Institute for Integrated Cell-Material SciencesVol.

52017 December

Kyoto University
Institute for Advanced Study

contents

02

FeatureiCeMS, where collaborative researchflourishes

07

iCeMS Frontrunners
Pursuing the unelucidated
structure of beauty
Mineko Kengaku(Professor)
Once a newly born neuron emerges,
it moves to a specific destination on
the cellular processes of other neurons
and glial cells. The cover image shows
cerebellar granule cell neurons moving
along carbon nanotubes, an in-vitro
reproduction of the phenomenonof baby (or young) neurons movingaround in the brain. Turn to page 7 toread the full story.

10

iCeMS Fund — Help us grow11

iCeMS in brief

Feature

iCeMS, where collaborative research flourishesMa
Si teren ia
ce lsMany researchers in different areas, such as cell biology, chemistry, and physics, work together at iCeMS. By sharing
their individual perspectives and discussing issues again and again, they devise new approaches. We asked two ofthese researchers, who are conducting a joint research project at iCeMS, about the attractiveness of this method.

Mathematical model shows
the mechanisms ofa molecular phenomenon

Everything obeys physical and chemical laws, andliving things are no exception. iCeMS has lead theworld in imaging and measurement methods. Using our own unique set of tools, we seek to unlock
life’s physical laws, such as how molecules transform chemical reactions into life, and how cells
build the structure of living creatures.

Create new materials
to change the world

Biophysics
Materials
Science

To understand cell
– the starting point of biology
All living creatures are made up of cells whose characters and roles are highly differentiated and specialized, yet which work collectively. All biology begins
with understanding the function of the cell, the minimum
unit of life. We probe howstem cells give rise to specialized cells with unique shapes
and functions, and how germ
cells magically transmit the genome to the next generation.

2y

Dan Ohtan Wang

Program-Specific ResearchCenter Associate Professor

Daniel Packwood

Junior Associate Professor

Understand the principle of life in physics approach

iCeMS’s
disciplines

All materials, such as glass, plastic and bronze, have the utility tocreate something of use. Today,
various materials are artificially created: for example, materials thatare easy for molding or ones that
can accommodate gas
molecules. At iCeMS,
collaborating
withknowledge from chemistry and biology, we
create novel materials
for something that has
not yet been invented.

CellbiologTwenty-two people in America
die every day due to a shortage of donated organs. Thereis an urgent need for a safe,
cost-effective alternative totransplantation. At iCeMS, ourteam develops cell-inspired
materials and nano-machinery to build an “environment”
in which cell tissue can growcomfortably.

TissueEngineering

iCeMS

Cell
Biology

Build the “environment”
for cell tissue

Chemical
Biology

Q1
Open the way forthe future of medicine
using molecular tools
As our ancestors used rocks as tools
to advance civilization, the invention of‘super tools’ allows us to do things hitherto undreamed. At iCeMS, using tools
made from cutting edge molecules, weseek to create newlife-changing drugs
and materials in thefight against, for example, cancer, AIDS,
arterial disease, andaging.

Works on the development oflive-imaging methods used toobserve individual cells in living
brains. This research observes
the actions that occur, and where
they take place in the brain, in
learning or memory processes.
Associate Professor Wang is interested in the RNA molecules that
direct the synthesis of proteins tobuild the body of a living organism
according to the genetic information in DNA. She intends to explore the mechanisms of forming
neural network structures in thebrain, starting with understanding how RNA works.

Works on the molecular self-assembly process, using mathematical theories and computers. The molecular
self-assembly process is a phenomenon by which molecules spontaneously gather to form a structured
or functional assembly. Snow crystal
growth and double-helical DNA are
examples of molecular self-assembly.
To develop, among other outcomes,
molecular-sized fine electronic circuits by applying this phenomenon
to nanotechnology, Packwood conducts computer analyses of the complex movement of molecules andtheir environment.

How did your joint research project begin?

During a 2014 symposium, I talked
with Ohtan about both of our respective research projects. At that time, I
was working for AIMR,*1 Tohoku University, and Ohtan for iCeMS.
Daniel studies self-assembly processes,*2 which overlap with my research themes in many aspects. In a cellunder stress, ribonucleic acid (RNA) molecules gather in a self-assembly process.
When the stress is removed, they returnto their original positions, which I thenobserved by the live-imaging method.*3 I
wondered why such a phenomenon occurred. My biological knowledge was notenough to infer the necessary conditions

for the phenomenon. I was a bit frustrated
at that time.
While I was discussing the topic with
Ohtan, some ideas about mathematical models came to my mind. Thesemodels could potentially reproduce themovement of RNA molecules. I thought
the idea would be worth giving a try.

*1 AIMR : Advanced Institute for Materials Research, Tohoku University. Founded in 2007.
*2 Self-assembly : A phenomenon by which molecules spontaneously gather to form a structured or functional assembly*3 Live-imaging method : A technique designed to visualize and observe tissues and cells in a living body

Daniel Packwood
Born in 1985 in Christchurch, New Zealand. Completed his PhD in chemistryat the College of Science of the University of Canterbury in 2010 and cameto Japan as a chemistry postdoc of the Kyoto University Graduate School of
Science. Has been at his present position since 2016, after working for the
Advanced Institute for Materials Research (AIMR) at Tohoku University.

Dan Ohtan Wang
Born in Shenyang City of Liaoning Province, China. After graduating high school in 1994, she entered the school of Bioscience and Biotechnology at the Tokyo Institute of Technology in Japan.
In 2004, she received her PhD at USC. She worked as a postdoc at UCLA, as a JSPS Postdoctoral
Fellowship for Overseas Researcher at RIKEN, and as an Associate Professor at iCeMS. Has beenat her position since 2017.

3

Feature: iCeMS, where collaborative research flourishes

Q2

What results have you seenfrom your joint research?

These are live-imaging data (photo). Under stress, intra-cellular RNA molecules
have gathered. Daniel reproduced the phenomenon using a computer model.
I developed a computer simulation method and explained the mechanisms behindthe phenomenon using an equation. The equation contains parameters (numerical values) that
represent, among other factors, liquid viscosityand molecule radius. Varying each parameter
causes the phenomenon to change. By examining how the phenomenon changes, it is possible to find out what factors are required for the
self-assembly process.

Dec, 2014
The two researchers
met with each otherfor the first timeand discussed theirresearch topics.

Q3

dd xxkk =
2 =
dt
dt 2
22

dt

During the 10 to 20 minutes that the
RNA molecules gathered, Packwood
clarified a mathematical formula to describe the influences on the molecules
and their movement.

Feb, 2015
Full-scale research commenced
when Packwood was at Tohoku
University. They had
meetings about once
every two months.

Verifications using varied parameters revealed that inter-molecular friction retarding molecular movements had a significant effect on the
self-assembly process. This finding enables us to draft further research plans,
which take this into consideration.
New research themes emerge
based on the solutions derived
by equations. This is a major role
played by mathematics.
Experimenting with all kinds ofconditions is a demanding task.
Simulations of various conditions enable us to infer, before the experiment,
which conditions are promising. Simulation is beneficial in that it saves us fromconducting experiments.

“This is it!” Finally,
they had the result!

What is themechanism behind
the gathering of RNA
molecules?

4dxc(xk )) Bg(t)]] dxkk ++ awawk (t)(t)[[c(xBgkk (t)kkdtApr, 2016
Packwood joined iCeMS. Withan increasing number of meetings, significant progress wasmade in their research project.

Some mathematicalmodels can be used
for understanding
phenomenon….

There
are
three things
essential forcellular imaging: a powerfulimagingsystemwith fluorescent molecular probes, thecreative mind and inquisitive eye of a researcher, and the cooperation of the cells.

What is the benefit ofworking together?

The photo on the left shows cells before
pressure is applied and on the right afterpressure is applied. The blue parts of
the image are DNA, and the green, RNA

Simulationsaremore
c o nv e n i e n tthan observing cells in practice. In an experiment, it is difficult to thoroughly track and control the environment in which cells are placed.
Simulations enable us to set up an ideal environment by means of mathematical expressions.
The imaging technique is useful for examining what is taking place in the cells.
However, to infer what parameters are importantamong factors that are not readily visible, suchas those that occur in environmental changes,
Daniel's equation played a key role.

t is
Wha ablensep
indis ur reo
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Wha able
ens
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i
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crase

I am the only member on the mathematical end. If anything, computers arealso powerful members. They are wonderful. Even going without eating and drinking, they are reliable
and never cry or worry [laughs].

They discussed again
and again, and after
trial and error manytimes……

Q4

What was the most rewarding moment?

When viewing the two sets of results
side by side and seeing Daniel's simulation results present a motion similar to my
imaging data, I was very excited.
We followed different paths ofthought, but arrived at the same point.
Computation alone did not reveal whether
the results would be useful or not. I was uncertain. I was reassured to see Ohtan wearing a broad smile.
Additionally, Daniel reported that thesubstances on the surface of the as-sembly seemed important. Previously, it wasthought that surface proteins were important for self-assembly processes. However, in
actual observation, I found RNA moleculeson the surface. Contrary to the traditional
hypothesis, he showed me a new way to
conduct research.
Mathematical models are like a compass pointing to a destination. Theysuggest the whereabouts of key points.

5

Fearture: iCeMS, where collaborative research flourishes

Q5
What do you think are
the good points about
conducting joint
research at iCeMS?

ives
pect
Pers ferent,
dif
are
at
so th ingstse h g!
mak
n
resti
t
in e

While purposes and goals are different
among different projects, all projects
share the same theme of “the molecu-

lar self-assembly process”. Once wemake a model, the idea is applicable to other fields. This is a unique

Our brain contains about 86 billion neurons and more than tenfold this number of glial cells, which create acomplicated neural circuit. In recent years, by developing cell visualization methods, the process and mechanismsof neural circuit formation have been gradually clarified. Professor Kengaku seeks to understand the mechanism
behind how the brain is constructed by studying the dynamic movement of developing neurons.

strength of mathematics and physics.

of study and have different thinking processes,
which allows us to find newthings. This is an interesting
aspect of collaboration.

Pursuing the unelucidated
structure of beauty
Mineko Kengaku Professor

Q6

6

necessary to illustrate
the functions and reactions unique to each molecule.

6Interview

We are in different fields

Because the work space on eachfloor is unpartitioned, researchers often see each other. We frequently have casual meetings; for instance,
when we pass each other, we say hi andstart discussing research topics.
It is a cultural characteristic of
iCeMS.
At iCeMS, it is easy to learn acrossdisciplines. All you need is the interest. Members here are strongly motivatedby curiosity.

There are no wall partitions between laboratories in
the iCeMS work space. The central open stairwell
creates an atmosphere for interaction among different
floors.

In biology “singularity” hasprimary importance. It is

Is joint research attractive or interesting ?

The most attractive point is that I
can use mathematical and physicalways of thinking to contribute to otherresearchers' projects, even if indirectly. I
am by nature a science nerd [laughs]. It
is sheer joy for me to learn in areas thatare new to me.
In the research conducted with
Daniel, I have realized the beautiful simplicity of mathematically-derived
answers. People I meet in joint research
are specialists in their respective fields, sothey are good teachers for me.
I have come to understand cells tosome degree, though below Dan'slevel.
Through the joint research project,
I have become aware that learningin areas other than my own enables me

to have a deeper understanding of myfield as well. In my field, I must grasp almost all the available information to bea leader on the frontlines of research.
While it is fun and important to go as far
as possible in one field, through joint research, I have additionally enjoyed growing my curiosity.
I feel it very human to pursue
cross-disciplinary joint research.
With research in my field, in which I am
familiar with the methodology, I follow,
for better or worse, a logical or mechanical sequence. However, conducting research with researchers from other fields
is fun because I need to start thinking
from scratch beyond the framework orprocesses to which I am accustomed.

“This is a deep world, like a universe.
I think it is so beautiful.” Kengaku
refers to neither a glittering jewel nor
the works of famous artists. She speaksof a Purkinje cell, orderly located in
the cerebellum. “As when people walkthrough a crowd without hitting others,
neurons stretch to make way for others.
In the end, they create a tissue that

Left: Multiplex fluorescent staining of an inferior olivary nucleus neuron axon (magenta)
coming into a Purkinje cell (blue) and a synapse molecule (green) .
Right: Graphic of a neural circuit made bytracing 3D images

looks like a peacock with open feathers.
Each cell acts with considerationand propriety, like a human. When I
see the world through a fluorescent
microscope, I find new things.” Shecannot keep cool when talking about
her research.
Kengaku joined iCeMS in October
2008 as a project leader. She works withyoung researchers and throws herself
into it every day. “I always cooperatewith students and other researchers. By
arguing with one another, we advanceonly with struggle. Sometimes I am
surprised by what my colleagues find,and it motivates me. By respecting eachother’s ideas and personalities, we makenew discoveries. This is my job.” With
this gentle attitude, Kengaku showsa feeling of pride. She has achieved
many results, but as a youth,

Mineko Kengaku
Born in Tokyo. Received a PhD in 1995 from the
University of Tokyo Graduate School of Medicine.
Held the positions of Postdoctoral Research Fellow
with the Department of Genetics at Harvard Medical
School, Assistant Professor and Junior Associate
Professor of Neurobiology with the Department ofBiophysics at Kyoto University, a Team Leader at
RIKEN Brain Science Institute, and of Associate
Professor with iCeMS. Has been at her current position since 2012.

7

Inteview: iCeMS Frontrunners

she did not aim to become a researcher.

Connecting with nature
as a young person
When young, Kengaku lived in
Higashikurume, a suburb of Tokyo.
There, she developed a fondness fornature. She ran in nearby mountains,chased insects or frogs until dark,caught and observed wild creatures, andread encyclopedia of animals at night.
Their behaviors and shapes attracted
her, and she gradually began to admirejobs related to animals. “Should I be aveterinarian? Or have a job protecting
wildlife?” She imagined her own future,but couldn’t decide on an occupation.
Kengaku decided to explore various
fields, so she chose the University ofTokyo, where students don’t have tocommit to their faculty upon entering.
“I noticed that I was more interested

in pursuing undiscovered truths thansomething already known. I wanted
to know the workings of life and thestructure of living things more fully, so
I chose the department of Biological
Sciences, Faculty of Science.” She was
especially curious about the functions ofnerves. In physiology class, extracting
the giant axons of squid and measuring
the organ potential of electric rays
absorbed her. “I thought that if I knew
the mechanisms of nerves, I could
unravel the mystery of creatures’ action
patterns.”

The joy of discovery led to
becoming a researcher
At graduate school, she conducted
experiments until the last train every
night. In those days she researchedneural differentiation. The nervous
system is an organ that stretches froma creature’s head to tail. In the nervous
system, neural tubes divide into sections,and each section organizes into thespinal cord, cerebrum, cerebellum andother parts. While humans have a large
number of genes, about 22,000, thisnumber cannot clarify the mechanismof complex neural tube differentiation.
During her graduate school, thismechanism was not yet unraveled. The
only thing already clarified was thatneural tubes gradually become nerves
through exposure to certain protein
molecules. Knowing this, she put
protein molecules called FGF on theundifferentiated embryonic cells of aclawed frog, changing the concentration
gradually. She noticed that embryoniccells turned into different parts of thebrain with different concentrations.
“The parts exposed to strong FGF
concentrations became spinal cord,

Work of a neuron in a neural circuit
1. Dendrite (input)

2. Cell body (integration of information)

8

The reality and the ideal thatwomen researchers face
While her passion for researchgrew, her path was full of setbacks. In
those days, women researchers in Japan
faced barriers too high to overcome.
“Now, many people say that womenshould work like men, but it was a
male-dominated society at that time.

There were many laboratories that
didn’t hire women at all.” Intrusive
thoughts always assailed her, such as“I have to give up my research beforelong”, but she couldn’t give up easily.
Kengaku followed her interest, and she
decided on a post-doctorate at Harvard
University.
Surprisingly, half of the laboratory
members were women. “I found myself
shut in a small world. They consideredscience as the one thing they lived for.
By them, I felt pushed to continue
researching what interested me.”After returning to Japan, Kengaku
was invited to Kyoto University by
Tomoo Hirano, one of her seniors
in graduate school. “I think Kyoto
University is a research mecca. Many
unique and famous researchers comehere. After Kyoto University, I moved
other places, but I wanted to return
because my husband was still in Kyoto.
Fortunately, iCeMS prepared theposition of project leader, allowing
Kyoto to challenge me again.”Treasuring
the curiosity to know

3. Axon (transmission)

4. Nerve ending (output)

and those exposed to weaker FGF
concentrations became the frontal
brain. When I found this pattern, I got
so excited that my leg trembled.”
Science is competitive. As a project
leader, Kengaku bears the responsibilityof success. Even with new findings,
she feels more relieved than happy.
“Graduate school was a treasure forme. Finding something big with a puremind becomes a moment you’ll neverforget.” This experience led her todecide to be a researcher.

Novel neuron in the developing brain,
moving with a long cellular process.
A cell nucleus (blue) moves forward by the force that
actin (green) and microtubules (magenta) create.

This is her ninth year at iCeMS.
While Kengaku is still crazy about
research, she also values life balance.
A picture taken when Kengaku was at Harvard
Medical School. With the members of the lab,she visited Chicago, where her boss (second
from the left) was born.

Kengaku took a tour of the factory in Haneda
Airport with her son. According to her, helikes airplanes, but is not very interested inbiology.

“It is hard to be successful at bothresearch and private life. Cooking forand eating with my son is the mostenjoyable time for me to think about
this nutritive balance.” These days, shecannot research from morning to night.
However, with a family she can returnto her roots and focus on the unsolved
questions she wants to research.
“Many young researchers tend
to focus on a fast way to help people,
researching drug discoveries or acause of disease. Of course, this isvery important. However, if you pay
attention to social needs too much,you’ll lose what really interests you. I
hope young researchers follow what
they want to know and value theambition to find new things. Creating
new knowledge is helpful for the futureof humanity.”9

iCeMS Fund - Help us growiCeMS in brief

At iCeMS, we develop new insights into the principles of life that distinguish living things from
non-living things, and harness these ideas to create bio-inspired super materials and devices that will
revolutionize health-care, medicine, industry and the Environment to create a sustainable world for us all.
Whilst much of the work we do here is Pure Science, we are absolutely certain that our researchcombining high-level chemistry, cell biology and physics, at the border between materials and life, will
meaningfully impact the world in which we live.
The research we carry out at iCeMS will help doctors to fight such perennial problems as heartdisease, cancer, and degenerative brain conditions, as well as develop invaluable new medicines andtherapies. Our revolutionary work also addresses key issues such as global warming, pollution, overdependency on fossil fuels, and the availability of clean drinking water.
Generous gifts from donors like you provide the financial and moral support needed to continue
and develop this research at the cutting edge of modern science. We are not merely content to improveexisting technologies, but seek to affect paradigm shifts in the way science may benefit humanity.
Help us to help the world. Together we can make a difference because we care.

DonorsiCeMS would like tosincerely thank all those whohave given their support.
Hiroshi Tanaka
Hiroyasu Tabe
Junko Kobayashi
Kenichiro Murai
Kenji Takano
Koichi Shirose
Masakazu Higuchi
Takako Yano
Takashi Tokunaga
Tomoko Kato
Yoshinori Takeuchi
Yoshiyuki Tsuda
Kyoto Gakuen High School

Individuals

Corporations /Organizations

DonationsContribution
tohealthcare

Activities forcontribution tosocietyiCeMS Fund

SupportResearches
iCeMS

Kyoto University Fund webpage

http://www.kikin.kyoto-u.ac.jp/contribution/icems/
10What’s new?

Next-generation drug
testing on Chips
Researchers, led by Ken-ichiro Kamei,
have designed a small ‘body-on-achip’ device that can test the side
effects of drugs on human cells.
The device solves some issues withcurrent, similar microfluidic devices
and offers promise for the next
generation of pre-clinical drug tests.

Body on a Chip

The ‘body-on-a-chip’ device is a novel in-vitro
human model that doesn’t use people or animals for drug discovery.

Getting closer to porous,
light-responsive materials

Solve social
issues

Producing promisingscientists of the next
generation

Research Highlights

Susumu Kitagawa and his colleagues
succeeded in developing a lightresponsive crystalline material thatcan control CO2 sorption by light.
Combining the rigid crystals of porous
materials like ‘wire-and-string puzzles’
enabled them to make a dynamic
scaffold. Based on this new idea,
it became possible to coordinate
the shapes and sizes of pores bymanipulating light. This made it easier
to collect and eject CO2 at any time.

UV Light
Vis Light

iCeMS invites high school students fromSingapore and Kyoto to its Science Festival
On November 10th, 2017, iCeMS held the “iCeMS
Science Festival”, and about eighty high school
students from Singapore and Kyoto visited iCeMS.
The students experienced science activities, such as
experimentation and observation, and had a fun timetalking with the scientists. At the end of the day, a quizsession was held based on what the students learnedon the day.

By combining crystals of porous materials like‘wire-and-string puzzles’, it became possible
to make a dynamic scaffold and coordinate theshape and size of pores.

Accessing DNA in the cell’s
powerhouse to treat disease

iCeMS holds international symposium

A team led by Ganesh Pandian Namasivayam succeeded in re-directing molecules of Pyrrole-imidazole polyamides(PIPs) to cross the mitochondrial membrane. This enables it to access mitochondrial DNA to treat some genetic
nerve and muscle diseases.
Schematic illustration of MITO-PIPs that selectively read a target DNA sequence

On May 30th and 31st of 2017, iCeMS held its 23rd
International Symposium, “Emerging Science for
Unlocking the Cell’s Secrets”, at the KUIAS Main
Building. Sixteen up-and-coming young scientists
from Japan and overseas delivered research talks,each leading to a lively discussion. About 160
researchers attended from Kyoto University andelsewhere.

11Explore the secrets of life and innovate for the good of society

iCeMS’s Mission- Explore the secrets of life by creating compounds to control cells- Create life-inspired new materials for the future
Global warming. Pollution. Disease. Aging. These major concerns
can no longer be countered by traditional single disciplinebased research. At iCeMS, cell biologists, biophysicists, chemists,
material scientists, physicists, and bioengineers share ideas andwork together to devise new ways to integrate cells and materials,
all for the greater good. We find inspiration through collaboration.
We leverage our critical mass of scientific and technologicalknowledge into purposeful, transformative innovations for thepractical benefit of society.
Size of meso-scale materials(iCeMS's research realm)

Chemical
Biology

TissueEngineering

Comparison withfamiliar things…

Molecule

Sesame(2 mm)

Mesoscopic Domain〜１nm

Biophysics

Cells

Vol.5
2017 December

Cell Biology

Watermelon(20 cm)〜１µm

Water ball
(2 m)

Medicine

iCeMS
Our World, Your Future

Materials
Science

Production K yoto University Institute for Advanced Study
Yoshida Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan
Phone: +81-(0)75-753-9755 | Fax: +81-(0)75-753-9759
E-mail: info@icems.kyoto-u.ac.jp
Website: http://www.icems.kyoto-u.ac.jp
Production/cooperation: Kyoto Tsushinsha Press,
Design: Takayoshi Nakasone

Environment andEnergyInnovation