Chemical Biology and Biotechnology
Professor SUGA, Hiroaki

Ribozyme, quorum sensing...
Opening the way from heresy to a leading edge
through friendly competition

Interviewer: Hiroshi Murakami, research associate

̶̶Professor Suga, you often tell me about your philosophy

type of study already became a trend by mid-1995. Now,

for research. Let me first ask you about your research

you can probably take such an approach in Japan. Back thenphilosophy because without discussing this it would bein Japan, however, there were very few researchers whodifﬁcult to go into the details of research.

would consciously try to integrate knowledge and ideas fromdifferent domains to create something new.

My philosophy is to do things that are heretical as much as
possible. Be heretical. And when the level of consciousnessof many people catches up, what has been considered to be̶̶At that time, chemistry and biology were considered to be

heretical evolves into a leading edge. But it is very difficult

two completely different things, werent they?

to find things heretical and move ahead with them. Whenyou do things heretical, you must be absolutely consciousIn the 1980s, that was how things were supposed to be inthat you are being heretical and you must be confident thatJapan. So, I went to the US and the ﬁrst thing I did was research

your heretical attempt will eventually turn into a leadingon catalytic antibodies. I began to work on the developmentedge. Otherwise, you would not be able to carry on with yourof an enzyme, using antibodies. The late Professor Satoru

heretical endeavor.

Masamune, under whom I studied at the Massachusetts
Institute of Technology (MIT), was a researcher specialized inOf course, I am sure that there are a number of people

organic chemistry. He had very aggressive ideas about biology

embracing heretical ideas. We must elevate our heretical idea

or science in general and I learned lots of philosophy ofand turn it into a leading edge before other people do so. That

science from him, that is, we must keep on trying somethingis our mission. Or I should say that it is the starting point of mynew. He was not at all interested in collaboration between

research activities.

industry and academia, though. Rather he was quite satisﬁed
as long as he was doing things he was interested in and if
these things were novel. Indeed, he was someone who truly

̶̶Starting from there, how have you proceeded with yourdeserved the title of scientist. Unfortunately, he passed awayresearch?

last year. In undertaking my research, I am sort of proclaiming
myself as being his successor to carry on his will.

I continued to study in Japan till I earned a masters degreefrom a graduate school. After that, I left for the United States.
The biggest reason I went to the US was because at that̶̶And then afterward, you became a postdoctoral fellow.

time Japan had very few researchers who were studying
both chemistry and biology at the same time, or those whoI served as a postdoctoral fellow at Harvard Medical School /were getting into the filed of biochemistry. I moved to theMassachusetts General Hospital (MGH). There I studied under

US in 1989. In the US, many researchers began to study bothProfessor Showstack. The professor is specialized in biology

chemistry and biology from around 1985 and 1986, and thisbut quite interested in chemistry, which I would say is the1point of our common interests. This is the ninth year since I

that can catalyze the aminoacylation of a t-RNA. In 2001,

became independent. But even today, what I studied over

we succeeded to evolve another ribozyme, which has thethere in Boston remains the main theme of my study. That issame catalytic function as the previous one but has a simpler

catalytic ribonucleic acids (RNAs). The focus of my researchmechanism, and we announced the findings in the EMBO

has shifted from catalytic antibodies to catalytic RNAs, thatJournal. Then, in 2002, we succeeded to isolate anotheris, from antibodies to nucleic acids, and to a technique toribozyme in an experiment focusing on a different concept

create artificial enzymes using nucleic acids. In this sense,and we published the result in Nature Biotechnology. As

my interests have been consistent. When I was studying

such, for three years in row after becoming independent, I

under Professor Showstack, he was hardly known to those

was able to announce research achievements in major science

specialized in chemistry. In the ﬁeld of biology, however, hepublications, thereby making my name known to thosewas quite famous and has been often cited as a Nobel Prizeengaged in this particular ﬁeld of science.

candidate. He is only 10 years older than I am. But he haddone a number of excellent works by the time I met him.

In terms of evolution, we were coming closer to theIndeed, I found him very bright and brilliant. He is a kind ofcompletion of an ideal ribozyme. But we still wanted toperson who freely shifts from one domain to another and in

further expand the technical aspects of the ribozyme. It was

this respect I was quite inﬂuenced by him.

around that time that you, Mr. Murakami, joined us as a
postdoctoral fellow at my laboratory. With your help, we madea major progress in developing technical applications. And

Creation of a catalytic RNA is to explore theorigin of life

now, we are here at the University of Tokyo to explore furtherdevelopment. For the moment, I am working with you, Mr.
Murakami, and other staff at my laboratory on what I believe
is a heretical project.

̶̶Now, let me turn to the evolution of catalytic RNAs.

Also, we introduced a ribozyme that is capable of catalyzing

Professor Suga, could you tell me speciﬁcally how you set up

oxidation reduction reactions in Nature Structural Biology inand develop this theme?

2003 and we are currently trying to expand this idea to evolve
yet another new ribozyme.

After serving as a postdoctoral fellow, I moved to the State
University of New York at Buffalo, where I took up an
academic post and set up a laboratory. The project idea camefrom what I had in mind when I was a postdoctoral fellow atProfessor Showstacks laboratory. While I was a postdoctoral

Quorum sensing, an interesting mechanism ofbacteria

fellow, I could not achieve the goal I had set for myself. So, I
was feeling compelled to attain that goal.
I am also engaged in another research project focusing on
The goal was to artiﬁcially create a catalytic RNA or a ribozyme.

applications. This has nothing to do with RNAs and catalysts.

Among various possible catalytic agents, I wanted to discoverThis is an attempt to discover a new drug that can inhibit

the one that enables a ribozyme to recognize a speciﬁc amino

intercellular communication in gram-negative bacteria. Thisacid and induce the aminoacylation of a transfer-RNA (tRNA),

intercellular communication is called quorum sensing ini.e. to bind the specific amino acid with an RNA via an ester

scientiﬁc language. Pathogenic bacteria, such as Pseudomonas

linkage. My original chemical interest in the creation of aaeruginosa which is one of pathogens responsible forcatalytic RNA stems from my interest in the origin of life. Thus

hospital-acquired infection, would not start doing any harm

the project, in a sense, was an attempt to experimentally

immediately after getting into the human body. Instead, they

explore the origin of life.

quietly increase in number. When the cell density reaches acertain level, however, they suddenly discharge toxin andThen, why does it have to be an amino acid? My interest

attack the host, namely, the human body. For bacteria, quorum

centered on what bridges the world of RNAs and the world

sensing is a gene manifestation control mechanism whichof RNAs and protein in the process in which the latter is bornthey have acquired in the process of evolution in order tofrom the former. And I wanted to discover an enzyme thatevade the immune system of human. On the other hand, seencan serve as a catalyst in aminoacylation reactions, a processfrom human infected with such pathogens, quorum sensing isin which an RNA meets with an amino acid for the ﬁrst time.

a very troublesome system that enables bacteria to determine

Furthermore, I was thinking about the possibility of technicalthe best timing for an attack. In the US, research on suchapplication to develop it into a catalyst to bind a non-natural

mechanism became a boom from around 1996 and a report toamino acid with a tRNA. These are the reasons why I took up

this effect was made shortly before I got the post at the State

this topic as my research theme.

University of New York. Then, from around 1999, it became
widely recognized that this mechanism is related to various

For the ﬁrst two years or so after setting up the independent

aspects of pathogenicity. At my laboratory, we launched thislaboratory, things were very tough, for instance, with thequorum sensing project in 1998. We began to produce results

physical space of the laboratory very limited. In 2000,from around 2002. Then, in 2003, we published two reports

however, we were able to publish in

Natural Structuralin succession in the January and June editions of Chemistry &Biology, for the first time in the world, the result of ourBiology. After returning to Japan, I have been working on thisexperiment in which we were able to evolve a ribozyme

project jointly with a private-sector company in the form of2

industry-academia collaboration. We will continue to work on
the project through collaboration with our corporate partner,

Recent Publications

focusing on the development of a new drug as our ultimate
goal.

36.
K. Ramaswamy, H. Saito, H. Murakami, K. Shiba, H. Suga* (2004)
Designer ribozymes: Programming tRNA specificity into

̶̶Professor Suga, I understand that you started this project,, J. Am. Chem. Soc. 126, 11454-11455.

Flexizyme

not with the intention of developing technical applications ofquorum sensing or for the purpose of inventing a new drug,

35.

but out of your pure interest in the mechanism of quorum

S. Tsukiji, S. Pattnaik, H. Suga* (2004)

sensing. Am I correct?

aldehyde by a NADH/Zn2+-dependent redox activeribozyme

Reduction of an, J. Am. Chem. Soc. 126, 5044-5045.

As it turned out, the development of a new drug has become
the ultimate goal. But yes, what prompted me to launch this34.

research was my pure scientific interest in the very fact thatS. Tsukiji, K. Ramaswamy, H. Suga* (2004) Ribozymes that use

bacteria have such an intercellular system. I believe that I am

redox cofactors, J. Pure Appl. Chem. 76, 1525‒1536.

among the ﬁrst group of chemists who have jumped on thissubject. In this regard, I think that I started as a heretic and33.

have been able to become a leading edge.

H. Suga* and K. M. Smith (2003) Molecular mechanisms of(October 19, 2004)

Chem. Biol. 7, 589-591.

bacterial quorum sensing as a new drug target, Cur. Opinion

32.

Curriculum Vitae

D. Hodgson, H. Suga* (2003) Mechanistic studies on acyltransferase ribozymes and beyond, Biopolymers 10,1077-1084.
Professor (2005-present), Research Center for Advanced
Science and Technology, University of Tokyo.

31.
H. Murakami, D. Kourouklis, H. Suga* (2003) Using a solid-Associate Professor (2003-2005), Research Center forphase ribozyme aminoacylation system to reprogram theAdvanced Science and Technology, University of Tokyo.

genetic code

Associate Professor (2002-2003), Dep. of Chemistry, University30.

at Buffalo.

S. Tsukiji, S. Pattnaik, H. Suga* (2003), Chem. Biol. 10, 1077-1084.

dehydrogenase ribozyme

An alcohol, Nature Struct. Biol. 10, 713-717.

Assistant Professor (1997-2002), Dep. of Chemistry, University
at Buffalo.

29.
H. Murakami H. Saito, H. Suga* (2003)

A versatile tRNAPost-doctoral Fellow (1994-1997), Massachusetts Generalaminoacylation catalyst based on RNA, Chem. Biol. 10,

Hospital/Harvard Medical School.

655-662.

Post-doctoral Fellow (1994), Massachusetts Institute of28.

Technology.

K. Smith, Y. Bu, H. Suga* (2003) Library screening for synthetic
agonists and antagonists of a Pseudomonas aeruginosa
autoinducer

Links, Chem. Biol. 10, 563-571.

27.
K. Smith, Y. Bu, H. Suga* (2003) "Induction and inhibition

Chemical Biology and Biotechnology laboratoryof Pseudomonas aeruginosa quorum sensing by synthetic

http://www.cbl.rcast.u-tokyo.ac.jp/autoinducer analogs", Chem. Biol. 10, 81-89.

RCAST

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

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