Institute for Integrated Cell-Material SciencesVol.

82019 November

Kyoto University

contents

02

iCeMS Frontrunners
Kazumitsu Ueda
Health Discovery Defying
Conventional Biochemistry06

The Other Half of iCeMS
Yoshiharu Tsuzaki
Information Technology Strategist

07

iCeMS in brief
MDR1 uses the energy of ATP hydrolysis to export lipid-soluble drug and harmful substances out of the cell,and plays an important role of human physiology and health. Turn to page 2 to read the full story.

Interview

9

In the world of science, a single discovery sometimes overturns many established notions. One such example is
ABC proteins, including MDR1 protein. Professor Kazumitsu Ueda is the world’s first person to isolate the MDR1
gene. ABC proteins are important players in human physiology and health. The workings of ABC proteins have manytimes defied the norms of understanding shared by scientists in the field of biochemistry. Before the discovery,
people around Professor Ueda criticized him for “pursuing irrelevant research”. Living by the motto “refrain frombelieving common notions”, he unswervingly continued his research and opened the way to uncharted territory.

Health Discovery Defying
Conventional Biochemistry
Kazumitsu Ueda
“ABC proteins” are a family of proteins in cell membranes, which transportvarious substances. Forty-eight genes are
expressed in human ABC proteins, ofwhich MDR1 was the first in the world
to be identified. Professor Ueda discovered it some 35 years ago.
Protection from Foreign
Substance Entry at Cell
Membranes

Kazumitsu Ueda
Born 1954 in Himeji. Received a PhD in agriculture
from the Graduate School of Agriculture, Kyoto
University in 1984. After working as Assistant andthen Assistant Professor at the graduate school, in
2003, he took the post of Professor at the graduate
school. He also worked as Professor at the Institutefor Integrated Cell-Material Sciences, Kyoto University between 2007 and 2017. In 2019, he retired
from the graduate school under the age limit andtook his current post.

2“Medication absorption greatly depends on the action of MDR1. For instance, you might have been advised not
to take a certain medicine with grapefruit
juice. The reason is that furanocoumarin,
a compound contained in grapefruit, inhibits the medication pumping functionof MDR1, which results in the small
intestine’s overabsorption of the drug. If

Program-Specific Professor
a blood pressure-lowering drug effect becomes excessively strong, for instance, it islife-threatening.” Professor Ueda’s speaks
gently in a low voice, invoking a medical
An example action of MDR1
Ivermectin

doctor’s sense of security.
MDR1 acts not only on medications, but also on the absorption of nutrients from everyday food. Nutrients areabsorbed by the small intestine, carried
to the liver, and transported to cells via
blood flow throughout the body. The
risk of absorbing lipid-soluble toxic
compounds, such as alkaloids producedby plants and microorganisms, is present
during this process.
Using energy, MDR1 exports hazardous substances that have enteredcells. For example, MDR1 wards off
disease by preventing the small intestine’s absorption of various lipid-soluble
harmful substances from food. MDR1 isalso active in brains and testes, preventing harmful substances from entering
these important organs.
“Before the discovery of MDR1, theconventional notion was that harmful
substances were detoxified by the liver.

A medication used
to kill ticks and parasites

Mousedeﬁcient in MDR1

Mouse
with normallyacting MDR1

In 1994, a Dutch researcher sprayed ivermectin
on a mouse deficient in MDR1. This resulted in
the death of the mouse. Compared with the normal mouse, the mouse deficient in MDR1 had
about a 100 times higher accumulation of ivermectin in their brain. This experiment revealed
that MDR1 functions to prevent harmful substances from entering the brain via blood flow.

Professor Ueda was a postdoctorial fellow
at the U.S. National Cancer Institute;with Dr Ira Pastan (lab chief, right) and Dr
Michael Gottesman (section chief, center).

However, its discovery
MDR1 functions Mechanism for discharging fat soluble drugs out of cells
revealed that we main①Before exportation②Intermediate③After exportation
tain good health largely
Outside the cell
due to the function of
Drug
Cell membrane
MDR1, alongside theliver’s detoxication acInside the celltion. All living things,
ATPfrom microorganisms
A
A
A A
T T
T
T
P
P
P P
to plants and to animals, possess ABC proADP Pi
teins, including MDR1.
Upon emerging as MDR1 takes a lipid-soluble drug from within the cell membrane into
single cells, it is thought the molecule and directly exports the drug out of the cell like a pump,a result of a structural change powered by ATP binding.
that living organisms
been used during prior treatment alsoacquired MDR1 to prevent lipid-soluble
lost their efficacy. Multidrug resistanceharmful substances present in their enwas implicated in more than 90% ofvironment from entering the cell. Since
deaths caused by cancer. Clarification of
MDR1’s discovery, many other structurthe mechanisms of multidrug resistanceally similar proteins have been found, also
was urgently necessary.
grouped into the ABC protein family.
“After I earned my Ph.D., I heard
MDR1 Against Common
that the U.S. National Cancer InstituteNotions
was looking for postdoctoral fellows. In
the 1980s, the technique of cultivating
Professor Ueda discovered thehuman cells in petri dishes was estabMDR1 gene when he studied in thelished in the United States, enabling
United States for two years from 1985.
researchers to cultivate multidrug-resisBefore then, he had worked at thetant cancer cells. I thought this presentGraduate School of Agriculture, Kyoed a chance for me to discover someto University, researching the actions
thing new.” Ueda grabbed this chanceof anti-cancer drugs on DNA. He wasand left for America.
specifically interested in the multidrug
While working on team research
resistance of cancer. At the time, the loss
tasks, he one day noticed that a certainof the efficacy of anti-cancer drugs withgene was overexpressed in multidrug-rethe recurrence of cancer several years
sistant cells. It was a membrane protein
post-surgery posed a problem. In thesegene. On the chance of encountering
instances, anti-cancer drugs that had not3something important, he promoted
the gene’s expression and observed thatby using energy, the expressed protein
pumped a lipid-soluble anti-cancer drugout of the cell. All institute members
were wide-eyed. No one had thoughtthat energy would be expended to remove membrane-permeating lipid-soluble compounds from the cell.
Before this discovery, many people
doubted the research direction pursued
by Professor Ueda. They thought thatanti-cancer drug resistance was caused
by too many genes and mechanisms,
which would remain unsolved unless avast number of genes were studied. Theirviews were quite understandable in lightof the basic idea that biochemical reactions show high substrate specificity.
For example, metabolic enzymes rec-ognize specific sugars and amino acids.
A one-on-one recognition mechanism
was thought to exist in biochemical reactions. Notwithstanding this, Professor
Ueda and other researchers witnesseda single transporter pumping various
types of compounds out of cells. The
transporter used the common characteristic of lipid solubility to recognize
the compounds. “No one imagined theexistence of a transporter like this. I was
extremely lucky.” The expressed gene
was named MDR1, using an acronym
for multidrug resistance.

His Research Mindset Originated on the Silk Road
“Believe not blindly in common
notions” is Professor Ueda’s motto. He
cultivated this research mindset when

Differences between common transporters and MDR1
Water-soluble compounds(eg sugars, amino acids, and ions)

Transporters moving
water-soluble compounds and ions

Cannot pass through thecell membrane because
the membrane consists of lipids.

Transporters are suited, respectively,
for different compounds.

MDR1

Lipid-soluble compounds

MDR1 by itself can export
various types oflipid-soluble compounds.

Cell membrane

Capable of entering cells
without the power of a transporter.
Some lipid-solublecompounds are harmful.

Membrane proteins known as “transporters” enable low-molecular compounds to pass through cell
membranes. Water-soluble nutrients such as sugars and amino acids by themselves cannot passthrough a cell membrane because the membrane consists of lipids. To enter cells through a barrier,therefore, transporters acting as pumps are essential. In contrast, lipid-soluble compounds readily
enter and exit the cell membrane. Some lipid-soluble compounds are toxic to the human body. Using
the energy of ATP hydrolysis, MDR1 transports harmful lipid-soluble compounds out of cells.

4

he studied at the Faculty of Agriculture,
Kyoto University. “At the time, it was
popular to travel with a backpack. Many
young Japanese people set out across thesea. Driven by this trend, and with anadmiration for the Silk Road, I visited
Turkey via the USSR and then traveled
to Iran, Afghanistan, Pakistan, and India.” He made a three-month pennilesstravel, overland by bus and train.
He saw directly that different countries, areas, and ethnic groups had quite
different ways of thinking and customs.
More than a few times, he experienced
that norms in Japan went against thecommon notions of other ethnic groups.
Departing from the norm, he quickly
acquired a clearer view. “Being skeptical
about common notions is an essential
attitude for scientists. At a press conference when he won a Nobel Prize,
Professor Tasuku Honjo said, ‘Do not always believe what textbooks say’. Common scientific notions can dramaticallychange after one discovery. I was criticized by many forerunners. However, I
came across the unknown after a steady,continuous research effort.”
Since the discovery of the MDR1
gene, Professor Ueda has spent nearly
30 years working on elucidating MDR1
structure by thoroughly rejecting unproven assumptions and examining every
conceivable hypothesis. Gradually he isshifting his research focus to other ABC
proteins, based on his work with MDR1.

One example is ABCA1 protein, essential in forming high-density lipoprotein(HDL) cholesterol (good cholesterol).
People with high HDL cholesterol levels
are less prone to arteriosclerosis, and hebelieves that tracking down the mechanism of ABCA1 formation of HDLcholesterol will lead to the preventionof myocardial infarction and other heart
failures, as well as cerebral strokes.

A Quest for
the Most Interesting
In March 2019, after many years ofservice, Professor Ueda hit retirement
age for the Graduate of School of Agriculture at Kyoto University. As a student,
he affiliated with several schools, enrolling in the engineering faculty of anotheruniversity and then the Department ofForest Science, the Faculty of Agriculture at Kyoto University. Finally, he selected the Department of Agricultural
Chemistry, the Faculty of Agriculture.
He took a roundabout path because
he wanted to know “what I would begood at and what fascinated me”. At

the engineering faculty, he was not interested in manufacturing; and at the
Department of Forest Science, he could
not memorize tree names, so he gave
up. While still undecided, he by chanceread Chance and Necessity published by
Jacques Monod, a French molecular biologist. Ueda instantly became capturedby the study of DNA. “DNA researchrequired only remembering names forfour nucleic acids and 20 amino acids.
The subject was best suited to an individual like me who was not confident inmemory retention (laugh).” After he enrolled in the Department of Agricultural
Chemistry, every day became exciting
and 40 years passed like an arrow.
Subsequently in April 2019, Professor Ueda was invited to become a
Program-Specific Professor at iCeMS,
where he had long worked as a Principal
Investigator while concurrently serving
for the Faculty/Graduate School of Agriculture. He was even involved in setting up the institute as a founding member. Because he knows of the confusion
during a hectic budding period, he is
happy with the institute’s current environment that fosters young researchers.
“This is my restart, as I turn over a newleaf. Although I am not sure how long I
can continue research, my curiosity forwanting to know what it is to be living is
inexhaustible. The mechanisms of living
At a carpet shop in Afghanistan; “The salesclerks
were very kind, although they were tough-looking.”

He became a student at an aikido school at theage of 60. He was fascinated by techniques
used to defeat the opponent without relying on
force or placing importance on winning or losing.
“I began practicing Aikido, as I really wanted to
do something that I could continue to improve
at, even when I am 70. Wearing a hakama is
not allowed before a certain rank. My progressis slow, but I’d like to wear it someday.”organisms are profoundly complex anddiverse. Humans, monkeys, and miceappear similar to each other in somerespects, but they are actually different.
They have evolved bodies best suited fortheir respective environments. As such,studying mice, however much insight itprovides, can never be enough to understand humans. Even seemingly familiarthings may reveal completely different
aspects from a different angle. Discoveries may be gained by coincidence. You
may pick up a stone at your feet anddiscover a valuable fossil. Research islike that. It excites me, so I cannot retire
from it. At iCeMS, young talented researchers find many new challenges, andtheir activities flourish in various ways.
I also continue to meet the challenge ofoverturning what is taken for granted.”
5

The Other Halfof iCeMS
Yoshiharu Tsuzaki
Information Technology Strategist
Specially Appointed Research Associate

People take for granted a reliable information environment. However, it is an essential partof research. For example, if your research results are on a virus-infected computer, yourdata and other confidential information can be leaked, allowing others to take credit foryour hard work and innovation. Even worse, an unreliable information environment may
result in discrediting or tarnishing the university and its reputation. Fortunately, Yoshiharu
Tsuzaki, who is in charge of information security at the Institute, strives to maintain a secure,convenient, and safe information environment.

Information security
investigation

Network connectivity
to services· Investigates iCeMS’ information
environment in cooperation with
Kyoto University’s Institute forInformation Management andCommunication· Provides connections to Kyoto
University’s email system and sharedstorage servers· Establishes the IT environment
for new laboratories (Internet
connections, etc.)

Inquiry support· Provides remote and on-site support
to resolve challenging computerissues· Physically assists staff to provide
the most appropriate solution toindividual issues

Information security awareness· Encourages researchers to install antivirus software· Educates staff about information security

Customized IT support
Tsuzaki•I love working at iCeMS
due to the amazing people
and supportive environment where
researchers and staff respect eachother. My primary responsibility is tooversee the Institute’s information
environment. Not only do I prepare
the information environment from theperspective of ease of use each time theroom use changes or new equipment isintroduced, but I also take pride in clear
and timely communication. Because
each person has a different degree of6

comfort with information equipment, I
tailor my response to the intent of theinquiry. Due to my continuous effort andingenuity, I have gradually earned thetrust of the people at this institute. It is agreat honor to be treated as a specialist
and a valuable part of the team.

Keeping information safe
Tsuzaki•Carelessness often results
in security issues. For example,
simple passwords make you vulnerable
to third-party hacking and downloading
malicious software (malware) might
infect your computer with a virus. Those

who think, "It won’t happen to me" tend
to be the most vulnerable.
My goal is to increase information
security awareness, but I cannot achieve
this alone. Unfortunately, universities,businesses, and researchers do not like tospend money or think about information
security until it is too late. However, if
each person on the network is conscious
about their behavior, information can beprotected. Thus, I will continue to help
everyone implement best practices,
allowing all researchers to focus on his
or her own projects.

iCeMS in brief
Research Highlights
OM technology allows an inkless, large-scale color printing process
Easan Sivaniah and colleagues use a technology called OM (Organized Microfibrillation)that adjusts crazing and precisely form fibrils to develop a material that reflects light of a
specific frequency that we recognize as a color through our eyes.
When polymers are under stress crazing occurs, producing fine fibers called “fibrils”.
Normally, crazing occurs randomly, such as when plastic products deteriorate. OM
technology made it possible to control the crazing and print on flexible and transparent
materials with a resolution of up to 14,000 dpi. This is expected to have various
applications, such as the development of inkless color printing technology and theprevention of banknote counterfeiting.

A very high resolution painting of approximately 1 mm width can becreated without ink.

Masateru M. Ito, Andrew H. Gibbons, Detao Qin, Daisuke Yamamoto,Handong Jiang, Daisuke Yamaguchi, Koichiro Tanaka & Easan Sivaniah(2019). Structural colour using organized microfibrillation in glassy polymer
films. Nature, 570(7761), 363-367

Towards safer, more effective cancer radiation therapy
using monochromatic X-rays and nanoparticles

New material captures carbon dioxide

Fuyuhiko Tamanoi and colleagues revealed that cancer
mass containing gadolinium
were completely destroyedwhen hit by monochromatic
X-rays.
Currently, radiation therapy
is widely employed as a primary method of cancer treatment, but problems exist with
the X-rays used to date, whichcause unwanted side effectand have difficulty reaching
Precisely tuned X-rays can more effectively hit
cancer mass without harming other parts ofthe cancer tissue. The researchbody by using gadolinium-loaded mesoporousgroup sent gadolinium into
silica particles. (Illustration by Mindy Takamiya)cancer spheroids using specially-designed silica nanoparticles. They then irradiated cancer spheroids
with a monochromatic X-ray using the beam BL14B1 at the large synchrotron facility (SPring-8). The results demonstrate that cancer spheroids
can be effectively attacked by irradiating with 50.25keV X-rays, which aremost suited to release Auger electrons from gadolinium. These findings are
expected to lead to the development of a new cancer radiation therapy.

Susumu Kitagawa and colleagues successfully developed a new porous material
that can selectively capture
carbon dioxide (CO2) andconvert it into useful organic
materials.
The porous material developed through this research
has a jungle-gym-like network
structure consisting of organic molecules and metal ions,which contain countless naThis new porous coordination polymer has prono-sized pores. These porespeller-shaped molecular structures that enable
selective CO2 capture and efficient conversion ofhave a high affinity towards
CO2 into useful carbon materials. (Illustration by
CO2 molecules and can selecMindy Takamiya)tively incorporate CO2.
The newly developed porous material not only captures CO2, but also increases the reactivityof CO2 to enable its conversion into useful materials. This material will
likely be utilized by technology that emits CO2, a major cause of global
warming, as a low-cost resource.

Kotaro Matsumoto, Hiroyuki Saitoh, Tan Le Hoang Doan, Ayumi Shiro, Keigo Nakai, Aoi
Komatsu, Masahiko Tsujimoto, Ryo Yasuda, Tetsuya Kawachi, Toshiki Tajima, Fuyuhiko
Tamanoi (2019). Destruction of tumor mass by gadolinium-loaded nanoparticles irradiatedwith monochromatic X-rays: Implications for the Auger therapy, Scientific Reports 9, 13275

Pengyan Wu, Yang Li, Jia-Jia Zheng, Nobuhiko Hosono, Ken-ichi Otake, Jian Wang, Yanhong
Liu, Lingling Xia, Min Jiang, Shigeyoshi Sakaki & Susumu Kitagawa, (2019). Carbon dioxide
capture and efficient fixation in a dynamic porous coordination polymer, Nature
Communication 10, 4362

7

iCeMS in brief

What’s new?
iCeMS to establish two on-site labs in UCLA and Taiwan

Sixty-two Japanese and British high school students visit iCeMS

Kyoto University has approved
iCeMS’ plans to establish
two on-site laboratories, the“Quantum Nano Medicine
Research Center (iCeMS andthe University of California Los
Angeles)” and the “Center for
Integrated Biosystems (iCeMS
and Taiwanese Academia Sinica)”. Last year, “The Smart Materials Research Center” was jointly established in Thailand by iCeMS and the Vidyasirimedhi Institute of Science and Technology (VISTEC). All together, iCeMS
will have three on-site laboratories once UCLA and Taiwan are launched.

On August 1st, 62 high school students from Japan and the UK visitediCeMS. High school students visited eleven booths that introduced
iCeMS research, where the students
learned about the fun and depthof science by touching researchequipment and participating in experiments. Many comments werereceived from high school students such as, “I found it important not only tofind answers but also to think together”, and “I thought it would be easier toget better answers if different professionals work together”.

Awards◦Susumu Kitagawa receives Emanuel Merck Lectureship 2019(May 13)◦Ryoichiro Kageyama receives Takeda Medical Prize(Sept 20)◦Aiko Fukazawa receives Brilliant Female Researchers Award(The JST President Award)(Oct 17)◦iCeMS holds SPIRITS International Symposium “Shaping Self-Assembled
Mesoscale (Bio)Materials with Microengineering”(Mar 28)◦Stem cell culture medium developed by the Hasegawa group wascommercialized(Mar 29)◦iCeMS holds joint symposium, marking the planned opening of the

Activities

Taiwan office(June 24-25)◦iCeMS holds Shanghai-Kyoto Chemistry Forum(Mar 23)◦iCeMS holds “iCeMS Future Day” and “iCeMS Fund Thanks Gathering”(Mar 25)◦iCeMS exhibits a booth at E-MRS 2019 Spring(June 27-30)

iCeMS Fund - Help us grow
At iCeMS, researchers from Japan and abroad devote themselves to research both day andnight. Research results may sometime lead to applications, such as saving the lives of those suffering from incurable diseases or improving the global environment 100 years in the future. On theother hand, pure science we do may not be readily understood by people in the early stage. No one
can predict the landscape we will be standing in after our challenges, however, we believe that our
research will steadily advance science.
In order for iCeMS researchers to continue moving forward, it is necessary to establish a stable
fiscal foundation. We appreciate your understanding of the activities and spirit of iCeMS, and we
thank you for your continued support through the iCeMS Fund.
Contact details
Kyoto University Institute for Integrated Cell-Material Sciences
Research Administration Office
Phone: +81-(0)75-753-9749 | E-mail: innovpe@mail2.adm.kyoto-u.ac.jp
Website: u.kyoto-u.jp/kuifiCeMS
Our World, Your Future
Vol.8
2019 November

Editorial note
Prof Ueda joined iCeMS at its establishment in
2007, and for many years has been supporting iCeMS
with his outstanding research and gentle smiles. He
always thinks outside the box, follows his curiosity,and enjoys everything. Listening to his story this time,
I felt that this mindset lies in both his life and research.
Personally, I have been a fanof him for a long time. We canfinally introduce his genial andcurious personality to readers, which makes me happyand excited.
Izumi Mindy Takamiya

Production Institute for Integrated Cell-Material Sciences at Kyoto University
Research Administration Office Public Engagement Unit
Mari Toyama, Izumi Mindy Takamiya
Yoshida Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan | Phone: +81-(0)75-753-9753
E-mail: info@icems.kyoto-u.ac.jp | Website: www.icems.kyoto-u.ac.jp
Facebook:@Kyoto.Univ.iCeMS | Twitter:@iCeMS_KU | Instagram:@iCeMS_KU
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