The University of Tokyo

UTokyo Innovation

Influenza and the Institute of Medical Science

Deciphering virus mechanisms and developing world-saving vaccines

XXX

2009 novel influenza viruses (H1N1) streaming out of infected cell.

XXX

Cross-sectional image of an influenza virus cluster ― the first of its kind in the world.

XXX

Diagram of a virus. Hemagglutinin (HA) and Neuraminidase (NA) are the proteins that combine to form the spikes on the surface of the virus and are also used to give the virus type its name.

Interviewer: Professor Kawaoka, could you tell us a little about your influenza-related research?

Kawaoka: We developed a technique known as “reverse genetics,” which manipulates genes to artificially synthesize a virus. Using this technique we can freely create various types of viruses, which has enabled us to create vaccines with greater efficiency and has given a tremendous boost to influenza research. Before we developed this technique, the conventional wisdom was that such “reverse genetics” were doomed to failure. Thus, it was without a great deal of thought or expectation that I implemented an experiment which turned out to be a success. Looking at my postdoctoral research data I got a real hunch that it would be possible to perfect the technique, so I gathered some people together to start a project. Each person was assigned one of the eight influenza genes and we all started together. After about six months we had succeeded in developing the technique.

Human knowledge is still extremely limited. We have only just scratched the surface of the natural world. If we delude ourselves into thinking that we know everything, then we wash our hands of the search for knowledge. There is also a tendency for such people to become closed-minded and shackled to their knowledge, which can prevent anything new from being discovered. However, in our line of work, unless we actually set out to get our hands dirty, we will never make any new discoveries. Contemplating something is only five percent of the process; the other 95 percent is putting our hands to work with a sense of single-minded purposefulness.

Interviewer: Speaking of viruses, aren’t they dangerous to handle?

Kawaoka: One of our important discoveries was that we were able to clarify which portion of a highly pathogenic avian influenza virus needs to be changed to attenuate its virulence. As it would indeed be dangerous to use a highly lethal virus with a 60% fatality rate to create a vaccine, it is necessary to first transform the virus into one with weaker pathogenicity. Through my research efforts in the 1980s, I discovered that pathogenicity can be diluted by changing a specific amino acid. By combining this discovery with reverse genetics it is possible to transform a highly virulent virus into a weaker one, enabling the safe creation of a vaccine. It is thanks to this process that vaccines for highly pathogenic avian influenza are now stockpiled around the world. The live attenuated influenza vaccine currently in use in the United States is one that was created using reverse genetics.

Interviewer: Is it true that you create vaccines by injecting the virus into chicken eggs?

Kawaoka: Yes. As the influenza virus is originally an avian virus, it normally reproduces well in chicken eggs. However, there is one problem that we have to deal with. Virus types that have been around in humans for a long time gradually become resistant to reproducing in chicken eggs. Although a large quantity of the virus is required in order to create a vaccine, the surfaces of the viruses change when they are made to reproduce well inside chicken eggs, resulting in the reduction of the vaccine’s potency.

There are some prevalent influenza viruses in humans that no longer propagate well in chicken eggs. However, by using reverse genetics to grow viruses in cultured cells, it should be possible to ensure that the surfaces of the viruses do not change and that they can be used in vaccines. That is what I am currently trying to do, so I launched a project to undertake this research in October 2013.

Another goal of ours is to develop a new kind of anti-influenza medicine. We aim to create a drug that makes it difficult for drug-resistant strains of influenza to emerge. Dr. Makoto Yamashita, who developed INAVIR, the anti-influenza drug that is most used today in Japan, has joined our project team. In order to bring a new drug to market, there is a great deal of knowledge and know-how that basic researchers are simply not aware of. It is therefore necessary to bring people on board who possess such knowledge. Accomplishing something new in a short period of time requires a great deal of preparation. That is what I am engaged in now with a tremendous sense of urgency, given that there is not much time left before I retire.

Interviewer: I hear that the motto of the Kawaoka Laboratory is “Save the World.”

Kawaoka: Rather than seeking to “contribute to the world,” our motto is a strong expression of our wish to “save the world.” It is incredibly important to have philosophical ideals in everything that we do. In order to realize such ideals, it is vital that we keep focused on what is most important to achieve them. In so doing, we won’t have time to concentrate on things that don’t matter. For the members of our team, philosophical ideals are also of the utmost importance in order to guide us towards a uniform direction.

Interviewer: What kind of place is the Institute of Medical Science to which you are affiliated?

Kawaoka: We are engaged in cutting-edge medical research; accordingly, our first priority is not to pass on learning and knowledge. For example, if I were to leave my position, all the members of my laboratory would also resign. The laboratory would be emptied and new people would join the institute. This is because at research institutes, it is not necessary for learning to be passed on. In undergraduate departments the passing on of knowledge is an essential factor, but it is different for research institutes. In the case of the Institute of Medical Science, all it has to do is to gather together researchers who will engage in research in the field of medicine that is most important at that given time. This is a style that I find suits me.

Interviewer: Wouldn’t you be sorry to see the laboratory you have built up simply disappear?

Kawaoka: I don’t have any sense of having built up anything. We are a group that has been brought together for the purpose of working towards a research goal and when the time comes we will disband, just like the pop group YMO did many years ago. Once we have reached a certain point, we will each go our separate ways and on to new activities. That is all.

Yoshihiro Kawaoka

Yoshihiro Kawaoka

Professor, Division of Virology and Director, International Research Center for Infectious Diseases, Institute of Medical Science
http://www.ims.u-tokyo.ac.jp/virology/
http://www.ims.u-tokyo.ac.jp/imsut/en/lab/lrclink/