Bio-Medical Information Networks
Professor Tohru Ifukube

Intervention in biological phenomena:
Applying results to create and adapt a model,
or ident ify systems

Interviewer : Takashi Mikuriya

̶̶First , could you please talk about your lab's research ingene B, which makes atherosclerosis better? It's easier toSystems Biology and Medicine?

publish an ar ticle in a world-renowned journal like Nature if
your work is easy to unders tand and conf irms preexisting

Well, I was born in 1953, the year Watson and Crick publishedtheories. It's harder to publish complicated findings about atheir famous paper on the double helix. When I was studying

phenomenon that f lies in the face of popular opinion. This

biology in high school, I became very interested in DNA.

sort of "reduc tionism" is especially prevalent in the scientific

As a student in the school of medic ine at university, I did

communi t y in Europe and Amer ica, but it won't br ing us

research on the genetic causes of disease. After graduationeven one step closer to finding the cause of atherosclerosis.

I searched around for a research topic and got interested in

So when I moved to RCAST, I stopped doing "reductionism"-

atherosclerosis, so I began to research on cholesterol.

t y p e resea r ch and began t ak i ng a care f ul look at therelat ionships between elements. That's how I hit on the

Researchers begin with a theory and then proceed fromnot ion of "systems."

there with their research. But nobody knows better than aresearcher how unreliable theories actually are. In 1990,

When I moved to RC AS T, I stopped using mice on mywhen I was in the United States, I succeeded in cloning a gene

research. In one sense, my experiments on altering mousethat codes for storing cholesterol in fat tissue, and I publishedgenes c rea te black boxe s. I wa sn't sa t is f ied with justan ar t ic le about it in the journal Nature. Some people

focusing on one gene by itself-I really wanted to see all themisinterpreted my f indings as a discovery of the gene thatgenes together. As luck would have it, in 2000 the humancauses a therosclerosis. But based on my exper iment s, I

genome was decoded and mapped, giving us a pic ture of all

knew that the ident ified gene was not the direct cause of

the genes in the human body. The total number is huge buta therosclerosis. I was surpr i sed at how my research got

at least it's f inite, so we set about collecting exhaustive data

overs impli f ied.

that would hopefully enable us to identify systems.

A f ter returning to Japan, I did some more experiments using

Around the same t ime, Sys tems Biology was developed-

mice. A therosclerosis generally doesn't occur in mice, so

mostly from research done in the US-which allows scientists

I crossed a mouse lacking the gene I discovered and two

to make biological predictions using computer models. Now,other types of mice with genetic irregulari ties that makethis is a kind of high-level reduc t ionism, which basicallythem more susceptible to atherosclerosis. As a result, on one

says that everything can be solved in terms of dif ferential

hand, the mice that were prone to atherosclerosis improved-

equat ions. My own v iew is that it seems strange to talkagain I published my findings in Nature. On the other hand,about solving di f ferential equat ions when you don't evenatherosclerosis worsened in the mice lacking the gene thatknow whether what you want to study can be expressed ascodes for cholesterol storing. Generally this way of thinking

dif ferential equations. The popular view now on dealing

does not work; what would happen if you t ake gene A,

with any complex system is to choose a model and then plug

which makes atherosclerosis worse, and combine it w ith

whatever phenomenon you're deal ing with into it. Now, in

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contrast to this, what we at RCAST call Systems Biology andS implifying one's predictions is f ine, but in fact medicat ions

Medicine is not simply about positing systems. The system

work by act ivat ing genes, so if its ef fect is prolonged, genes

as a whole may be too complex to fully understand, but by

will cont inue to oscill ate and t rigger var ious phenomena.

inter vening in a biological process, we can see whether a

In such a case, t he f i rs t wave might well occur just as

given phenomenon occurs the way we predicted it would, orpredic ted, but the second wave will occur differently. You

whether something different happens. If you're just goingend up consider ing such things when you try to understandto look at phenomena and create models, you could come up

the relat ionships between elements. The problem is, withw ith any number of dif ferent models. What we do instead

the third wave and beyond, so many elements come into

is to inter vene in an ac tual biological process and then alter

play that it's impossible to calculate or predict-right now twoand ada pt our model based on the resul ts, or ident i f y awaves are the limit , I think.

system-we t ake that as the most impor tant f irst step.
̶̶ Las t year you and Prof essor Masaru Kaneko of Keio̶̶ P r e d i c t i n g m e c h a n i s m s o n e s t e p b e y o n d g e n e

Uni ver s i t y publ i shed Reverse Sys tematology (I wanami

a c t i va t ion to c rea te new med ic a t ions wi th fewer s ide

Shoten). Could you tell us about that ?

ef fec ts
The impetus behind the book was what you might call "pop

How do you feel about your research now?

evolut ionary biology"-for example, when people talk about
things like the "love gene" or the "criminal gene." The public

What I've become most acutely aware of is that the special

tends to think genes are responsible for everything. But ascharacter ist ic of a system is that in it, biological phenomena

one should realize from the fac t that we talk about "geneare repeated over and over with incremental changes. When

activation," genes are in fact passive, not active, and are only

an ac t ivat ing s timulus is int roduced, it t r iggers a signal

one part of a system that is subject to control. There may bethat terminates it-what we call an autotermination signal.

such a thing as an "intelligent system," but there's no such

Usually act ivation will cease at that point, but if a continuous

thing as an "intelligent gene"-that's what we believe. But

st imulus is introduced, it sets up a cycle; when the stimulus

in society at large it's exac t ly the opposite; genes are theis repeated for a cer tain amount of time, the number ofactive agent and people are just vehicles. I've even heard

ac t ivated factors increases. This increases the number ofpeople theor i z ing about "self ish genes" and that sor t ofinac t ivat ing fac tors, and ac tivat ing effect is suppressed.

thing. Anyway, a while back I was talking to my old f riend

But when act ivated factors become fewer, the number of

Kaneko (Professors Kodama and Kaneko at tended junior

inactivating factors also decreases. If the stimulus continues,

high and high school toge t her). He was saying that eventhen the number of act ivated f actors increases again-thisin economics people hold some very simplistic views, such

is what we call oscillation. Oscillation is a basic biologicalas the per formance principle. He argued that once you boil

pr inc iple. For example, it determines the number of ourdown a complex process to one mechani sm or element,

vertebrae-if a certain protein activates and inactivates itself

you t hreaten the integ r i ty and sustainabil ity of the ent ire

seven times-seven oscillat ions-then we get seven vertebrae.

organizat ion.

That is to say, the periodicit y of oscillat ion func t ions like aclock.

̶̶ W h a t s o r t o f r e s p o n s e s h a v e y o u h a d t o R e v e r s e
Systematology?

In the ca se of a t herosc lerosis, the problem is that whiteblood cells adhere to the ar ter ial wall and pass into it.

Well, because I quoted some people in the book by name,Super f icially, the way they adhere appears the same, but

I t hough t I'd ge t a lot of angr y responses f rom people

we've discovered that the phenomena occurring during thewho prac t ice elemental reduct ionism, but in fact I haven't

first oscillation and second oscillation are in fact dif ferent.

received a single ser ious objec t ion. Of course, I've heard a

We be l i eve t hat when genes are ac t iva ted dur ing the

lot of, "What you say is f ine in theory, but it doesn't have any

f irst oscillat ion, what's more impor t ant than the fac t thatpractical validity." My response to that is not simply to assert

the oscillat ion occurs, is that a system of oscillat ion wi ththat elemental reduct ionism is wrong-the main issue now isincremental change is established. Cholesterol lower ing

what individual results can we produce, what medications

medicat ions are designed on the presumpt ion that when

can we create, what prescr iptions can we give to patients,

a gene oscillates, you can introduce a cer tain stimulus andusing the methodology that emerges from this new systemsuch-and-such will occur. But what we're doing is taking it

we've identif ied called "Reverse Systematology."

one s tep fur t her. In ot her words, we're t ry ing to predic t
wha t phenomena will occur a f ter t he gene is ac t i vat ed,

I think the decisive factor in making this a f ield of study withand design a medicat ion accordingly. This could reduce

pract ical validity will be the question of temporal dynamism.

side e f fect s. We believe such drugs would have a highYou see this not only in biological cycles, but take Chinesesocial value, so we're t r ying to use t his process to predict

history, for example, with the rise and fall of dynast ies, ormechanisms one step beyond gene act ivation to create new

economics, with cycles of boom and bust. When you look

medicat ions.

at these, they're not simply about repet ition, but repetit ion
with incremental change-that's what's cr i t ical. I suspect̶̶So it's rather like letting the f irst wave go past and thenthat a variety of cont rol mechanisms under lie these cyc les,making your dec ision based on what the next wave looks

and the interaction between them is also strong. When an

like?

economic bubble bursts, the ripples created by these various
mechanisms produce an inter ference phenomenon, which2can resul t in a massive wave-then you get a meltdown of the

we're look ing for, in other words, is a "development of

entire control system. If not-if the ripples simply dissipate-genome based ant ibody therapeutics" that works as both ayou can get long-term economic stagnation that just simmers

diagnostic drug and a therapeutic drug-one that can create

without setting up a cycle.

the antibodies that detect the extra protein created by gene
oscillation, and then use the same ant ibodies to help f ight

Because cells and biological organisms age and die, it'scancer as well. In other words, the Future Drug Discover y

impossible to control an entire system, so we end up with

Project is not part of our systems research per se-we plan tosmall cycles, like those we experience in our daily lives, anduse the large amount of data we've collected to narrow in onlarger historical cycles-it's those larger cycles that I believea target and then, in the next stage, move to development of

impact the rise or fall of an entire nation or civilization. Whata drug that combines diagnosis and treatment.

we need to do is understand the relationship between small

Separate from that, the funds we've received from the Kowa

cycles and large c ycles.

Endowment will immediately enable us to build up our
system base with new drugs. The Future Drug Discovery

̶̶So you're saying that these large waves represent cultural

Project is a response to the scientific tidal wave unleashed byshif ts, and at each historical turning point there are always

the decoding of the human genome, and we think of it morelots of small disturbances. That probably explains what's

as a commercial enterprise. The Kowa Endowment, on thehappening now at the beginning of the 21st century with allother hand, will give us the freedom to undertake a long andthe upheaval in the world. What's fascinating about the booksustained examinat ion of the principles of systems research,is how it interweaves history and biology to make its points.

and look for new drugs to treat diseases.

Separating noise from signals: What signals cantell us about how micro phenomena turn into
macro phenomena

̶̶ The Systems Biology and Med ic ine Laboratory t hat

Earlier I said it's impossible to calculate the third osci llation

I think my future lies outside the university in the pr ivate

you direct, Professor Kodama, now employs some 100
researchers. Where do you think you'll go from here?

and beyond, but for biological organisms we can try tosector. Take the drug Pi tavastatin, which I helped Kowa

orchestrate the overall system. For example, as long as blood

Pharmaceuticals develop, for example-it now has sales ofpressure, blood sugar, and cholesterol are each kept with aabout 20 billion yen per year, and its main competitor Lipitol

certain range, there are mechanisms we can use to control

has annual sales of about 1.2 tr illion yen. Taking that into

the system even as oscillation occurs, thereby maintaining

consideration, I think I will probably end up branching out

homeostasis. To do this, I think there are two main biologicalfrom RCA S T and going commer c ial. If the Future Drugissues we need to address.

Discovery Project proves to be a success, I'd mos t likely turnit into a research center independent of the universi t y. To

The first is the quest ion of noise versus signals. In terms ofme, that seems to be the direction I'm headed in.

how we can separate out signals from background noise, we
now know that signals are interpreted in a time sequence. It's

In t ha t respec t there's one thing I f ind ver y d i f f i cul t.

easier to understand if you think about music-if you hear a bit

Speaking as a member of a research project team, a pr ivate-of the middle of a song you might not recognize it, but if you

sector lab has more advantages than a university lab because

hear it sung form the beginning you will. In the same way, we

its part of a much bigger research effort. On the other hand,know that biological signals are sequenced chronologically.

whi le a univers ity lab has fewer advantages, the relative

So if somet hing happens wi thin a temporal f ramework, we

freedom it provides of ten yields very interesting material.

can interpret that as a signal. That's the dynamism of signals.

The problem is that if you don't attain a critical mass thenthe research you produce ends up being worthless. The

The other is the question of how micro phenomena become

problem is how to motivate researchers and maintain a highmacro phenomena. Various phenomena are occurr ing

level of motivation. Motivation research in science hasn't

all the time on a micro level, just as there are always lots

been talked about much in Japan. The challenge is how toof important social phenomena around us, but what getsdevelop a research style that combines science's intellectual

everyone's attention is when they emerge on a macro level,component-data-oriented, labor-intensive intellectual skills-

like the bursting of Japan's bubble economy or the long-with its creative component-one that utilizes the individuality

term recession. I'm interested in the mechanisms at work

and imagination of your researchers.

behind the transformation of micro problems into macro
ones. Methodologically speaking, on a micro scale we need̶̶Listening to you, it strikes me it's the human, creative

to separate out signals from noise, and then figure out

component of research which is exciting for you, isn't it?

what these perceived signals can tell us about how micro
phenomena will become macro phenomena-t hese are two

What interests me most is the historical element of repetitionareas of research I plan to pursue.

and change, and trying to f igure out when incremental

Repet i tion with incremental change: Its
historical implications, and how to predic t thenex t big wave

doing that is creating a dynamic synergy among researcherschanges will build into a great big wave. One of the keys toin the laboratory.
Today's di scussion has been very illuminating. Even for̶̶Professor Kodama, you started the Future Drug Discovery

someone like me who's basically a social scientist, this has

3conf irmed my sense that the context of your work in theProc. Natl. Acad. Sci USA 1998, 95, 10123-10128

natural sciences is essentially the same as ours in the social
sc iences. The idea of transformation through incremental

7. Suzuki H, Kur ihara Y, Takeya M, Kamada N, Kataoka M,

c ha nge, and second and t hi rd osci l lat ions, is ver y

Jishage K, Ueda O, Sakaguchi H, Higashi T, Suzuki T, Takashimasociological. Thank you very much.

Y, Kawabe Y, Cynshi O, Wada Y, Honda M, Kur i hara H,
Aburatani H, Doi T, Matsumoto A, Azuma S, Noda T, Toyoda(July 10, 2005)

Y, Itakura H, Yazaki Y, Hor iuchi S, Takahashi K, Kruijt J-K, vanBerkel T-J-C, Steinbrecher U-P, Ishibashi S, maeda N, Gordon S

Links& Kodama T.
"Resistance to atherosclerosis and susceptibility to infection

RCAST

in scavenger receptor knockout mice"

http://www.rcast.u-tokyo.ac.jp

Nature, 1997, 386, 292-6

Laboratory for Systems Biology and Medicine

8. Kurihara, Y., Kurihara, H., Suzuki, H., Kodama, T., Maemura,

http://www.lsbm.org/site̲e/index.html

K., Nagai, R., Oda, H., Kuwaki, T., Cao, W-H., Kamata, N., Jishage,

Recent Publications

Yazaki, Y. (1994).

K., Ouchi, Y., Azuma, S., Toyoda, Y., Ishikawa, T., Kumada, M.,&
"Disruption of mouse endothelin-1 gene results in lethality
Journal Articles

and craniofacial anomaly in homozygotes and elevated bloodpressure in heterozygotes"

T. Kodama Or i g i nal papers writ ten in English

Nature, 368, 703-710

1. Koga T, Matsui Y, Asagiri M, Kodama T, de Crombrugghe B,

9. Matsumoto, A., Naito, M., Itakura, H., Ikemoto, S., Asaoka, H.,

Nakashima K, Takayanagi H.

Hayakawa, I., Kanamori, H., Aburatani, H., Takaku, F., Suzuki,"NFAT and Oster ix cooperatively regulate bone formation"

H. Kobari, Y., Miyai, T., Takahashi, K., Cohen, E.H., Wydro, R.,

Nat Med. 2005 Jul 24; [Epub ahead of print]

Housman, D.E., & Kodama, T.(1990).
"Human macrophage scavenger receptors: Primary structure,

2. Koga T, Inui M, Inoue K, Kin S, Suema t su A, Kobayashi

expression, and localization in atherosclerotic lesions"

E, Iwata T, Ohnishi H, Matozaki T, Kodama T, Tniguchi T,

Proc Natl Acad Sci U S A, 87(23), 9133-9137.

Takayanagi H, Takai T.
"ITAM-mediated costimulatory signals cooperate with RANKL

10. Kodama, T., Freeman, M., Rohrer, L., Zabrecky, J.,

for bone homeostasis"

Mat sudaira, P., & Krieger, M. (1990).

Nature 2004 428(6984):758-63.

"Type I macrophage scavenger receptor contains α -helicaland collagen-like coiled coils"

3. Tanaka T, Yamamoto J, Iwasaki S, Asaba H, Hamura H, Ikeda

Nature, 343(6258), 531-535.

Y, Watanabe M, Magoori K, Ioka RX, Tachibana K, Watanabe Y,
Uchiyama Y, Sumi K, Iguchi H, Ito S, Doi T, Hamakubo T, Naito

11. Rohrer, L., Freeman, M., Kodama, T., Penman, M., &M, Auwerx J, Yanagisawa M, Kodama T, Sakai J.

Krieger, M. (1990).

"Activation of peroxisome proliferator-act ivated receptor"Coiled-coil f ibrous domains mediate ligand binding by

delta induces fatty acid beta-oxidation in skeletal muscle andmacrophage scavenger receptor type II"attenuates metabolic syndrome"

Nature, 343(6258), 570-572.

Proc Natl Acad Sci U S A. 2003 Dec 23; 100(26): 15924-9.
12. Kodama, T., Reddy, P., Kishimoto, C., & Krieger, M. (1988).
4. Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida"Pur if icat ion and characterization of a bovine acetyl low

H, Saiura A, Isobe M, Yokochi T, Inoue J, Wagner EF, Mak TW,

density lipoprotein receptor"

Kodama T, Taniguchi T.
"Induc t ion and A c t i va t ion of t h e Tr an s c r i p t ion Fa c tor

13. Okazaki, M., Hara, I., Tanaka, A., Kodama, T., & Yokoyama,

NFATc1 (NFAT2) Integrate RANKL Signaling in Terminal

S.(1981).

Dif ferent iat ion of Osteoclasts""Decreased serum HDL, cholesterol levels in c i rrhosis of the

Dev Cell. 2002 Dec;3(6):889-901.

liver"N Engl J Med, 304, 1608.

5. Terauchi Y, Kodamam T, et al.
"Increased insulin sens i t i v i t y and hypog l ycemia in mi celacking the p85a subunit of phophoinositide 3 kinase"
Nature Genetics, 1999, 21. 230-235
6. Cynshi O, Kawabe Y, Suzuki T, Takashima Y, Kaise H,
Nakamura M, Ohba Y, Kato Y, Tamura K, Hayasaka A, Higashida
A, Sakaguchi H, Takeya M, Takahashi K, Inoue K, Noguchi N,
Niki E and Kodama T.
"Ant iatherogenic effects of the ant ioxidant BO-653 in threedifferent animal model"

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