Norio Nakatsuji, Institute for Frontier Medical Sciences, Kyoto University Credit: Copyright, Kyoto University

Across the globe, human embryonic stem (hES) cell research has expanded rapidly. Recent annual meetings of the International Society for Stem Cell Research (ISSCR) showcased hundreds of posters and presentations using hES cells. From 2000 to 2005, the number of publications detailing experiments on hES cell lines has multiplied more than 40-fold1. Yet the Japanese scientific community has been surprisingly slow to contribute to the field.

Given Japanese scientists' prominence in tissue stem cells and animal ES cell research, this is unexpected and strange. The problem is bureaucracy. To conduct experiments even on established hES cell lines, a laboratory must procure separate equipment and space. Research plans must undergo redundant approval processes that exaggerate trivial concerns. A requirement that all scientists must obtain individual permission from the government before performing any work with hES cells hinders the training of young scientists and visiting scholars. We desperately need more rational rules that do not inhibit scientific progress.

Japan should and could be a major player of hES cell research

Japan is a major player in stem cell research overall. The latest prominent example is Dr. Shinya Yamanaka of our institute, who has produced artificially induced pluripotent cells by reprogramming mouse fibroblasts2,3.

For many years, many Japanese laboratories including ours have worked on mouse ES cells. We have also derived several cynomolgus monkey ES cell lines4, which have been used by many laboratories for preclinical research such as deriving dopaminergic neurons to transplant into monkey models of Parkinson's disease5. In 2003 we derived three hES cell lines6. These have been distributed to more than 30 laboratories throughout Japan, totally free of cost and with generous material transfer terms. Recently, we collaborated with laboratories across the globe to characterize hES cells for the International Stem Cell Initiative7.

Surprising delay of hES cell research in Japan

Nonetheless, Japan is lagging behind in hES cell research. At the ISSCR meeting held in Cairns in June 2007, only three of the hundreds of posters on hES cells came from Japanese laboratories (including two from our laboratory). At the annual meeting in March 2007 of the Japanese Society of Regenerative Medicine, only 5 posters among 430 posters used hES cells.

A recent survey article on hES research found rapidly increasing publications around the world, but the contribution of Japanese scientists was surprisingly small1. By 2005, more than 400 research papers using hES cells had been published; only 5 were from Japanese groups. The worrying situation is not improving: Japanese groups have published only a handful of articles since then.

Since the first hES cell line was reported in 1998 (ref. 8), many countries convened public discussions to shape policies surrounding hES cell research. With a pro-science government and without major objections from religious or other groups, Japan was recognized as one of the world's permissive countries. In principle, Japanese policies and guidelines9 are moderate and similar to many other countries. For example, hES cell lines can be derived using surplus embryos from fertility clinics. Even somatic cell nuclear transfer seems to be allowed under very strict oversight and regulation, although the government guidelines are not yet finalized.

What delays hES cell research in Japan?

If the principles governing hES cells in Japan are permissive, what is hampering hES cell research in Japan? The main reason is a redundant and irrational regulatory process.

Our guidelines require approval both by research organizations' ethics committee (an institutional review board (IRB) expanded to include a lawyer, bioethicist and layperson) and by a designated government committee. This may make sense for experiments that destroy human embryos or involve human subjects. However, the duplicated approval process is required simply to use existing hES cells in the laboratory. We must apply for the approval every time we change or expand the approved research plan to include new experiments, add new persons to the research team, change the room used for experiments, or simply extend the period of the research plan, such as from 3 to 5 years. These regulations fall outside the global consensus described by the international guidelines compiled by the ISSCR10, which clearly state that laboratory use of existing hES cell lines does not require the kind of scrutiny necessary when scientists work with embryos directly.

In other countries, researchers can begin experiments using existing hES cell lines within a month. In Japan, satisfying all the regulatory requirements can easily take a full year. That burden certainly discourages Japanese scientists from embarking on hES cell research, at least in Japan. With accelerating global competition, smart young scientists in Japan avoid hES cell research; the delays and handicaps keep them from performing work necessary to publish articles in respected journals and establish their careers.

Government officials heard no consolidated objective opinion from the scientific community and chose a stance calculated to avoid criticism.

These cumbersome processes became formalized in Japan in 2001 when the current guidelines were issued, in the wake of ethical concerns stressed by nonscientists who did not consider practical implications or essential distinctions, such as whether embryos, ES cells and cells differentiated from ES cells should be regulated differently. The scientific community failed to launch a unified, rational response to the proposed guidelines and their implementation. Few scientists at the time worked in hES cells. Those who did not were indifferent. Scientist leaders, mainly working outside the field, were eager to be seen as cautious, and did not consider how regulations could hinder progress. Government officials heard no consolidated objective opinion from the scientific community, and chose a stance calculated to avoid criticism. They considered only the praise zealous restrictions could bring, but not the cost to science and society. However, the resulting delays and distractions damage the interests of our country and people, especially patients who could potentially benefit from treatments developed from hES cell research.

No quick improvement in sight for Japanese situation

Once a rule is established in Japan, it is very difficult to change. Government bureaucrats do whatever they can to keep established policies from being recognized as misguided. They vigorously defend the status quo, no matter what it is. That regulations are being amended at all is a testament to how extreme the problems with hES cell regulations are.

However, although MEXT (Japan's Ministry of Culture, Sports, Science, and Technology) describes upcoming relaxation of hES cell regulations as extensive, they remain much more restrictive as compared with international consensus described in the ISSCR guidelines10. Cells that have been differentiated from hES cells are no longer subject to double regulation in some cases, but the core problem of duplicated oversight for the laboratory use of existing hES cell lines has not been addressed. It is still unclear how difficult it will be to obtain permission from MEXT to ship hES cells across international borders for international collaborations. The opposite strange possibility is that the foreign scientists may find it much easier to obtain and use our hES cell lines than domestic scientists will.

The irrationality falls into three main areas, each described below.

hES cells cannot be studied in the same room or with the same equipment as animal cells

The MEXT committee's interpretation of research guidelines requires that experiments using hES cells be carried out in specified rooms, where experiments using animal cells are not allowed. The rationale for this rule has nothing to do with contamination or safety. Instead, it is argued, growing hES cells in the same room as animal cells is an affront to human dignity. (Bizarrely, growing animal feeder cells alongside hES cells is permissible.)

These rules are an affront to common sense. Laboratories pursuing hES research purchase duplicate equipment and designate space for hES cells only. Rather than allocating scarce resources to hES research, many Japanese laboratories avoid pursuing it altogether.

The government ethics committee warps IRB discussions

All the research plans must be approved both by an organization's institutional review board (IRB) and by the MEXT committee. Although the requirement is not official, the MEXT committee demands a transcript of the IRB meeting and then scrutinizes it to see whether the IRB thoroughly discussed whether the research plan is technically and ethically sound. Worse, the regulations are vague, giving MEXT complete freedom to interpret whether IRB discussions are adequate. This has the effect that IRB members do not strive to be thorough in their examination of a research plan but rather strive to convince MEXT that they are being thorough in their examination. Such IRB discussion becomes overdone and exaggerated.

This practice smacks of government censorship. In democratic societies, oversight committees such as IRBs should be totally independent to follow their expertise and conscience. However, our situation gives the clear impression that the MEXT committee ultimately controls IRBs.

Certification requirements hinder training and cross-training in hES cells

Before starting experiments on hES cells, all laboratory members must receive training in handling animal ES cells plus coursework on bioethics. The rationale is that otherwise hES cells would be wasted in inefficient experiments by untrained persons. However, once a line is established, hES cells are not a limiting resource. The cells grow rapidly and can expand 10-fold in a week.

The rule requires every new postdoctoral fellow, graduate student and technician to receive both IRB and MEXT approval before starting experiments. After August 2007, junior laboratory members require only approval by the IRB. Still, they must take a government-sanctioned bioethics course and technical training before they can apply for approval. Although each university or research institute formulates contents of the technical training and bioethics teaching, it must submit the planned contents to the MEXT committee for approval.

Such a situation discourages scientists from starting hES cell research, because they cannot try out techniques without making a serious commitment to the field. It is almost impossible to provide training courses on hES cells. These restrictions also keep us from teaching practical techniques of handling hES cells to visiting scientists.

Concluding words

I hope that the current situation in Japan will change soon enough for the Japanese scientific community and Japanese hES cell lines to steer a rapidly progressing field. To foster change, Japanese scientists should raise honest, anxious and uninhibited voices testifying that the present rules in Japan are irrational, that they impede scientific progress and, ultimately, damage the citizens and national interest of Japan.