Dr. Mitsuru Furusawa asked why DNA was double-stranded and came up with the theory of asymmetric evolution. Results were published in the Journal of Theoretical Biology and in Proceedings of the National Aacademy of Sciences. This project successfully demonstrated that creative and fundamental questions could be answered by ERATO projects. The Furasawa team was multidisciplinary, including theoreticians and experimentalists in molecular biology and cell biology. Two of the scientists were non-Japanese, one has since joined Wayne State University as a faculty member. There was also an industrial component on this project: two individuals from Daiichi Pharmaceutical. Interestingly, Furusawa recruited Dr. Doi, who will start a new project next year.
Because there is substantial Drosophila subspeciation in Hawaii and a good established fly colony or set of colonies at University of Hawaii, Dr. Daisuke Yamamoto will start an interactive project there. The project is in its first year, and the primary effort is directed at assembling the team, which thus far consists of a researcher from Germany (Dr. Kei) and one from China (Dr. Xu), and five Japanese scientists. Yamamoto will recruit molecular biologists from various places. The overall team will include two Hungarians, an American (not from the Hawaii group), a French female (who is not an ERATO employee, but will study the behavior of the scientists), and a Japanese. Dr. Yamamoto has no female scientists except technicians and attributes this to the applicant pool and the apparent poor quality of the female candidates.
An interesting spin-off of this project has been the continuation of work by the Ministry of Agriculture and Forestry involving transgenic swine. Dr. Joh-E Ikeda, the project director, expressed some concern about (1) the duration of the projects, (2) the lack of ERATO laboratory facilities, and (3) the lack of core research outside Japan. He suggested that a seven-year duration for ERATO projects would be better and that an ERATO home laboratory would be advantageous, since at present, each project undergoes a year start-up, which he felt was unnecessary. Ikeda also recommended that there be some core research outside Japan so that the individuals in ERATO could learn Western philosophy, particularly the way American scientists conceptualize research.
Dr. Seiji Shinkai, the director, commented that three items were indispensable for ERATO projects: (1) money, (2) equipment and materials, and (3) the facility. A university has manpower and laboratories but very little money, which is tightly regulated when available. When one has a research idea, he can get resources but must carry out the research as specified. There is little flexibility for investigating new directions. This is the opposite of the ERATO program.
Shinkai was critical of a lack of communication and understanding that can occur between the Ministry of Education (Monbusho) and the Science and Technology Agency (STA). He noted that Monbusho allowed him to work only one day per week on the project, and he was unable to work on the research after the ERATO project at the same level in terms of funding and facilities available at the university. He noted that in ERATO, if a postdoctoral researcher does well, he can actually progress careerwise in the scientific community. If one does not make full use of the resources and flexibility, however, then the doors will not open later. Such performance-oriented evaluation is new in Japan and is a positive outcome of ERATO.
Finally, he presented an image that describes the influence and importance of ERATO projects well: he likened ERATO to being able to draw on a completely blank sheet of white paper, whereas with Monbusho, one primarily fills in between the lines, as in a child's coloring book. The JTEC panel was impressed with his candor and his opinions, given the importance of the day, the Final Symposium on the Chemirecognics project, for his own career.
Industrial researchers were not involved in the Biomotron project. Most of the researchers came from universities. Osaka University, for example, is the home of the project director. This panel's guess was that if he could, Dr. Yanagida would employ more students. Typically, he utilizes 80% physicists and 20% biologists.
The project did not include foreign researchers, primarily because of the additional time that would be needed for adequate training. Instead many established foreign scientists in the field visited and stayed at the project for a couple of months to one year to collaborate with them as visiting researchers. This project is an example of excellent basic research, noted worldwide for its quality. Another impressive aspect of this project was the fact that the space was a converted warehouse, with no prior laboratory facilities, let alone equipment. ERATO helped to secure the space and convert it into a state-of-the-art laboratory.
The project was divided into three subgroups, typical of all ERATO projects. The JTEC panel was very impressed with Dr. Ishihara, who was the single female scientist to present her work. It is likely she will pursue opportunities overseas upon project completion.
Discussion centered around the Osaka Bioscience Institute (OBI) and the conversations Dr. Osamu Hayaishi had early on with Mr. Chiba over the formation of ERATO. Hayaishi helped formulate the ERATO policy that considers the person's personality, vision, and insight when choosing project directors. His work at ERATO was conducted entirely at OBI, which in turn, he had initiated with the mayor of Osaka. Of the twenty-seven researchers, eight continued on at OBI after the project ended. Ten went back to the universities from whence they came, half of these to the same position. The JTEC panel felt this was rare. In addition, Dr. Watanabe worked with Hayaishi originally and now has his own IJRP project.
The panel's interview was with Dr. Koda, a staff scientist from the Institute of Physical and Chemical Research (RIKEN). The Superbugs project ended in 1989. Dr. Koda now has an IJRP project with Michigan State University on microbial evolution. More than other projects, this work has attracted the interest of many companies. Two postdoctoral researchers from Michigan State, resident in the RIKEN labs during our visit, expressed concern about the flexibility of laboratory procurement procedures. Furthermore, they felt that group meetings were formal, which inhibited their making significant progress. They suggested that four foreign people in a laboratory might change interpersonal dynamics so that the conversation would revert to English.
During a recent visit to Japan, Rita Colwell had an opportunity to visit researchers at the Japan Marine Science and Technology Center (JAMSTEC) who are carrying on and expanding some of the work pioneered in the ERATO Superbugs project. Her observations offer a perspective on what happens at the conclusion of an ERATO program. ERATO's Superbug project ran from 1984 to 1989. Its director was Dr. Koki Horikoshi, very much a traditional leader in that he was older and more established. His project was to look at unusual microorganisms, particularly bacteria that grow at very high pH (12, 14, close to absolute basic pH), like alkalophilic bacteria that grow in solvents. Horikoshi actually isolated a bacterium that grew in practically full-strength toluene, for example. It was an interesting feat that took two or three years. The 1988 JTECH review panel concluded that the work that was done, however, wasn't truly innovative in the sense of being high-risk. Then Horikoshi's focus of interest became extremophiles.
The Superbug project was a reasonably successful ERATO project, in that some new, young scientists had been trained and several successful patents had come out of the project. For example, the bacteria that were capable of operating at very high pH and had a proteolytic activity were utilized in a very popular detergent in Japan. So there were successful applications of this ERATO program.
What is interesting is that, subsequently, Horikoshi was selected to lead a Superbug continuation project in Yokosuka through JAMSTEC. Five scientists were recently asked to carry out a review of that program: Dr. Harlan Helderson from the University of Massachusetts, Dr. Ian Dundis from the Bergen Rienvow Tech Center in Norway, Dr. Rita Colwell from the University of Maryland Biotechnology Institute, and two researchers from Japan: Dr. Koichi Oada, who heads the Ocean Sciences Research Institute of the University of Tokyo Marine Microbiology Group, which is itself converting to marine technology, and Dr. Tadashi Matsunaga of the Tokyo University of Agriculture and Technology. This team reviewed Horikoshi's JAMSTEC project on November 9-10, 1995.
The program at Yokosuka turns out to be rather extraordinary in that $5-20 million a year has been expended since 1991. At this JAMSTEC project there are 29 researchers working on deep sea research; and from 1992-1995 there were also 21 researchers from six countries who came in to work with them. Engineers and scientists at this project spent two years constructing an incredible facility that allows them to collect microorganisms under deep sea hydrostatic pressure and grow them continuously in culture, transferring them constantly under pressure. These scientists also have developed the capability of working at very high temperatures, to better preserve and study deep sea hydrothermal vent bacteria.
Researchers at the Yokosuka JAMSTEC program, called "Deep Star," have built two submersibles. In addition to the Shinkai 2000, which allowed them to go to 2,000 meters, they have built the Shinkai 6500, which will allow manned (human-operated) descent to the deepest trenches of the world's oceans, to a depth of 6,500 meters, which will be the world record as soon as that has been accomplished. (It either already has been done in one of the dives or will be very soon.) They are also developing another submersible, a "tethered" vehicle that will, by remote operation, allow them to collect samples in the deep sea.
The Deep Star project is unique in that it targets only deep sea areas and microorganisms in that environment. It is an extension of Horikoshi's Superbug project; but it goes into its focus very extensively, to the very deep part of the ocean. This has necessitated the development of a considerable amount of expensive and unique hardware.
Five groups in the JAMSTEC Deep Star project are focused on organic, solvent-tolerant microorganisms. This is the extension of Horikoshi's original ERATO project, with the addition of hyperthermophiles, bacteria that grow at temperatures of 110-140 or 150oC under high pressure; psychrophiles, bacteria that grow at very low temperatures (this, of course, is a characteristic of the deep sea); and barophiles, bacteria that grow only with hydrostatic pressure. JAMSTEC researchers have succeeded in isolating two obligately barophilic bacteria that function only with high pressure. They are doing some work on preservation and culture collection and have started some research on the genetics of these marine bacteria.
Basically, the Deep Star program has developed a very unique set of engineering skills for construction of submersibles and of isolation and incubation chambers for research. These engineering capabilities are not matched anywhere else in the world. It is clear that the next phase of the creative basic research work that spun off from ERATO provides a capability and commitment for much longer support -- 15 years -- and this has enabled the group to devise an apparatus for very precise sampling of microorganisms and the capability of studying the properties of microorganisms under natural conditions.
The Deep Star project was possible only because of Horikoshi's previous experience and equipment; but as the new facilities are now available, expansion into molecular techniques has been introduced. This expansion represents a next phase and an opportunity for young scientists. One of the very strong recommendations made by the review team is that in the next round, the next five years, leadership be initiated by Horikoshi, but that one of the "young tigers" aged 35 to 40 be groomed to take over. Unfortunately, there isn't anybody on site among the younger workers who can take on this leadership. That seems to be a shortcoming, and it may well be a shortcoming of the ERATO projects in general, at least of the older ones, not to have a capacity for cultivating the next head or director from within the group.
The JAMSTEC Yokosuka facility is the premier center for this kind of research in the world. The only other related programs are Ifremer in France and Wood's Hole in the United States. But these are secondary; they really do not have the capacity, the skills, and the breadth of the JAMSTEC Deep Star program. Some institutions are beginning such studies. The University of Maryland Biotechnology Institute is doing such studies in Baltimore -- but the engineering side, as invested in by JAMSTEC, is unique.
The five-year-old Deep Star project has obtained good results. For example, new selective procedures have resulted in the isolation of a number of solvent-tolerant strains in mutants. The mutants are the next step, since solvent-tolerant strains came out of the ERATO technology. JAMSTEC researchers are beginning now to look at the fundamental mechanisms of membrane proteins for tolerance, and they are also looking for commercial use in bioconversion applications. What are particularly interesting are the barophiles that have been isolated, adding to the very meager knowledge of these organisms, and the molecular-genetic studies of baro-tolerance, especially in the identification of a very specific protein that appears to be correlated with the capacity to grow under pressure. The Deep Sea staff have begun studies of the psycrophiles, the bacteria capable of growing at very low temperatures, around 0-10 degrees, and they are looking at the interrelationships of temperature, salinity, pressure, and other environmental parameters. The results are in a very early stage but constitute a sound basis for launching this major research program on systematics, biodiversity, and preservation methods.
Horikoshi has provided strong leadership. He has brought in scientists from within Japan and from other countries. The key factors have been the flexibility and recruitment aspects of the program. The publication record has been very good. The Deep Star program researchers published 24 original papers by 1994. By the end of 1995 they had published about 56 papers total, and these paper have been published in very good journals. Researchers at the Deep Star program have also made 132 presentations around the world.
At this stage of development of the program, the review committee concluded that a very healthy beginning has been made for Deep Star, but that in the next phase several factors will be critical. Every effort, this panel believes, must increase collaboration with universities and other research centers in Japan and abroad; must increase communication with the disciplines that are involved -- engineering, molecular biology, protein chemistry, and so forth; and must maximize opportunities to interact with related basic sciences.
One of the interesting aspects of the Deep Star program is that it brought in external peer review. The panel believes that this is a characteristic brought forward through the experience of Horikoshi, not only from working with overseas scientists, but from working within the ERATO program.
One of the JAMSTEC program's shortcomings, however, is its inability to fund scientists from abroad and from other universities to come to work at Deep Star. The program depends on the ability of scientists to bring in their own money, and that is a bit unrealistic.
Deep Star provides a very interesting example of an extension of an ERATO program. It shows the influence of some of the characteristics that George Gamota was referring to in the Introduction that are unique to ERATO, and it demonstrates the influence of ERATO to extend a research area into an entirely new, broader area, in this case, to extend deep sea research into the fields of deep sea molecular biology and biotechnology.