Furthering radiopharmaceutical research and development in Japan and the transfer of technology: An interview with Dr. Ming-Rong Zhang, Director of the Department of Advanced Nuclear Medicine Sciences at QST

Promoting international research mobility is an essential condition for robust research and development. To this end, it is important to internationalize the research ecosystem, promote international human resource exchange, and ensure that Japan is a part of the international brain circulation network. Under this special topic, we will introduce the current status of, and challenges associated, with Japan's research efforts to promote international intellectual talent exchange to produce outstanding research results, as well as to increase the attractiveness of Japan's research environment, which is necessary for captivating foreign researchers. We will conduct a series of interviews with relevant people in the field. In this interview we spoke to Dr. Ming-Rong Zhang, Director of the Department of Advanced Nuclear Medicine Sciences at the National Institutes for Quantum Science and Technology (QST).

Joined QST after graduating from university in China and came to study and experience in the private sector in Japan

Director Ming-Rong Zhang of the Department of Advanced Nuclear Medicine Sciences in the Institute for Quantum Medical Science at QST is from Yangzhou city, Jiangsu Province, China. After graduating from the Faculty of Pharmacy at China Pharmaceutical University in Nanjing, he studied at Okayama University in 1986 as a Chinese Government Scholarship student, earning a master's degree and a PhD in Pharmaceutical Sciences. Following this, he accepted a post-doctoral position at the National Institute of Radiological Sciences (NIRS) (which later merged into QST in 2016) in 1998 after working in a private company for approximately four and a half years.

Zhang's hometown, Yangzhou, was also the hometown of Jianzhen Huanshang, who traveled to Japan in the eighth century, during China's Tang Dynasty. The Jianzhen temple is only five km away from Zhang's parents' house, and since childhood he has known about the saga of 'Jianzhen Dongdu' (the monk's story traveling to Japan) as well as the Toshodaiji Temple that Jianzhen founded in Nara. When Zhang was growing up, China Pharmaceutical University was one of the few colleges in China. It promoted exchanges with Gifu Pharmaceutical University in Japan, providing a setting suitable for communicating with Japanese professors, and he was interested in going to Japan to study. During his senior year of college, Zhang applied to and successfully qualified for the Chinese government's scholarship program to study in Japan. He learned Japanese intensively for eight months before coming to Japan. "Studying in Japan was the best choice for me at the time. Japan enjoyed a better quality of life than China and was at the leading edge in the academic fields, including organic chemistry," recalls Zhang.

At Okayama University, he majored in pharmacology for both his master's degree and doctorate. "At first," he said, "the Japanese language and technical terms were a challenge to grasp but I managed to keep at it. The thing I appreciate about Japan is that university professors patiently nurture their students. I think many of my professors cared more about training their students than generating immediate results. Such professors are what we call 'mentors.' I was given assignments to make presentations at academic conferences, and by taking advantage of these opportunities, I was able to improve my Japanese language skills. After every conference presentation, I felt that my Japanese language proficiency had improved. Even today, I really appreciate the steady Japanese approach to developing human resources."

After earning his doctorate, Zhang joined a private health food company, working on the extraction of natural products. "In 1998, when I was considering changing jobs so that I could make the most of my knowledge of chemistry, I came across a classified ad in a pharmaceutical journal for a job opening in the Japan Science and Technology Agency's (JST's) Core Research for Evolutional Science and Technology (CREST) program." Zhang applied for a post-doctoral position in the program 'Protecting the brain,' which was led by Dr. Tetsuya Suhara, then at NIRS (currently Managing Director of the Quantum Life and Medical Science Directorate at QST). "Delivering immediate benefits to people through the use of radiopharmaceuticals and being able to readily see the outcomes of my research was a big attraction for me," Zhang explains. His endeavors in the development of radiopharmaceuticals began in this post.

After the first two years of post-doctoral research, he worked as a technical staff member operating the accelerator (cyclotron) and was employed as a fixed-term staff member. Subsequently, in 2007, he obtained the position of tenured staff member, and after serving as a team leader and group leader, he was promoted to Director of the Department of Advanced Nuclear Medicine Sciences. He is currently the leader of a group of approximately 60 researchers and supporting staff. "With the help of my excellent staff, I can do my best work. We have a variety of people in our group, including excellent researchers and technical staff. Everyone has their own individual qualities, and we should show them respect and keep that in mind in our work. Regardless of the various ways of thinking, we share the same mission: to complete the development of radiopharmaceutical agents and bring them to the clinical stage."

World leader in research and development of PET imaging agents

Zhang is engaged in the research and development of radiopharmaceuticals. There are two main types of radiopharmaceuticals being researched at QST: those for diagnosis and those for therapy. One is a radiopharmaceutical for use in PET, an imaging technique that accurately determines the location of cancers and other diseases. Let's take for example the diagnosis of dementia. When a radionuclide-labeled compound is injected into a patient, the compound will bind and aggregate to the beta-amyloid that is believed to cause dementia, allowing the PET images to display where the disease is occurring.

In terms of radiopharmaceutical therapy for cancer, drugs are injected into the human body to treat the cancer by irradiating it directly inside the body. Zhang said that he was originally involved only in the development of PET imaging agents, but later he began researching therapeutic agents as well.

"In the case of PET, there are more than 120 agents actually available for the purpose of clinical use at our facility, and 70% of them are amenable to brain-related applications. The research objectives of PET have evolved over time. For example, in the 1980s, the research themes of dopamine and schizophrenia were the focus, and then in the 1990s, sleep and anxiety were investigated, among others. As we entered the 2000s, dementia became a focus, including Alzheimer's disease and, more recently, non-Alzheimer's types of dementia. In that period, a PET imaging agent that my collaborators and I had developed was patented, and the patent was sold to a German company. Although it ultimately did not reach the clinical stage, this was the first drug I was able to implement into society. There are roughly 10 drugs developed by our group that have reached the clinical stage. Currently, we are conducting clinical research of a diagnostic agent for dementia that we developed in collaboration with medical doctors in brain function research," said Zhang as he sketched the trajectory of his own research.

The PET radiopharmaceuticals and manufacturing technology developed by QST are world class. To date, 128 radiopharmaceuticals have been manufactured and are available for clinical research. Homologous facilities in the U.S. and Sweden trail Japan, and have only 30 to 40 pharmaceuticals, and this difference is very significant. Japan's first PET clinical research was implemented in 1979 at NIRS. Today, PET radiopharmaceuticals are being developed in QST not only for Alzheimer's disease but also for non-Alzheimer's types of dementia. The drug for the latter is unique and has already been patented. It is currently undergoing clinical trials in Japan, China, the U.S., and other countries.

The development of medicines to treat dementia has been a major recent challenge, and PET radiopharmaceuticals play a very effective role in its treatment. This is because PET can be used in advance to determine whether or not a dementia treatment drug can be administered to a patient. The outcome of the treatment depends considerably on when the therapeutic agents are administered to the patient. Early administration is more effective, and beyond a certain point, the effect is no longer positive. With PET radiopharmaceuticals, the progression of the disease can be monitored by clearly probing where and how much beta-amyloid and other similar substances are accumulating in the brain. Consequently, they are highly regarded as diagnostic agents. In the future, it is expected that the PET diagnosis of dementia will be covered by insurance.

Furthermore, PET is also used as a tool for the development of drugs in general. For example, when a pharmaceutical company develops a drug, it can confirm before clinical research whether the candidate drug goes to the brain or is excreted via kidneys, etc., by using PET to efficiently and reliably observe how the drug moves through the body, thereby facilitating clinical research. Zhang commented that various joint studies with pharmaceutical companies are already under way.

He added that he is working on two approaches to upgrading PET radiopharmaceuticals. "One involves improving the way PET radiopharmaceuticals are manufactured. In the case of ordinary medicines, you can take as long as you need to produce them and not worry about radiation, but with radiopharmaceuticals, the key challenge in development is to make them quickly, efficiently, and more importantly, with minimal radiation exposure to the staff." The half-life of the radioactive nuclides embedded in PET radiopharmaceuticals is only a few hours, and the products cannot be stored in the laboratory, so they must be prepared just before their administration. "The other approach involves further improvements in the radiopharmaceuticals we make. Even though a drug may work well in animals, it does not always do so in clinical research for humans. When it does not work, it may be necessary to redesign the chemical structure of the agents. For example, if a drug does not get into the brain successfully, we try to improve it by increasing the lipophilicity in the chemical structure to pass through the blood−brain barrier."

Radiopharmaceutical therapy in cancer using targeted radionuclides, is more advanced in Germany and the U.S. than in Japan. This is because the daily maximum permissible dose of radiation at each facility is strictly regulated in Japan, thereby making it less feasible to use radiopharmaceuticals for treatment. "Japan is somewhat behind the curve in the therapeutic application of (radioactive) drugs in clinical practice," he said, "but Japan is running on its own track when it comes to the production of actinium, which is now the most promising among the nuclides for use in targeted radionuclide therapy. Its commercialization is also being considered and is gaining worldwide attention. I think it's probably right to say that we are the world leader in the technology for producing actinium from a small cyclotron."

With regard to the commercialization of research results, Zhang himself has not been engaged in launching any venture companies, but some venture companies have invested in the promising business potential developed by his lab. In this approach to investment, the venture company receives preferential patent licenses and financial compensation for the research.

Internationalization of the research environment and international brain circulation

With regard to 'internationalization in terms of accepting foreign talent, Zhang estimates that QST is more advanced than Japanese society as a whole, and the Department of Advanced Nuclear Medicine Sciences, which he leads, is the most cosmopolitan community in QST. "Our institute is an International Atomic Energy Agency (IAEA) Collaborating Centre, so we regularly receive people from IAEA. In my department alone, approximately 10 people come and go each year, staying for a week at minimum and up to a year at maximum. I think there is a lot of coming and going internationally at QST," Zhang says. "We have people from China, Iran, Cambodia, and many other countries in our department. There are many people from Southeast Asia, which is indicative of Japan's strong influence in the area. When these people return to their home countries and play a valuable role, Japan and those of us responsible for training them will be highly valued. This is something that I really enjoy."

Academia is still highly respected in Japan, so you can devote yourself to research

"The place where I trained and developed my career, Japan, is now my home. While I could understand nothing about things initially, I have been able to gradually adapt to life in Japan. If you are determined and serious about your academic studies, Japan is one of the best destinations. Despite changes in Japan's society, there is still an environment that lets you focus on learning, so you can dedicate yourself to your research. In both the U.S. and China, society is changing too rapidly, and several young people are unable to adapt to the environment, causing various social problems and distortions. Here in Japan, the dignity of academia and the respect it receives still persists, although it is gradually changing. Of course, each place has its benefits and drawbacks. You can take your time to do research in Japan, but there may be a problem in that Japan's younger people are unable to keep up with the rapid changes taking place in the world."

Challenges to the continuation of internationalization

With regard to furthering Japan's internationalization and international brain circulation, Zhang identifies several issues. The first is that few people leave Japan for foreign countries. "Every year, we look for staff members to go abroad, but very few respond. If I were younger, I would naturally choose to go, but today's young people unfailingly tend to look for stability. They may feel that life in Japan is so comfortable and convenient that they do not see the need to go to a foreign country and face challenges. My children also say that they can do well in Japan without going abroad. This is one of the hallmarks of a mature society. The recent COVID-19 pandemic may also have had some impact. With regard to institutional matters, for example, researchers on fixed-term positions face job insecurity by design and are anxious about the consequences for their job if they decide to go abroad, making the decision difficult for them," Zhang says.

It is noteworthy, by the way, that many students in China want to study abroad and that overseas work experience is an essential part of their career trajectory. For example, more than three years of post-doctoral experience is a prerequisite for getting a university teaching position. This is a big difference between China and Japan.

As mentioned earlier, Zhang pointed out that while QST has made considerable progress in accepting foreigners, there are still difficulties and challenges in Japan as a whole. He noted that, among other things, the tenure system at Japanese universities and other institutions is a daunting barrier for foreigners. Additionally, he added that there were complex issues for foreigners in settling down in Japan, such as language and housing problems.

A mission to pass on skills related to research and development

When asked about his future goals, Zhang said, "For now, I plan to carry on my work in Japan," before adding,

"What I value most now is the transfer of technology. My lab serves as a foundational structure for cutting-edge research, supported not only by researchers but also by technical staff with craftsmanship. With regard to the automated synthesis system of PET radiopharmaceuticals that you just saw in the lab, its prototype was made by me by processing a punching board. However, nobody does that kind of work anymore, and people are using an off-the-shelf product supplied by a research equipment company. This approach ends up with limited innovations. When the young come here, I tell them that they can create a basic synthesizer themselves by processing a punching board, and that by doing so they can learn the principles of synthesis of PET radiopharmaceuticals before they start working on the development of radiopharmaceuticals."

"Our structure is supported by technical staff, most of whom use so-called traditional craftsmanship. Without them, the technology would be lost. It is no exaggeration to assert that this technology supports Japanese society. Basically, to put it in an extreme way, researchers can choose to go wherever they want to worldwide, and this lab will still run just as well without them. The fact is that it is the technical staff that we cannot do without. The problem is how to transfer their skills to the younger generation. This, I think, is what I should invest most of my efforts into going forward."

"We should further improve the medicines we have been working on, engage in various communications with pharmaceutical companies, and contribute to society. In parallel, I believe it is my role to move along with the times by making our technology more advanced and efficient."

(Interview conducted at the headquarters of QST at Inage, Chiba, on August 30, 2023)
Interviewer: Yoshihiro Higuchi,
Director for Global Strategic Issues, Japan Science and Technology Agency (JST)
Editing: Ki Sou, Editor-in-Chief of Keguan Japan, APRC, JST

<About QST>

National Institutes for Quantum Science and Technology (QST)
Under the basic objective of 'achieving a sustainable future society through quantum science and technology,' QST promotes research and innovation in quantum technologies, including research on quantum medicine/medical care, quantum energy, and quantum beams.
It is a core institute for quantum science and technology research in Japan.

QST homepage: https://www.qst.go.jp/site/qst-english/

Back to list of interviewees