Strategic Programs for Innovative Research Field 1 Supercomputational Life Science14

2016.3 Vol.
CONTENTS

Open Up SPECIAL TALK

Discussion meeting

Computational life science carving
out a new era of life science
Toshio Yanagida ／ Akinori Kidera ／ Yukihiro Eguchi

RIKEN

Approach to the four Themes during the past five years and its achievements

Theme 1 Simulations of biomolecules in cellular environments

2

Yuji Sugita RIKEN

6

Hideaki Fujitani Research Center for Advanced Science and Technology, The University of Tokyo6

Shu Takagi School of Engineering, The University of Tokyo

7

Satoru Miyano The Institute of Medical Science, The University of Tokyo

7

Theme 2 Simulation applicable to drug design

Theme 3 Hierarchical integrated simulation for predictive medicine
Theme 4 Large-scale analysis of life data

ZOOM IN Close-up on SCLS Research
Theme 1 Simulations of biomolecules in cellular environments

Visualizing the real molecular pictures, which are not identified
through experimentation, through the use of computing power- Searching the structures of histone tails Jinzen Ikebe

Japan Atomic Energy Agency

Theme 3 Hierarchical integrated simulation for predictive medicine

8Integrated simulations of the nervous system and musculo-skeletal
system for reproducing Parkinson’s disease symptoms
Naoto Yamamura

The University of Tokyo

Theme 4 Large-scale analysis of life data

From supercomputing analysis of big cancer genome data to life
science and medical care
Seiya Imoto

The University of TokyoSCLS Gotcha!

910Report on workshop for media personnel, titled"2nd Forefront of life sciences led by K computer!"

11

Supercomputational Life Science 201511

- The K computer creates the future of science and society -NEXT STAGE・Challenging the priority issues on post-K computer

Priority issue (1) : Innovative drug discovery infrastructure through functional
control of biomolecular systems

Subtheme A Advancement of MD and associated algorithms
by post-K computer
Yuji Sugita

RIKEN

Subtheme B Development of next-generation drug design

computational techniques

Mitsunori Ikeguchi Graduate School of Medical Life Sciences, Yokohama City University
Priority issue (2) : Integrated computational life science tosupport personalized and preventive medicine

1213Subtheme B Supporting personalized medicine by data

assimilation based biological simulation

Shigeo Wada

Graduate School of Engineering Science, Osaka University

Subtheme C Bridging basic medicine and clinical medicine

by fusing heart simulation and molecular simulation

Toshiaki Hisada UT-Heart Inc.

www.scls.riken.jp/

1415

Discussion
meeting

Strategic Programs for Innovative Research Field 1, special discussion meeting

Reflecting on the five-year activities of“Supercomputational Life Science”

Computational life science carving
out a new era of life science

The Strategic Programs for Innovative Research Field 1 “Supercomputational Life Science” (SCLS), which aim to produce
the world’s leading research products in the field of life science by utilizing Japanese High-Performance Computing
Infrastructures (HPCI) centered on the K computer and got into full swing in FY2011, will come to an end at the end of FY2015.
We interviewed Dr. Toshio Yanagida, Dr. Akinori Kidera and Mr. Yukihiro Eguchi, who have significantly contributed to thepromotion of the project, to find out the achievements they attained in the course of research activities for the purpose of
exploring the potentials of computational life science for forecasting and controlling biological phenomena, and applying
such achievements to medical care and drug development, as well as the perspectives they obtained for future developmentof computational life science.

Is computational science useful after all?
− How did you feel when SCLS
started?

Yanagida：Actually, when I was
appointed as Director out of the blue, I
felt a little embarrassed, asking myself
why I was appointed as Director in spiteof my career as a specialist of singlemolecule measurement, and the factthat I had never been professional incomputers. I remember that, in my firstspeech, I said: “I doubt if computational
science will ever be so beneficial to life
science” (laugh).
Kidera：Yes, I remember that (laugh).
Yanagida：I think I made such a speech
because I had an impression that

2 BioSupercomputing Newsletter Vol.14

something had been achieved in thefield of life science without any deep
knowledge, and I felt no need to knowcomplex processes. However, as amatter of common sense, life scientists
were empirically thinking that it wastime for a change, and obliged to ask
themselves what they should do to
overcome such a situation. Meanwhile,measurement technologies such as
genetic analyses did not stop advancing,
and the complexity of data wasincreasing beyond our understanding.
Thus, as the momentum for recognizing
the importance of computing
increased, I gradually started to gain anunderstanding.
But when we started, we recognized
the sheer lack of computer power.
In spite of that, when the members
started to make efforts to use the K
computer, we recognized the potentialof the K computer for giving birth toa science which is different in kind,and the Director changed his mind
and got earnest about promoting ourefforts. All this happened thanks to theefforts made by those in computational
science.
Kidera：The first speech of Dr. Yanagida

was so impressive and striking. If I
remember correctly, I said: “Please

RIKEN HPCI Program for
Computational Life Sciences
Director

RIKEN HPCI Program for
Computational Life Sciences
Deputy-Program Director

RIKEN HPCI Program for ComputationalLife Sciences
Deputy-Program Director

Toshio Yanagida

Akinori Kidera

Yukihiro Eguchi

Computational life science is a new academic
field. To keep it growing
and maturing, it is essential to continuously
expand the major bases
and conduct outreachac tivities. And above
all, the enthusiasm of
researchers for cultivating and fostering thisacademic field is a must.

With expansion ofcomputational scope,
one future challenge
is to provide interfaces
which can be readily used by many life
scientists, rather thandeveloping computers requiring a wider
range of expertise.

I think that the key tobroadening the horizon of computational
life science is “a successful experience.”
Once “a success experience” like the heart
simulator “UT-Heart” iscreated, studies in thef ield will be accelerated significantly.

(RIKEN)

don’t say something which would
discourage the researchers” after his
speech (laugh). His statement was so
striking that I couldn’t help giving him
a warning. Why? Because his statement
was right on the mark. In a word, atthat time, computational science did
not offer any results which would truly
contribute to life science. SCLS waspreceded by the “Next-Generation
Integrated Simulation of Living
Matter (ISLiM),” in which we basicallyconducted software development.
Although its achievement forms thebasis of this project, we were engaged
only in software development but notallowed to use the K computer, so we
did not get to attain any achievements
which would convince life scientists.
Besides, no clear or specific attention
was directed toward the kinds oftargets, calculation methods ordesired achievements. So, as to theachievement of ISLiM, we could only
say “We succeeded in developing
general-purpose software. It’s amazing,
isn’t it?” As we knew that, we did notwant Dr. Yanagida to make a statement
which would reiterate that. However,once we started to use the K computer,
we marveled at its potential, andfound our specific targets and what weshould see, while the research system
to achieve them was prepared. As
researchers knew how they should use
the K computer to do computations,they became experienced to someextent and confident, and finallywere no longer afraid of what Dr.

(RIKEN)(RIKEN, Yokohama City University)

Yanagida says. That was when the
project was halfway finished. At last,
the image of life science based on the
supercomputer was emerging, andachievements were being made little
by little. After that, research activities
progressed more rapidly by gaining
more momentum. We have had five
years so far.

Yanagida：In that sense, I succeeded in
my first speech (laugh).
Kidera：Let alone succeeding… Anyway,
the strongest impact was your firstspeech and various organizationalchanges at the intermediate stage.
That is, you stressed the importanceof thinking how to collaborate withlife scientists who are outside thefield of computational science. I
believe that the project got rollingsmoothly only because of such efforts.
Before then, though researchers
were not withdrawn into the shellof computational science, theysuccumbed to a vague and indefinable
sense of understanding by creating
an excellent piece of software without
definitive products. But now, it isdifferent.
Yanagida：No, actually, I said moregently: “Computers are interesting,but they will be more interesting if
you apply them to understand themechanism of life together with life
scientists” (laugh). In this way, a newscience was born, which was different
in kind.
Eguchi：As Dr. Yanagida said at the
beginning of the project, unlike otherfields, only little-known researchers
use computers in the field of life
science. In a word, this is still aminor field quantitatively as well as
qualitatively. The researchers were
not sure about what they should doin this situation. That has been true.
But, I wonder if it is still true evennow. What should we do under suchcircumstances? In my opinion, themost important thing is to connect
those researchers involved in research
activities using the K computer withthe research sites of universities andprivate companies. I always worked
with the hope that those universities
and industries approach and see theresearchers who use the K computerand discover its usability, potential
for drug development or feasibility inmedical settings, and they consider to
use it by seeing it working. I started likethat. Specifically, one successful projectused “MP-CAFEE” developed by Dr.
Fujitani. At first I consulted Dr. Kidera,
and he answered: “I think that ‘MPCAFEE’ would be friendly to everyone.
The others are too professional andunfriendly to laypeople.” Consequently,
a group was formed for industries
based on “MP-CAFEE.” At first, it was
joined only by two pharmaceuticalcompanies. But now, it has been
joined by more than 20 companies.
Maybe, such a “connection” between
university researchers is very important,and I believe it is essential for outreachactivities.

BioSupercomputing Newsletter Vol.14 3

Discussion
meeting

Computational life science carving out a new era of life science
Excellent achievements in each of four Themes−I would like to ask what kinds ofachievements have been madeduring the past five years withregard to the four Themes of
SCLS.

Kidera：In each of the four Themes,
achievements have been made, which
are slightly different from each other.
In the ISLiM, the need for softwaredevelopment was first advocated.
However, what was required actually
resulted in achievements which would
be significant to life science. The mostsignificant theme at that time was theinterconnection of the hierarchicallayers of life. Life consists of spatiallysmall to large components, that is,molecules to cells, organs and theentire body, and temporally short tolong phenomena on a tremendously
wide scale. We were required to maketheir interconnections understandable
in detail. I truly felt it would be
impossible, as the K computer was
still unavailable. But the only way was
to keep trying. After the start of SCLS,
calculations on the K computer level
were made possible for the first time,
and the way to connect the hierarchyof life began to open up, although it
was only in its beginning. For example,
for the molecular-level research of
Theme 1, efforts were made to handle
the biological phenomena of cell
scales containing a lot of proteins andbiomolecules, and a simulation, which
may be the first cell model accurately
reproducing the behaviors of proteinsand so forth in cells, is about to be
developed.
Theme 3 is a challenge to thehierarchical connection on a larger
scale. In this Theme, the heart simulator
called “UT-Heart” was developedby miraculously establishing aconnection from the molecular scale
to the organ, heart. This is truly amarvelous achievement. Needlessto say, if molecules are handled at
the same level as Theme 1, even the,
K computer s capacity cannot copewith them. However, by adopting thesame spirit, a model representing the
behaviors of upper cardiac muscle cells
was successfully developed, resulting
in a very accurate and sophisticatedwhole heart model. Furthermore,
Theme 3 tackled a more challenging
theme, that is, to connect the brain,
nerves, muscles and bones, and built
an entire body model, which is now
about to be put into practice. For
Theme 3, I believe that not only thehierarchical connection was realizedbased on a simulator consistingof diverse algorithms on small tolarge scales, but also an integrated
hierarchical simulation was realized.
By making full use of the K computer,the answer to ISLiM’s issue, that is,hierarchical connection, is sufficient.
As a result, we are finally getting
ready to respond to various questions
concerning life science.
As Dr. Yanagida told us at the
beginning, in the field of traditional
life science, connections including
the hierarchical one were forcibly
built in many ways. The genotype
and phenotype are good examples.
In Theme 4, large-scale computations
were carried out by using the K
computer for analyzing a hugequantity of data to thoroughly researchthem and find out their relationships,
focusing on the fact that thephenotype is more complicated. Suchlarge-scale life data analysis is now
about to enable a connection between
the genotype and the phenotype ina real sense, and clarification of theircomplicated system. Not only has thedata analysis become large-scaled. The
phenotype is information on diseases
from clinical sites, while the genotype
is information on patients of thosediseases. Efforts are being made tobuild a system by gaining the trust of
medical doctors on site in that diseases
might be understood by connecting
the genotype and the phenotype,
and to enable their connection in
the true sense. This is truly the mostmarvelous thing. It is highly valuablethat an infrastructure was built on
which information obtained by thenext-generation sequencer in clinicalpractice is being utilized as truly useful
information.
Theme 2 was built around Dr. Hideaki
Fujitani, who was invited to respondto direct social demand: “What is thesupercomputer used for? Achieve
results!” I was surprised by him at first,
who responded to the question “Canthe K computer develop a drug?” bysaying “It’s worth trying.” I was secretly
wondering if he was really sure.
However, contrary to my expectation,
he ultimately achieved three outcomes
which led to the preclinical stage
including an antibody. Of course, I
believe he gained much support fromvarious parties, but he successfully
demonstrated the fact that such avariety of results can be obtained byuse of the K computer for a limited
time. This is a great achievement.
His attitude in pursuit of maximum
efficiency also greatly stimulated
this strategic field. The researchers
involved in the project including us
had much to learn from him.

Life science led by computational science
Yanagida：Above all, I would like tostress the fact that the computer
power of the K computer madethe achievement of such outcomes
possible. Some may think that, evenby using a low-performance computer,such outcomes could have beenachieved with more time. That is nottrue. It is evident that every Theme has

4 BioSupercomputing Newsletter Vol.14

tackled issues which could not havebeen solved without the computer
power of the K computer. As I said
earlier, the project demonstrated thatcomputational science was changing
the quality of life science. I think that is
the important point.
Kidera：For the hierarchical connection,for example, we actually want an

infinite computer capacity. However,the capacity is limited. Researchers
are always thinking what to do withinsuch limitations. The computation
method depends on the upper limit.
However, with the advent of the K
computer, computational flexibility,
as well as the range of potentials tobe pursued, increased. I think thisis truly significant. In future, we will
have much more opportunities. The K
computer is, so to speak, a prototype
which will bring such opportunities.
Eguchi：I have a feeling that these four
research groups are fundamentallychanging the concept of life science.
In recent years, we have witnessed
astounding progress in measurement
technologies, and we can now obtaina huge amount of data at one time.
As a consequence, there is growing
demand for a method to describe aphenomenon in an integral mannerbased on a large amount of data, asin the case of Theme 4, instead of
conventional life science in whichattempts are made to understand aphenomenon by focusing on a certain
part of the data obtained. The K com-puter responds to suchdemand. I am confident
that unprecedented
research styles whichwere not realized before
will emerge one after
another.
Yanagida：Quite a few life
scientists still believe thatcomputers are a kindof tool which supportand demonstrate theirexperimental results and tentative
theories. However, computational
science is not just to support life
science. I hope they understand thatcomputational science is pioneering
life science. It is in a position to leaddata-driven life science.
To this end, I hope that those withpotential for understanding the mostadvanced software programs tackle
life science, and make full use of the K
computer to explore new data-driven
life science fields. Computational
science is already a part of life science.

Toward an era where life scientists use computers perfectly−How do you plan to build on theachievements obtained in thepast five years?

Kidera：I think that research activities
and their outcome using the K
computer will sprout forth buds when
computer resources increase further
in future. We successfully built asolid model for conducting research
activities, that is, how to accept a large
amount of information, how to handle
it, and what outcome should beachieved. I hope that more researchers
will participate in this field.
Yanagida：What was achieved by
the K computer is not necessarily
sufficient. If a computer equipped witha computer power 100 times greaterthan the K computer is developed,
we will want to do the computations
to connect hierarchies further, andto solve more general problems. For
example, we may want to understandhow the heart works as part of theentire physical system, or how it iscoordinated with mental status. I wasa university physiology professor,
and the most important area for
medicine is physiology. For example,
we want to know the physiologicalconditions of the entire body, such as
how the mental status controls theimmune response. I am confident thatcomputational life science will pave
the way for the understanding of this

aspect, too. This will revolutionize thefields of life science and medicine.
Eguchi：I think it is measurement
technologies and computers thatare going to change the field of life
science. However, even if a computer
increases its capacity 100 times, highprecision calculation would not be
possible without the developmentof measurement technologies.
Measurement technologies also
have to evolve in response to thedevelopment of computational
science.
Yanagida：You are right. Modern
measurement technologies do notmeasure a complex thing as is. Under
this hypothesis, a target phenomenon
is focused on, simplified, and thenmeasured. So, around 99% of data isdiscarded, as only the data satisfying
the hypothesis is left. A measurer will
provide 100 times more data than atpresent provided that any measured
parameter of the entire body can beevaluated by the computer. Also, withsuch a system, a measurer will be able
to provide required data accordinglyand enter it into the computer for
subsequent computations. It will
also become possible to survey thereaction after the introduction of
a drug in detail by focusing on thetarget through computation andmeasurement. Measurement methods

will change, and the quality of life
science will also change, which will
drive a paradigm shift.
Kidera：In my opinion, data assimilation,
which enhances simulation accuracy
by taking experimental data into amodel, will be recognized increasingly
as a key concept in the field of life
science. For this purpose, at the frontof life science, researchers are now
required to use computers. That is tosay, there’s no need to open up thefield of computational life science. It
can be integrated into the field of life
science. It would be rather ideal.
Eguchi：You mean that computers andsoftware programs are becoming likeconventional test tubes and reagents.
If the time comes when we can see
computers in a life science laboratory
as ordinary items, we will no longer
need to use the words “computational
life science,” right?
Kidera：I think it was the first projectto draw words like “We cannot doanything without a supercomputer
any more” from some researchers at
the site. I hope that the number ofsuch researchers will increase.
Yanagida：I am sure that the time will
come when life scientists make full useof computers like test tubes.

BioSupercomputing Newsletter Vol.14 5

Discussion
meeting

Approach to the four Themes during the past five years and its achievements

Theme １ Simulations of biomoleculesin cellular environments
Molecular dynamics simulation iscommonly used as a method to find out
the relationship between the molecular
movement (dynamics) of macromolecules
such as proteins and nucleic acids, and theirfunctional structures. While conventional
co mp u t ati o ns we re t arg e te d o nl y atsimulations under water or in lipid bilayer
membranes, the objective of this Theme
was to study molecular dynamics in arealistic cellular environment (biomoleculesin cellular environments). At the initialstage of the study, we received criticism
for ambiguity of specif ic computation
targets. So we closely re-examined our
research targets, and decided to focus
on two research subjects: “modeling of
signaling pathways considering cellularenvironments”, and “multi-scale modelingof chromatin and nucleosomes”. A researchmethod termed “multi-scale simulation”
played a fundamental role in this Theme.
With the participation of specialists inquantum mechanics/molecular mechanics(QM/MM), all-atom molecular dynamics,
coarse-grained molecular dynamics andsingle - par ticle simulation, biologicalphenomena from molecular to cellularscales were success f ully analy ze d byusing molecular models with dif ferent
resolutions. In particular, for the former,
unprecedented large-scale simulations,such as all-atom molecular dynamics forbacteria cell cytoplasm, single-particle
t o e n g a g e i n my r e s e a r c h a c t i v i t i e ssimulation for EGF signal pathways, andb y s t r e n g t h e n i n g c l o s e co o p e r a t i ve
QM/MM computations taking the cellular
relationships with other experimental
environment into consideration, wereresearchers.
co n du c te d thro u gh th e us e o f th e Kcomputer. For the latter, we succeededin performing freeenergy calculations on
Molecular crowding
MEK/ERKEGF pathway
Proteinin cytoplasm
phosphorylation andnucleosomes using a numcrowding
molecular crowding
Proteinsystemin solution
ber of replicas, modeling ofa tri-nucleosome throughcoordination between Small
Angle X-ray Scattering (SAXS)Modeling of signaling pathways considering cellular environments
and mole cular dy namic s(MD/SA X S and CGMD/
Multi-scale modeling of chromatin and nucleosomes
Chromosome
Double-stranded
SAXS), large-scale chromatinDNA
Acetylation
Nucleosome
modeling based on coarseof a histone tail
Chromatin
grained dynamics, and soforth. At this point, finally, theimage of our initial objective,
Function of transcription factors“biomolecules in cellularFig. : “Modeling of signaling pathways considering cellularenvironments”, assumed aenvironments", and "multi-scale modeling of chromatin andtangible form. I will continue
nucleosomes”.

Theme 2 Simulation applicableto drug design
Life activities are based on the atomic
interaction and molecular reactions within
the lives, whose behaviors are ruled by
the physical principles such as quantum
mechanics and thermo-dynamic statistics.
Molecular force field well describes ther o o m t e m p e r a t u r e b e h av i o r s o f b i omolecules such as water, small molecules,
proteins, nucleic acids. We developed
FUJI force field for accurate and unified
d e s c r i p t i o ns o f b i o m o l e c u l e t a k i n gadvantage of high level quantum molecularorbital calculations. Since the simulation
should be checked by quantitative comparison with experiments, we developed thebinding free energy calculation methodof MP-CAFEE utilizing Jarzynski equality innonequibrium thermodynamic statics tocompare with binding constants commonlymeasured in the drug development. In
the collaboration with Professor Lindahl at
the Stockholm University, we developed*SIMD kernels of GROMACS molecular
dynamics suite, which are highly optimized

Research Center for Advanced Science andTechnology, The University of Tokyo

Hideaki Fujitaniand doubly speed up the K computer
performance.
The project target proteins were decided
after careful investigations, IT company
members engaged in the fragment basedd e n ovo d e si g n o f d r u gs , Un i ve r si t yresearchers performed MP- CAFEE on the K
computer, and pharmaceutical companies
per formed synthesis and assay of thedesigned compounds. We per formed*Molecular dynamics computation program accelerated at theassembler level through use of the vector processing function

6 BioSupercomputing Newsletter Vol.14

RIKEN

Yuji Sugita

about 30 0 MP- C AFEE calculations forthe cancer target protein and the mostpromising compounds are now underinvestigational new drug enabling study(animal test).

Fig. : Cancer target protein and drug (A) Fragment based de novo
design (B), MP-CAFEE result by the K computer (C)School of Engineering,
Theme ３ Hierarchical integrated
The University of Tokyo
Shu Takagi
simulation for predictive medicine

The objec tives of this Theme are to
reproduce the functions of tissues andorgans as an assembly of various cells
at a level never explored before and, topredict clinical conditions and contributeto medical treatments. For instance, forthe brain-nervous and musculo-skeletal
system, we have conducted our researchwith the aim of reproducing the differencesin tremor and rigidity, and the postural,
maintenance dis ord er in Par k ins on s
disease by integrating the NEST, which
succeeded in a brain-ner vous systemsimulation consisting of the world’s largest
number of neuron cells, the multi-scale
skeletal muscle simulator Hi-MUSCLE which
reproduces the behaviors of an entire
muscle as an assembly of muscle fibers, andthe generalized musculo-skeletal simulator
K-Body. As to the achievements up to now,
we succeeded in reproducing the β-band(approx. 15Hz) tremors in the basal ganglia
which are caused by the lack of dopamineand observed it in animal tests using amonkey, and simulated the behavior of thesignal that reduces its frequency by halfin the thalamus and transmits it from thecerebral cortex to muscle fibers throughthe spinal cord, resulting in the tremors ofhands（see article “Zoom in” on page 9 ofthis issue）.
For simulation of the circulatory system,
the achievements made by the multiheart disease. For simulation of thrombosis,
scale and multi-physics heart simulator,
through this project, we proposed
UT-Heart, are significant. It succeeded
new analysis methods to evaluate drugin realiz ing a 3- hier archy simulatio nefficacy based on an integrated analysis ofintegrating sarcomere, cardiac muscle cells
simulations and flow chamber experimental
and the entire heart for the first time inresults, and obtained new f indings
the world, making a significant impact toconcerning the functions of antiplatelet
the field of computational science. A video
drugs.
created based on those achievements got
the Best Visualization or Simulation Award
from the International Conference
SIGGRAPH, an authority in the fieldof CG, in 2015. Up to now, this video
has received over 250,000 views on
YouTube (English version) (see Fig.
below), and this heart simulator is
now renowned globally rather thanin Japan. Furthermore, the simulator
has already entered the stage ofpredicting clinical conditions using
clinical data, and a comparison withclinical results demonstrated its
feasibility in accurate postoperative Fig. : Image from a video of UT-Heart, which received overprediction of pediatric congenital 250,000 views on YouTube

Theme 4 Large-scale analysis of life data
The K computer has made a "warp" of medical
and life sciences into a new dimension.
In some cases, cancer is caused by a virus
infection. Japan is the major endemic area of
human T-cell leukemia virus type I (HTLV-v). After
infection during infancy, a highly malignant
blood cancer called adult T-cell leukemialymphoma (ATL) develops after a latent periodof a few decades. A large-scale omics data
analysis that was conducted using the world’s
largest number of ATL cases (400 cases or more)revealed the full details of genetic abnormalities
of ATL, and successfully discovered the targets
for the development of new therapeutic drugs(Nature Genetics 2015). Also, a large-scale data
analysis clarified the comprehensive histology
of colon cancer which evolves spatiotemporally,
obtains heterogeneity and develops metastasis
to the liver, and its simulations were conducted(PLoS Genetics 2016). In the prediction of effects
on anticancer drugs in individual patients, theworld’s largest-scale gene network analysis was
conducted based on gene expression data of
more than 600 cancer cell lines, and data forsensitivity and resistance against more than
100 kinds of drugs, to build an infrastructure forindividualized anticancer drug administration
with the world’s highest accuracy and precision

The institute ofMedical Science,
The University of Tokyo

Satoru Miyano(PLoS One 2014).
The body temperature of a baby is very
high, because his/her brown fat cells generate
heat. However, as he/she grows up, those cells
disappear. Meanwhile, in case of a lab mouse at
4˚C, its fat cells are known to be converted into
beige anti-metabolic cells which are different
antigenicity against cholera is advancing
from brown fat cells, and generate heat 100
dramatically in cooperation with immunology
times stronger than that generated by skeletal
researchers. There is a high expectation formuscles. By performing a large-scale genevaccine development through the use of the K
network analysis, the relationship between
physiologically active substances involved in thecomputer.
inflammation pathway called IL-1β
and the heat generation mechanism
was discovered for the first time,
and the molecular mechanism of
conversion into anti-metabolic cells
was completely unraveled (Fig.)(Cytokine 2016).
W ith the advent of GHOS TMP which carries out massive
parallelization and high-speed
search of homologous sequences,
the analysis of the metagenomeof human feces can be completed
w i t h i n 10 m i n u t e s , a n d t h eidentification of resident bacteria Fig. : A large-scale network analysis made possible only by
w h i c h c a n s t i m u l a t e c r o s s - the K computer clarified the mechanism of conversion into

●See the URL on the right for detailed information on this reportanti-metabolic cells.

http://www.scls.riken.jp/eng/newsletter/Vol.14/openup.html
BioSupercomputing Newsletter Vol.14 7

Close-up on SCLS Research

Theme 1 Simulations of biomolecules in cellular environments

Visualizing the real molecular pictures, which are not identified
through experimentation, through the use of computing power- Searching the structures of histone tails Molecular Modeling and Simulation Group, Japan Atomic Energy Agency

Jinzen Ikebe

For sustaining life, all living beings(or terminals of histone proteins) (i.e.

including human beings are undergoingacetylation), the chromatin condensation isdiverse chemical reactions (i.e. metabolism)

decreased, activating the gene expression

in their bodies. Metabolism is produced by(Fig. 1). To understand the mechanism fortranscription proteins which are synthesizedswitching gene expression on and off, it is(o r e x p r e ss e d) b as e d o n t h e g e n e t i cnecessary to examine how the structuresinformation recorded in DNA. By expressingof histone tails change due to acetylation.

as many of those proteins as necessary

H o w e v e r, a s h i s t o n e t a i l s a s s u m e a

w h e n re quire d, li v in g b ein gs s t r ic tl ynumber of structures called “intrinsicallyregulate their metabolism. Abnormalities indisordered states”, it is impossible to survey

the mechanism for regulating the genetic

the molecular structures in detail using

expression constitute a factor for causing

experimental methods such as cr ystal

cancer or genetic disorders. To elucidate

structure analysis or NMR spectroscopy.

this mechanism, we are conduc tingAlso, as histone tails carr ying positive

research by using a molecular dynamics

electrical charges strongly cling to DNA(MD) simulation which traces the structuralc a r r y i n g n e g at i ve e l e c t r i c a l c h a r g e schange in proteins on a computer.

through electrical forces, conventional MD

DNA is folded into compact structures ina cell nucleus. The structural unit formed bysimulation has not identified the diverse
structures of histone tails sufficiently.

DNA wrapped around the histone proteins is

As part of a project for the K computer,called a nucleosome, and a fiber of packed

we succeeded in developing a new MD

nucleosomes called "chromatin". Whensimulation method called adaptive lambda

the chromatin structure is condensed,

square dynamics (ALSD). This method

transcription proteins cannot access DNA

allows us to examine diverse structures of

to decode the genetic information, and thehistone tails by intentionally scaling theirgene expression is disabled. Meanwhile,ifelec trical charges in the simulation toacetyl groups are added to histone tails

eliminate the clinging to DNA. As a result,by using the computational power of thesupercomputer, detailed pictures of histone
tails, which had not been revealed throughconventional experiments or simulated
computations, emerged for the first time,such as the fac ts that the acet ylation
reduces the structural size of histone tails,
leading DNA wrapped around histone
proteins to relax easily and thereby allowing
struc tural changes in chromatin to bepromoted. (Fig. 2), and that acetyl groups
are ac tively exposed over the sur faceof nucleosomes as a marker to induce
transcription proteins. We will fur therclarif y the gene expression mechanismand embark on research activities aimed
at application such as the development of
new drugs through the ALSD simulation
method.

Fig. 1： Gene expression is mainly activated through acetylation ofhistone tails.

Fig. 2： (Left) Atomic model around a histone tail. (Right) Changes in the DNA spatial
distribution through acetylation. DNA tends to emerge in the red area, and does not in
the blue area, compared to when the acetylation process is not carried out.

● See the URL on the right for detailed information on this reportand profile of the author.

http://www.scls.riken.jp/eng/newsletter/Vol.14/zoomin01.html

8 BioSupercomputing Newsletter Vol.14

Close-up on SCLS Research

Theme 3 Hierarchical integrated simulation for predictive medicine

Integrated simulations of the nervous system andmusculo-skeletal system for reproducing Parkinson’s
disease symptoms
School of Engineering, The University of Tokyo

When you intend to move your bodyvoluntary, motor commands generated
inside your brain are transmitted from the
motor cortex to the spinal cord throughnerve fibers. In the spinal cord, the motor
commands are integrated and coordinatedwith the feedback signals from muscles, skinand so forth, and sent to the motor neurons
which are connected to the muscle fibers.
When motor neurons are activated, all of
the muscle fibers innervated by the neuron
contract and produce force that causes joint
movement.
Any trouble in the process from thecerebral nervous system to the musculoskeletal system may develop motor
d y s f un c ti o n . Par k ins o n's d is eas e is aneurological brain disorder that resultsfrom degeneration of neurons in the basal
ganglia which controls movement. The
degeneration of neurons creates a lack of
the neurotransmitter called “dopamine”,
causing the movement dysfunctions. The,
motor symptoms of Parkinson s disease
include resting tremor, rigidity, bradykinesia
and postural instability, but the mechanism
whereby such symptoms are generated
remains unexplained. We are developing an
integrated simulator of the central nervous
and musculo-skeletal systems of the entire
human body with an aim to provide a useful
tool for investigating the mechanisms
u n d e r l y i n g m o to r d y s f u n c t i o n s , a n d
exploring effective therapeutic approaches
through the use of computer simulations.

Simulatorof the cerebral
nervous system

Naoto Yamamura

Our simulator is an integration of asimulator of the cerebral nervous system
consisting of the basal ganglia, thalamus
and motor cortex circuits, a simulator of thecerebrospinal nervous system computing
th e a c ti v i t y o f m oto r n euro ns , an d asimulator of the musculo-skeletal systemcomputing behaviors of the musculo skeletal system from the activity of motor
neurons, which were developed by the DoyaResearch Group (Okinawa Institute of Scienceand Technology Graduate University), theNakamura Research Group (The Universityof Tokyo), and the Takagi Research Group(The University of Tokyo) respectively, so
as to expand them over the entire humanmusculo-skeletal system (Fig. 1).
Fig. 2 shows an example of an integrated
simulation based on a central ner vous
system model and a human upper arm
musculo -skeletal model in Parkinson’s
disease. The neural activities in the motor
cortex, thalamus, basal ganglia in the brain,
the activity of motor neurons in the spinal
cord and the joint angle of an elbow joint are
shown through time. The upper side of eachneuron is projected to the biceps muscle,
while its lower side is projected to the triceps
muscle. In the basal ganglia, abnormal neural,activity specific to patients with Parkinson sdisease are reproduced. For neurons in thethalamus, alternate neural activities are
reproduced with a frequency similar to thatof Parkinsonian tremors (4 to 6Hz) in the

Basal ganglia, thalamus
and motor cortex circuits

Motor command

Simulator of
the cerebrospinal
nervous system

Simulator of
the musculoskeletal system

Fig.1：Simulator integrating the musculo-skeletal and nervous system.
“MN” means motor neuron, and “IN” means interneuron.
● See the URL on the right for detailed information on this reportand profile of the author.

biceps and triceps. The output from thesimulator of the cerebral nervous system
is sent to the spinal cord as the pyramidal
tract activity of the motor cortex, and motor
neuron activity is computed by the simulatorof the cerebrospinal nervous system. The
simulator of the musculo-skeletal systemcomputes the force of contraction basedon motor neuron activity, and tremor-likemovements are observed in the elbow joint.
The development of this integrated
simulator enables the simulation of humanbody movements originating from activityof the central nervous system. Using thissimulator, we will proceed further with ouracademic studies with an aim to reproduce
motor symptoms such as Parkinsoniant r e m o r a n d r i g i d i t y, u n d e r s t a n d t h emechanism generating such symptoms, andeventually develop treatment methods.

Brain – motor cortex

Brain – thalamus

Brain – basal ganglia

Spinal cord
– motor neuron
Musculo-skeletal– joint angle

Fig.2：Integrated simulation of the cerebral nervous, cerebrospinal
nervous and musculo-skeletal systems in Parkinson’s disease. The black
dots represent neural activity.

http://www.scls.riken.jp/eng/newsletter/Vol.14/zoomin02.html

BioSupercomputing Newsletter Vol.14 9

Close-up on SCLS Research

Theme 4 Large-scale analysis of life data

From supercomputing analysis of big cancer genome
data to life science and medical care
Health Intelligence Center, The Institute of Medical Science, The University of Tokyo

Seiya Imoto

We use a supercomputer to analyze cancer

Thanks to the breakthrough of the

genome data for identifying abnormalities

next-generation sequencers, the costof systems in cancer, and finally aim torequired for determining the entire DNA

create prediction methods for drug efficacy

sequence continues to decrease at a paceand side effects, and novel treatment andfaster than Moore’s law. Nowadays, it isprevention methods. Genes form a complex

as low as 1,000 dollars. This technology

communication network depending on thealso enables measurement of the amountphosphorylation of proteins they produce,of messenger RNAs produced by eachthe interaction between proteins, and thegene. We are now in an age when we cancontrol of expression of other genes. Thisreadily obtain individual genome data andsystem generates the proteins required togenome-related data. Nevertheless, themaintain our lives. Meanwhile, cancer isamount of human genome data or RNA

believed to occur due to accumulation ofdata is overwhelming. The volume of whole

various acquired mutations in genomes.

genome sequencing data is around 200GB

Such mutations may cause some genes

in terms of a contemporary measurement.

to produce abnormal proteins and thenConsequently, supercomputing capacity isdeactivate them, abnormally activate them,indispensable for data analysis.

or even make them acquire new functions.

Whereas we simply refer to “cancer” as a

Such “failures” of genes affect the network

type of disorder, it bears diverse genomicof genes mentioned above. If the systemvariations and mutations. They differ fromfalls into an uncontrollable state, “cancer” ispatient to patient, and even one patient

said to have occurred.

may have multiple cancer-cell populations

whose genomes are damaged in different
ways. Research activities to understandgenomic mutations which determine“cancerous characteristics,” such as highmalignancy and drug resistance, arecurrently in progress.
We successfully established a new data
analysis method called “NetworkProfiler” byusing statistical theory. This method allows
us to find differences in the gene network
which determines the characteristics ofcancer cells, such as drug resistance, basedon data obtained by measuring the amountof RNAs produced by each gene (i.e., RNA
expression data). By using this technique,we extracted the gene network relating to
the effects of approx. 100 kinds of anticancer
drugs based on data for more than 600
cancer cell lines. This was made possible
only by using the K computer. Currently,
we are engaged in the development of adata analysis technique which can moreaccurately forecast the effects of anticancer
drugs for each cell by combining data fromthis gene network with a great amount ofdata on genomic variations from the nextgeneration sequencer, so as to perform

Sensitivity

ResistanceFig. ：Sensitivity to anticancer drug Elesclomol (horizontal axis) and transcription factor activity
prediction value (vertical axis of the upper panel).
It shows that, for example, while AIRE controls strongly the controlled genes in cancer cell lines highly
sensitive to Elesclomol, its influence is limited in resistant cancer cell lines.
The lower panel shows the biases depending on cancer types. A slight bias toward sensitivity is observedin bladder, while a bias toward resistance is observed in blood. However, no significant biases areobserved in other cancer types. The resistance and sensitivity mechanism of Elesclomol is expected toemerge beyond cancer types.
●See the URL on the right for detailed information on this reportand profile of the author.

10 BioSupercomputing Newsletter Vol.14

a comprehensive analysis. The results ofsuch an analysis will lead to individualized
medical treatments based on the genomic
data.

http://www.scls.riken.jp/eng/newsletter/Vol.14/zoomin03.html

Report on workshop for media personnel, titled"2nd Forefront of life sciences led by K computer!"
Planning and Coordination GroupRIKEN HPCI Program for Computational Life Sciences

The workshop for media personnel,"2nd Forefront of life sciences led by K
computer!" was held on Wednesday,
September 30, 2015. The purpose of thisworkshop was to widely inform press
personnel of research achievements delivered by integrating this cutting edge
supercomputer with life science, as well
as of new science dreams arising out ofsuch achievements. Four representatives
tackling research subjects under Strategic Programs for Innovative Research
Field 1 Supercomputational Life Science(SCLS), and two representatives tacklingpriority issues for the post-K computer,delivered lectures from the Tokyo Liaison
Office of RIKEN and RIKEN Advanced
Institute for Computational Science (via
teleconference).
Six lecturers gave stimulating presentation of the research objectives, theachievements exclusively attained by the
K computer, and the future applicationand evolution in industrial areas under

the four research subjects:“Hierarchiof abnormalities in cancer, the results of,cal integrated simulation for predictive
ATL s large-scale analysis, and the cramedicine,”“Analysis of the molecular
nial nerve system and musculo-skeletal
dynamics of proteins and nucleic acids
system, indicating their wide-ranging
in cellular environments,”“Innovativeinterests in diverse research fields. The
drug development enabled by the suworkshop sessions were held in Tokyo
percomputer”and“Large-scale analysis
and Kobe in the presence of a number ofof life data,”peppered with their own
press personnel. We appreciate their atfuture initiatives and dreams. Also covtendance and strong interest. For a sumered were the future prospects for themary of the lectures and non-classified
potential breakthrough achievements
presentation documents, please visit thesoon to be witnessed in the field of life
website of SCLS (http://www.scls.riken.
sciences thanks to the projects of thejp/information/material.html).
post-K, which is expected to succeed
the K computer, under the titles,“Integrated computational life science
for individualization and preventive
medicine”and“Drug development
innovation enabled by the post-K.”
According to the results of thequestionnaire survey conducted afterward, what impressed the participants were the research activities directed at understanding the diversity
A lecture held at the venue in Tokyo- The K computer creates the future of science and society -Supercomputational Life Science 2015

Planning and Coordination GroupRIKEN HPCI Program for Computational Life Sciences

SCLS comes to an end in March 2016.
To present its final achievements, a
symposium titled“- The K computer creates the future of science and society Supercomputational Life Science 2015
(SCLS2015)”was held in the Takeda Hallon the Asano Campus of The Universityof Tokyo, on Tuesday, October 20 and
Wednesday, October 21, 2015. This twoday symposium was attended by 143
persons including those from educational institutions, research institutions,private companies and governmental
entities, as well as general citizens.
At the international workshop held on
the first day, four researchers from over-

Lecture sessionseas laboratories and four researchers
from SCLS delivered lectures to present
the research activities being conductedat the forefront of computational life
sciences. At the achievement report session held on the second day, 15 SCLS
researchers reported the latest researchachievements attained through use of
the K computer, such as analysis of intercellular molecular dynamics basedon molecular dynamics simulation, prediction of binding of drug development
candidate compounds based on highprecision binding free energy calculation,
hierarchical integrated simulation, andexhaustive analysis of abnormalities incancer, and received a great response
from the attendees. The poster session
was attended by 29 persons, and offeredan opportunity for participants in the
symposium to exchange opinions andinformation in a lively and active way.
With positive comments such as“Irealized that unprecedented achievements are being made at a pace which
was unthinkable only five years ago,”
and“I believe that some of the software
programs and approaches developed bythem have sufficient potential for leading
the world,”we are pleased that this symposium provided a precious opportunity
to think about the future of computational life sciences,whose importance isincreasing as part of
the further development of life sciences.
Taking this occasion,
we would like to extend our cordial thanks
to all the lecturers andparticipants.

Poster session

BioSupercomputing Newsletter Vol.14 11

NEXT STAGE

We interviewed four Subtheme leaders of priority issues 1 and 2 in “Flagship 2020” Project (post-K computer project for the development

Priority issue (1) : Innovative drug discovery infrastructure through functional
Subtheme A

Advancement of MD and associatedalgorithms by post-K computer

Priority issue 1, Subtheme A,
Supervisor

Yuji Sugita
RIKEN

Under this issue, we engage indesign work is carried out by focusing on

required for maximizing efficiency of theoverall computing efficiency, that is, by

acceleration and algorithm development
post-K molecular dynamics simulation.

For drug design application, molecular
dynamics simulation covering various
target systems is required. In addition
to simulation forecasting of protein andligand binding conditions based on asmall system consisting of several tens
or hundreds of thousands of atoms, andthe dynamics of membrane proteinsor protein complexes consisting of a

maximum of one million atoms, it isnecessary to compute a large-scale system
consisting of 10 million atoms or morein the case of a biological system like avirus or cellular environment. To allow thepost-K to handle such biological systems,

both hardware and software to optimize

adopting a co - design metho dolo gy.

Together with priorit y issue 1, RIKEN
Advanced Institute for Computational

S ci e n ce an d Fuji t su L imi te d are co designing a molecular dynamics software

called GENESIS developed under the

initiative of RIKEN. We plan to allow smalland medium-scale systems to implement

a number of simulations with different
parameters and ligands simultaneously
using a post-K, and large-scale systems tochallenge complex and large computation
limits by using all the nodes of the post-K.

By adopting a new molecular dynamics

GENESIS, we will attempt to simplify andaccelerate the computation of molecular
dynamics and the analysis of free energy

necessary for drug design through useof the post-K. We will also publish theresulting software and computation sothat general users can use them at thesame time as the release of the post-K toencourage their use.

algorithm for drug design application
under priority issue 1 in the sophisticatedLong-time dynamics algorithms

Generalized-ensemble algorithms(Kitao, The University of Tokyo)(Sugita, RIKEN)

Temperature exchange

MD acceleration
by Post-K computer
Sugita, RIKEN

Structure prediction

Co-design SW

Important issue 1

Kobayashi, Jung, RIKEN

AICS, RIKENFree energy computation method(Ikeguchi, Yokohama City University)

Independent MD

GENESIS

Fujitsu Limited

Coarse-grained modelling(Shinoda, Nagoya University)

QM/MM method(Hayashi, Kyoto University)
Structural change

Initial state

Final state
Coarse-grained

All-atomChemical reaction

Under Subtheme A, “Post-K MD acceleration and algorithm deepening,” we will make the molecular dynamics software program called“GENESIS” more sophisticated with a view to the post-K concept through the co-design process, and adopt advanced MD algorithms
sequentially.

12 BioSupercomputing Newsletter Vol.14

Challenging the priority issues on post-K computerof a machine that will succeed the K computer) promoted by the Ministry of Education, Culture, Sports, Science and Technology.

control of biomolecular systems
Subtheme B

Development of next-generation drug
design computational techniques
One of the nine priority issues
designated under the concept of thep o s t- K c o m p u t e r, “ I n n o v a t i v e d r u g
discover y infrastructure throughfunc tional control of biomolecularsystems,” is now going to star t infull swing. In this priority issue, I was
appointed as a supervisor for Subtheme
B, “Development of next-generation drug
design computational techniques.” In
Subtheme B, we will work unwaveringly
on computing methods for drug designand structural biology, which are notattainable with conventional computing
capabilities, by using the sophisticatedmolecular simulation sof t ware andalgorithm optimized for the post-K to
be developed under Subtheme A, so
as to pave the way for the integrated
co m p u t a t i o n a l d r u g d e s i g n s y s te m
to be developed under Subtheme C.
Specifically, first of all, we set a goal tocontrol dynamic molecular func tions
by focusing on motions and structuralchanges of drug design target proteins.
Computing methods for conventional
computational drug design often treat

Priority issue 1, Subtheme B,
Supervisor

Mitsunori Ikeguchi
Graduate School of
Medical Life Sciences,
Yokohama City University

the structures of target proteins as firm
and immovable, in accordance with thelock-and-key model. However, actually,
the structures of proteins are very softand often change due to the binding ofcompounds such as pharmaceuticals.
In this issue, we try to understand andco n t r o l t h e m o t i o n s a n d s t r u c t u r a lchanges of target proteins by capitalizingon the superior computing capabilitiesof the post-K. The next issue is to control
the interactions between proteins, andthose between nucleic acids and proteins.
In recent years, bio -pharmaceuticals
containing proteins as medicinal
chemicals such as antibody drugs also
have been developed. Such proteins andnucleic acids are much more complex
than low-molecular weight compounds,
and their steric structures are flexible.
Therefore, it is necessar y to conduc tlarge-scale computation using the post-K
in order to compute the interac tions
between molecules in detail. Our issues
also include the entire computation ofvirus capsids and computation targetedat the cellular environment where a plural

Dynamic molecularregulation

Ikeguchi, Yokohama City
University

Interaction between
proteins

Fujitani, The University ofTokyo

Intracellularenvironmental target
Sugita, RIKEN●See the URL on the right for detailed information on this report.

number of biological supermoleculesa r e i n t r i c a t e l y e n t w i n e d . A c t u a l l y,these targets are supergiant systems,
which could be computed only by the,world s leading supercomputers. This
would be an unprecedented challenge.
As described so far, this is already an
attractive research theme only in termsof computation. However, its value will
be increased by closely coordinating withexperimental system measurements. In
this issue, we plan to conduct research
activities in cooperation with the mostadvanced structural biology experiment
facility SPring8 and NMR facilities. We
sincerely hope that we can implement
unprecedented computations for drug
design using the post-K.

Interaction between nucleic
acid and protein, sub-nuclear
targets
Kono, Japan Atomic Energy
AgencyOutline of Subtheme B “Developmentof ne x t- gener ation dr ug design
computational techniques.” It consistsof the subjects “dynamic molecularregulation,” “control of interac tionb e t we e n p r o te i ns ,” “co nt r o l o finteraction between nucleic acid andprotein,” “sub-nuclear environmental
target,” “intracellular environmental
target,” and “viral target.”

Viral target

Shinoda, Nagoya University

http://www.scls.riken.jp/eng/newsletter/Vol.14/nextstage01.html

BioSupercomputing Newsletter Vol.14 13

NEXT STAGE

Priority issue (2) : Integrated computational life science to support personal
Priority issue 2, Subtheme B,
Supervisor

Subtheme B

Shigeo Wada

Supporting personalized medicine by data Graduate School ofEngineering Science,assimilation based biological simulation
Osaka University
The development of measuring
techniques which enable non-invasive
observation in the body such as MRI, X-ray
CT and ultrasonic echo has contributed
si g ni f i c antl y to th e a d v an ce m e nt o f
medicine. Meanwhile, the developmentof computing science enabled dynamic
phenomena to be analyzed at diverse
dynamic layers from biological moleculesand cells to tissues, organs and individuals,
resulting in the reduction of the distances
between biology, life sciences and physics.
One of the roles of bioengineering is
to apply understanding of biologicalphenomena from such physical aspects tomedicine. However, in the field of evidencecentered medicine, much importance is
attached to measurements, and technicalanalyses based on mathematical models are
not utilized sufficiently in clinical practice.
As the amount of data available becauseof progress in measuring devices increases
and the target phenomena become more
complicated, sophisticated diagnosis andtreatment require deep understanding of
the biological phenomena observed, andanalysis of a huge quantity of measurement
results. However, no medical engineering
techniques to support such tasks have so far
been developed.
The purpose of this Subtheme is todevelop a computational simulator
acceptable to the medical field where
actual measurement data are importantby assimilating and integrating largescale physical simulations of the biologicalbody through use of the post-K computerwith biometric data supplied in various
forms, and build fundamental technologies
to suppor t personalized medical carebased on the medical and biological dataof individual patients. For a large-scale
simulator which can only be created withthe post-K, we will develop a whole-brain
circulation and metabolism simulator whichconnects cranial nerve activity with brain
circulation. By providing the medical fieldwith physical data obtained from the data
assimilation based biological simulation, we
will evaluate the biological functions in the

14 BioSupercomputing Newsletter Vol.14

human body correctly and quantitatively
and build a database, and create new
medical engineering technologies built
on computational science in order toensure sophisticated diagnosis, treatment,
prevention and forecast methods which
support a healthy, long-lived society.
Coordination with brain science research activities

Disease state evaluation

Provision of new research platform with awith brain science research activities
Drug eﬃcacy evaluationCoordination
view to understanding brain functions byDisease state evaluationof new the
research
platformwith(nervous)aDiagnosis and treatmentProvision
brainʼselectrical
Drug eﬃcacy evaluation viewintegratingtounderstanding
brain
functions
supportand treatment
activity and physical(bloodﬂow)bydata
Diagnosis
integrating the brainʼs electrical (nervous)
supportactivity and physical (blood ﬂow) data
- Brain aneurysm

Treatment plan
Remediation
Treatment plan
Databasecompiling
Remediation
Database compiling

Simulator of brain circulation data
infarction
assimilation- Brain- Brainaneurysm
disorder Simulator of brain circulation data
contusion(Shigeo assimilation
Wada, Osaka University) - Brain- Brain
Fluid acoustic simulator in oral cavity -- Speech
infarction
Cleft lipdisorderand palate- Brain contusion(HirooOsakainUniversity)(Shigeo
Wada,
Osaka
University)
Fluid Tamagawa,acoustic simulator
oral cavity --Speech
Deglutition disorder
PC-MRI

Brain function measurement

Data reproduction
Brain function
measurement(Data assimilation)
Data reproduction
Brain
Physiome.jp (Data assimilation)
blood ﬂow
Physiome.jp
Simulator of whole-brainBrain- Cleft lip and palate(Hiroo Tamagawa, Osaka University) - Deglutition disorderUltrasonicwave
PC-MRI
Tongue motion
Ultrasonic wave
Tonguecontrol
motionBlood ﬂow
control

Cranial nerve
Cranialnerve
systemBlood
ﬂowcontrol
control

Motion control

Motion control

Metabolism- Understanding- Understandingthe
theneuralneuralcontrol
controlmechanismmechanismwhich
whichstabilizes
stabilizesmotions
motions- Understanding
thebreakdown- Understanding the breakdown
mechanismmechanismdue
duetotocertain
certaindisorders
disorders

MRI
and PETsimulator(Shigeo
Wada,
Osaka University)(Shigeo Wada, Osaka University)

Live cell

Metabolism

Simulator integrating the neural
Simulator integrating the neuraland musculoskeletal system
and musculoskeletal system(Taishin(TaishinNomura,
Nomura,Osaka
OsakaUniversity)
University)

MRI and PET simulator

blood ﬂow
Simulatorof whole-brain
circulationand metabolism
circulation
and Osaka
metabolism(Shigeo Wada,
University)(Shigeo Wada, Osaka University)

systemMulti-scale and multi-physics

Liveimaging
cell
imaging

Microcirculation migratory

Multi-scale and multi-physics
simulator of circulation
simulator of circulation(ShuTakagi,
Takagi,
The
Universityof Tokyo)(Shu
The
Universityof Tokyo)

Microcirculation migratory
cell analysis platform
cell analysis platform(HideoMatsuda,University)(HideoMatsuda,OsakaOsaka
University)- Diseasestate
evaluation- Diseasestate
evaluation- Drugeﬃcacyevaluation- Drugeﬃcacyevaluation- Diagnosis
treatment- Diagnosis
andandtreatment
supportsupport
Blood
ﬂow
Blood
ﬂow
andandorgan
motionorgan
motionSubthemeA
SubthemeA
individualization
CancerCancer
individualization
medicinemedicine
and prevention
and prevention
The University(Satoru(Satoru
Miyano,Miyano,
The Universityof Tokyo)of Tokyo)
Predictionof cancer
metastasis
Predictionof cancer
metastasis

Biomolecular
Biomolecularmechanismmechanism

Subtheme
C C
Simulator
Subtheme
Simulatorofoffocused
focusedultrasoundultrasound
Whole-heart
simulator
Simulator
beam
Whole-heart
simulator
Simulatorofofheavy
heavyparticle
particle
beam(Toshiaki
Hisada,UT-Heart
Inc) Inc)(Shu
Takagi,
The
UniversityofTokyo)(Shu Takagi, The University of Tokyo) (Toshiaki Hisada, UT-Heart

Predictionof bloodofclot
Prediction
blood clot
formationformation- Cardiac- infarction
Cardiac infarction- Brain infarction- Brain infarction

Motordisorders
disordersdue
duetotoParkinsonʼsParkinsonʼs diseaseMotordisease Sophisticated diagnosis
disorderdiagnosis(Posturaldestabilization
destabilizationandand frozen
frozen gait)
Cardiacdisorderdiagnosis
Sophisticated diagnosis Cardiac(Posturalgait) andandandtreatment
supporttreatment
supportandtreatment
treatmentsupport
support(a)Overall image of Subtheme B

Cardiac infarction, blood pressure

Cardiacinfarction,pressure
ﬂuctuation,etc.,duebloodtoﬂuctuation,etc.,duetocerebrovasculardisorder,cerebrovasculardisorder,stress or excitationstress or excitation

Circulatory

systemCirculatory
systemCranial nerve
Cranialsystemnerve

Speech disorder, aphasia andSpeech disorderdisorder,dueaphasia
anddeglutition
todeglutition disorder
cerebrovasculardisorder due tosystemcerebrovascular disorder

Inﬂuence on motor functions andsomatic
reﬂexesdue tofunctions
Parkinsonʼs
Inﬂuence
on motoranddisease,reﬂexes
tensionsdue
or excitation
somatic
to ParkinsonʼsOral system

Oral systemdisease, tensions or excitation

Nutrient and oxygen supply,
revascularization through exercise,

Nutrient and oxygen supply,
cardiac rate, muscle action, etc.
revascularization through exercise,cardiac rate, muscle action, etc.

Musculoskeletal
systemMaintenance of homeostasis of biological bodyLife-sustaining

velopharyngeal function,breathing motion, etc.

Musculoskeletal
systemMaintenance of homeostasis of biological bodyLife-sustaining

Mastication, tongue motion,
velopharyngeal function,
Mastication, tongue motion,breathing motion, etc.

Maintenance of high-order bodily functions

Maintenance of high-order bodily functions
Improvement of QOL

Improvement of QOL

Support of personalized preventive medicine
to support the long-lived and aged society

Support of personalized preventive medicine
to support the long-lived and aged society(b)Objective and relevancy of each research subject
Fig. 1: In Subtheme B, we will extend the simulation technologies developed by the K computer, anddevelop the biological body’s physical simulator based on each patient’s medical and biological data
for the blood circulating system that plays the major role in life sustenance, the neural-musculoskeletal
system responsible for body movements indispensable for the maintenance of QOL in the aging society,and the oral system responsible for speech.

Challenging the priority issues on post-K computerized and preventive medicine
Priority issue 2, Subtheme C,
Supervisor

Subtheme C

Bridging basic medicine and clinicalmedicine by fusing heart simulation andmolecular simulation
Currently in the middle of transitionf r o m t h e K co m p u te r to t h e p o s t- K
computer, the “importance of planningresearch activities by forecasting
progress in computers and the necessity
for developing technologies for
implementing this” are further increasing.
We are urged to think outside the box
and steadily deepen our academic
understanding.
I would like to briefly present what weare going to achieve under the post-K
project over the coming 10 years. The ideaof our research activities is reflected in thesubtheme, “Bridging basic medicine andclinical medicine by fusing heart simulationand molecular simulation.” In development
ac tivities by UT-Hear t so far throughthe use of the K computer, multiscale
simulation technology connecting microcontraction proteins which constitute thesarcomere with macro heartbeats was
successfully developed. In this technology,
a mathematical model, in which ATP isbound to the myosin head whose arm

Toshiaki Hisada
UT-Heart Inc.

is expressed as a spring and undergoes
hydrolysis, causing stochastic oscillations
to/from actin f ilaments, is def ined inaccordance with statistical mechanics,
and the resultant contraction force of thesarcomere is computed. For the post-K
project, we will take this technology further
to develop a sarcomere model consistingof coarse-grained molecular simulation
models, and coordinate with the heartmodel. We consider that this will enable
us to, for example, understand how theload observed and measured at the macrolevel is conveyed to the molecular level andactivates the intracellular signal transducing
system, and clarify the mechanism forcausing pathological conditions. Moreover,by using the molecular model, we willbuild the ion channel which controls
the input /output into/from the cellsof various ion currents which containcalcium ions that modulate the motion ofcontraction proteins, and simulate binding/dissociation to/from drugs, to evaluate therisk of arrhythmia caused by drugs to the

The molecular model within the sarcomere iscreated with resolution at the amino acid level.
By combining molecular-level abnormalities withthe heart’s macro-pump functions through theuse of multiscale simulation technology, we will
clarify the relationships between the structuralchanges in molecules reported in heart failure
and pathological conditions, leading to thedevelopment of new treatment methods.

heart. This will enable swift screening ofcandidate compounds which produce side
effects on the heart and make the processof drug design more efficient. This study
will be conducted in tandem with Priority
issue 1.
T hrough go o d luck , we witness e dmilestones, that is, the emergence of the
K computer and subsequent evolution to
the concept of the post-K. However, time
passes so fast. Our achievements must
be good enough to make constructive
discussions during the next 10years. We
would like to create a new milestone in thehistory of computing science by keeping
our spirits high and concentration intense.

There are four to six major ion channels
involved in arrhythmia. Side effects of candidate
compounds on the hear t will be forecast byc o m b i n i n g U T- H e a r t c h a n n e l m o d e l s w i t hopening/closing transition probability defined
based on molecular simulation, with the molecularsimulation of binding/dissociation for each drug.

Drug

CafeMol sarcomere molecule model
Shoji Takada, Kyoto University

μ2lib ion channel molecule model
Tohru Terada, The University of Tokyo

Research concept of Subtheme C “Bridging basic medicine and clinical medicine by fusing heart simulation and molecular simulation”●See the URL on the right for detailed information on this report.

http://www.scls.riken.jp/eng/newsletter/Vol.14/nextstage02.html

BioSupercomputing Newsletter Vol.14 15

Reflecting on remote interactive lecture titled “Foundations ofComputational Life Sciences”
Since FY2014, we have offered remote lectures on computational life sciences, which isa cross-disciplinary research field of life sciences, science and engineering, for university
students, postgraduate students, postdoctoral researchers, university teachers,
laboratory researchers and company researchers. Thanks to the cooperation of anumber of researchers, we created curricula so that they can learn the most advanced
fields of computational life sciences in a structured manner, and we contributed to thebuilding of standard curricula of computational life sciences in the future. We had much
positive feedback from approx. 450 trainees from Japan and overseas, such as, “I was
impressed because the lecture covered the most advanced knowledge in a wide rangeof fields with explanation of basic knowledge,” “I was satisfied as the lecture provided
me with knowledge about computational tools and their concepts,” and “I was inspired
because application examples were brand new and unprecedented.”
The cutting-edge the K computer is located in the Kobe Port Island area, where the
Education Center on Computational Science and Engineering, Kobe University, and
SCLS are headquartered. The area also enjoys beneficial geographic conditions as the
Kobe Biomedical Innovation Cluster (KBIC). We strongly hope that such a structured
educational program of computational life sciences will be instrumental in developing
human resources for research and development in the field of computational life
sciences, creating innovative technologies, and contributing to the advance ofcomputational life sciences and the prosperity of KBIC.

Foundations of Computational Life Sciences Ⅱ

Integration of life sciences, science and engineering for understanding of life and application to health and medicine”(15 sessions in total)⃝Date : October 7 (Wed) in 2015 – February 3 (Wed) in 2016 Every Wednesday 5:00 p.m. - 6:30 p.m.
⃝Location : 1F the school building of Faculty of Engineering, Kobe University C3-101 (Creative Design Studio on Technology ２)

The 39th Annual Meeting of Japanese Society of Biorheology⃝Date：June 18 (Sat) – 19 (Sun) in 2016
⃝Location：The Tokai University Club (Chiyoda-ku, Tokyo)⃝Theme : Biorheology based on medicine-engineering collaboration on thrombotic events, blood flow and arteriosclerosis⃝Annual President: Shinya Goto (Cardiovascular Medicine, Department of Medicine (Cardiology), Tokai University School of Medicine)

Editor’s noteThis will be the final issue of the "BioSupercomputing Newsletter" since the first issue published in 2011.
We started to issue the Newsletter with the desire to launch a reading material which would be handy and plain for every age bracket from high school
students to general adults, and encourage them to get interested in cutting-edge research fields of computational life sciences. In issuing each volume, as I
came to know the dedication of researchers, I increased my desire to convey their ardent beliefs and dedication to you all. I believe that this has driven me
to creative activities, incited enthusiasm for my job, and deepened my interest in life sciences. As a spokesperson, I am so honored to have had such great
opportunities.
We would like to extend our cordial appreciation to our readers and those involved in its issue for their long-time support. We would be very grateful toreceive any comments or opinions regarding the Newsletter. We solemnly ask for your continued support for the field of computational life sciences. (E. Jinnai)

Strategic Programs for Innovative Research Field 1

Supercomputational Life Science

SPIRE (Strategic Programs for Innovative Research) is a MEXT program aiming to produce ground-breaking results in computer science technology
by maximizing the benefits of the HPCI (High Performance Computing Infrastructure) centered on the supercomputer K computer, andencouraging developments in five research fields that need to be strategically addressed.
“Supercomputational Life Science” has conducted research with the mission of understanding and predicting life phenomena based on large-scale
simulation and advanced data analysis, and to apply these results to design and implement medicine and medical care with its research.

BioSupercomputing Newsletter Vol.14 2016.3
RIKEN HPCI Program for Computational Life Sciences
7-1-26 Minatojima-minamimachi, Chuo-ku, Kobe Hyogo 650-0047, Japan
Tel : +81-78-940-5835 Fax : +81-78-304-8785

Issued: March 2016

RIKEN 2016-014