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Opening Discussion

Yoshiyuki Sakaki, Akiyoshi Wada, Yoshiki Hotta
Ten years at GSC, the institute that began a new era of genomics

Towards the Next Steps -Based on Genomic Information

Nagami I think the 10 years since the establishment of GSC has been the "genomic era", speaking even on a global level. Could you tell us about what GSC has been doing during this genomic era?

Omic Space

Wada When Faraday came up with his law of electromagnetic force, a businessman asked him, "What good is it?", to which Faraday replied, "What use is a new-born baby?" I think the same reasoning can be applied to the genome. Up until this point, researchers who won the race for funding were able to take on all the projects, and research proceeded in a vertical administrative manner. However, at GSC I thought we should perform a wide range of research, based around the concept I proposed of omic space. (See page 7) Some people think that the work on the genome is finished, and the next step is proteins, but that is not the case. The genome is the foundation from which life branches off in its many directions, while being influenced by the external environment. I wanted to advance the idea to the world that it was necessary to think in terms of this kind of general, or "omic," space.

Sakaki I think that the greatest characteristic of GSC is that it has continued to read the genome, while also carrying out analysis of genes and proteins. For example, the successful development of mouse gene analysis techniques by Yoshihide Hayashizaki's group have led to the discovery of vast quantities of ncRNA. Upon becoming the Director in the second stage of GSC, I thought that it was necessary that genomics move on from the analysis of each level of omic space to an understanding of how life functions as an integrated system comprising all these levels, and as the first step towards this understanding I began working on the Genome Network Project. The successor to the Protein 3000 Project, the Target Protein Project, is also oriented towards this goal. I believe that the two projects will fuse with each other, and we will obtain a picture of a large molecular network.

I also realized the importance of "comparative genomics" as a means to thoroughly understand the human genome. For example, once a detailed comparison between the human and chimpanzee genome was performed it became possible to see temporal changes in living organisms from a novel perspective. Although this approach has not grown enough to launch a new national project, that kind of work let us see previously unknown mechanisms of life.

Furthermore, as I believe Dr. Wada has said many times, over the last 10 years, GSC has given a sound education to the next generation of young researchers who will support a new age of life sciences. At present, GSC is enthusiastically taking in graduate students from Yokohama City University, Tokyo Institute of Technology, and other institutions, as well as young researchers from overseas.

Nagami Dr. Hotta, how do you view the last 10 years?

Hotta Well, I was really looking at things from outside, but the first thing I can say is that the Japanese team made a significant and highly visible contributions by sequencing 6% of the human genome under the powerful leadership of GSC. Some people said that Japan only contributed 6%, but if you look at the conditions of the budget, insufficient political, academic back-up around that time, you can see that GSC made a great achievement. Also, as has already been said by Professor Sakaki and Dr. Wada, GSC has been constantly looking to the next step and taking on a variety of new challenges, and I have great respect for this.

However, saying that, I myself never felt like moving into and doing something in the field. What I mean by that is, it needs tens of people to produce one paper on a genomics project. As this idea was very new to biology at that time, I was quite confused. I didn't really want to jump headfirst into a world where nobody knew who was producing what. Gathering large amounts of manpower and getting as much information as possible was an approach seen in the field of high energy physics, however I still think that it is yet uncommon in biology. In a sense, the Human Genome Project was a challenge that ran contrary to common sense from the perspective of biology, and the secret of its success is its target molecule-DNA. If we had to start by trying to read whole c-DNA sequences or protein profiles, we would certainly have failed.

Nagami Yes, despite running contrary to what was common sense at that time, GSC's strategy was right on target.

Sakaki I believe that GSC has successfully presented new approaches in biology.

Hotta Absolutely. I think there were two scientific innovations that came out of the success of the approach of "reading everything". The first was the development of more rigorous scientific inquiry into evolution. We obtained a means to compare not just the differences in a few genes, but the differences between whole genomes. This "comparative genomics" approach has enabled us to rewrite the genealogical trees with a more quantitative basis. The second reform came in the field of "development and function". Without specifying each individual gene, you could scrutinize genes with given functions, as well as genes of unknown function, based on genome data. Once unknown candidates are found, we can carry out more systematic analysis. From those two perspectives, the contribution of the genome sequencing has been far more than expected.

But, even though the whole genome has now been read, and all the "players" are up on the stage, there is yet insufficient logical methodology for elucidating the role played by individual players or for reading the overall scenario. Right now we are still trying to pick out the individual players and investigate what they are doing, but I suspect there are probably other ways of going around it when we really master the ways of handling genome data. That's the kind of hunch I have at the moment.

Sakaki I think that information science could be one of the "other ways" that Dr. Hotta is speaking about. At GSC, information science is not carried out as a purely academic discipline, but as a science with firm roots in biology. It is territory that is difficult to visualize at the surface level, but we are trying to process a vast amount of data in order to extract new knowledge. There is still room for improvement in our approach, but it is now possible to do things that were not possible with classical biology.

Nagami An example that symbolizes what you are saying could be how GSC is using sheer computing power alone to produce newsworthy techniques.

Sakaki The idea of using computer science to push forward research into the structure and function of proteins came out of GSC. That was thanks to Dr. Makoto Taiji, who developed MDGRAPE-3, the world's fastest and most accurate protein structure simulation computer here at GSC. We were also helped greatly by the research carried out into processing complex NMR data by Peter Güntert from Switzerland. They were truly torchbearers of the "other methods" that Dr. Hotta mentioned.

Nagami So, moving into this age of novel methodologies, what are the challenges for GSC?

Sakaki I see there being two axes around which our genomics research will revolve. The first is moving from the genome, the genetic blueprint, to a fundamental understanding of the mechanisms of life. The second, which falls under the category of comparative genomics mentioned previously by Dr. Hotta, is the study of the evolution and diversity of organisms against the axis of time. Through its "Genome Network Project", GSC is looking deeply into the life phenomena displayed by individual players on the biological stage. For example, based on sequence information, gene expression profiling, and protein-protein interaction are being analyzed to produce a diagram of the network of molecules that are involved in life phenomena. Having said that, we are having to work hard to cope with the vast amount of data being produced by the latest measurement technologies. There is currently a similar project underway in United States known as the "ENCODE Project", but it seems that their initial choice to target only humans has been revised due to the complexity of their target, and they are now adding other organisms like the fruit fly and the nematode worm. Given the difficulty of analyzing such a variety and volume of information, we are experiencing the same problems.

Nagami We are experiencing problems, but we are also clearly moving towards new goals, wouldn't you say?

Sakaki Absolutely. Even in the field of DNA sequencing, there are sequencing techniques that are a world apart from the conventional methods, and we can now get two to three orders of magnitude more data in any given length of time. Using this technology, it is possible to comprehensively and rapidly read the genomes of the vast medley of microorganisms that inhabit environments such as soil or the sea. This is what is referred to as metagenome analysis. I would like to put forward the rather extreme opinion that if genomic sequence is sufficient as a representation of the "data" of a living thing, we are approaching the stage where we can obtain the data for every organism on earth.

I believe that, in the future, in order to link the evolution that occurs on the horizontal axis of time with the mechanisms of individual organisms on the vertical axis, we will need machines with immense computational power and logical analysis. Also, I think that genomics will play an important role in elucidating the dependence and symbiotic relationships that exist between living things in ecosystems, where organisms live in a mutually dependent manner.

Dr. Wada's "Four Principles of GSC"

Upon the establishment of GSC, Dr. Wada laid out the following four principles to represent fundamental GSC policy. These principles were designed as a means to unravel the various life phenomena and life strategies by consistently carrying out research into the five levels of life phenomena, namely, the genomic foundations, transcriptome, proteome, metabolome, and phenome.

  1. Organisms have a complex micro-structure, and are functional bodies capable of developing into various species. In order to properly understand life and accurately link this understanding to industrial applications, it is essential to conduct research comprehensively from all angles, spanning the information, structure, and function of organisms, and then to elucidate their "life survival strategies".
  2. It is necessary to use all the tools available in the fields of physics, chemistry, mathematics, engineering, and information science. Furthermore, the entire research process (sample preparation, high speed automated measurement of structure and function, data analysis, reading meaning into the data, and modelling) must be integrated and harmonized to obtain the optimum research results. This will enable us to respond to the expectations that society had at the time at which the center was established.
  3. It is vital that there is a lot of exchange of information and cooperation between those carrying out pure, fundamental research and those in applied develop-ment. Japan must ensure that it keeps its unique intellectual property and spreads its de facto standards.
  4. In order that the wisdom of mankind can develop and welfare can improve, it is necessary to carry out international collaborative research, ideally with Japan taking a positive lead role.