that some major instruments, such as theanaerobic chamber that is over 20 years old, are becoming difficult to maintain and may need

replacement. It is clear to me that SBRC will need to be able to secure sufficient funding not only
for the new projects, but also for maintaining what is already in place.
I would like to add another general comment. It is my understanding that, as an accelerator
research organization, KEK operates large-scale facilities and associated experimental
equipment and provides machine time to researchers for their own research. Typically, users
analyze the obtained data in their own laboratories. However, due to the specific nature of life
sciences, providing machine time alone is not sufficient in the field of life sciences. Therefore,
large-scale accelerator organizations around the world (for example, DESY in Germany andSLAC in the United States) have established dedicated life science research centers to supportusers. Although the current IMSS support for the development of the SBRC in accordance withthe trend in the world is highly commendable, it is important to recognize that the resources of
the IMSS have limitations in meeting current needs. It is my strong recommendation that KEK
as the parent organization needs to make more efforts to promote the life sciences.
Despite all of these comments, I still am confident that the future of SBRC is quite bright. I was
positively impressed by efforts such as creation of a virtual cryo-EM facility that would allow
users unimpeded access to instruments located in a number of sites and not only to the ones
operated by SBRC. Efforts to cooperate with the other synchrotron facilities in Japan andelsewhere are also laudable. Although Photon Factory may lose some of its international users
due to becoming a bit obsolescent, it is still crucial for assuring progress for structural biology
research in Japan. The move to create a unified, virtual cryo-EM facility is a step in the right
direction. With strong management and very capable staff I am confident that the future of SBRC
is assured.
Sincerely,

Alexander Wlodawer, Ph. D.
Senior Investigator, Center for Structural Biology, NCI
Fellow, American Crystallographic Association
Cc: Professor Toshiya Senda