[Special Feature: The Future of Regenerative Medicine] Developments in Regenerative Medicine and Challenges Centered on Ethical Aspects

2019/06/05

The year 2019 may later be remembered as the year when "regenerative medicine using iPS cells truly took off." This is because the start of several clinical applications was declared, including spinal cord injury treatment by Keio University, heart disease treatment by Osaka University, and Parkinson's disease treatment by Kyoto University.

After Professor Shinya Yamanaka of Kyoto University won the Nobel Prize in Physiology or Medicine in 2012, the question "When will iPS cells be available for actual treatment?" was asked from the audience at every lecture. I remember Professor Yamanaka answering with a serious expression, "I think it will still be 10 or 20 years away." Before I knew it, that "10 years away" is now right before our eyes.

However, the start of treatment for a small number of people in such regenerative medicine is on a different dimension from that treatment becoming widely popular as "commonplace medical care." There are many hurdles to overcome before many patients can benefit.

Regenerative medicine research had been attempted in various ways even before the appearance of iPS cells. Among them, embryonic stem cells (ES cells), known as "pluripotent cells" obtained from fertilized eggs, were attracting expectations as bringing a breakthrough to medical care. Because they have the ability to grow into any tissue in the body, they were considered ideal for creating cells and organs for transplantation, and there were multiple plans for clinical application. However, these cells faced the ethical problem that the fertilized egg, which is the beginning of life, must be destroyed when they are created. The Pope and U.S. President Bush (the son) objected to ES cell research, and the U.S. federal government temporarily stopped providing research budgets. The reason iPS cells were enthusiastically accepted by many doctors, researchers, and patients was that they could be easily created from skin or blood cells and were superior in convenience, and in addition, it was thought that there would be no need to destroy fertilized eggs, eliminating ethical hurdles.

Certainly, if iPS cells are created from the patient's own cells, grown into the cells or tissues necessary for treating the disease, and then transplanted back into the patient, there would seem to be almost no ethical problems. However, as can be seen from the first clinical study for age-related macular degeneration treatment conducted by RIKEN Project Leader Masayo Takahashi in 2014 using the patient's own iPS cells, this method takes a long time to prepare and is expensive. Partly because it was the world's first regenerative medicine using iPS cells, thorough quality checks through cell genome analysis and other methods were required, and it is estimated to have cost about 100 million yen to treat one person. With this, widespread adoption is difficult.

Why are such strict quality checks necessary? iPS cells are easily created by inserting multiple genes that act as reprogramming factors into blood or skin cells, and they can be increased infinitely if conditions are right. As is often said, this proliferative property is similar to cancer cells, and if they start to run wild for some reason, it could lead to the occurrence of unwanted tumors or cancer. If cells such as nerves or cardiac muscle created from iPS cells become tumorigenic and compress surrounding tissues or become cancerous, they must be removed. However, there is no clear "yardstick" for how to keep such risks low, or in other words, what and to what extent should be investigated to confirm that the risk is sufficiently low. As a result, cells used clinically often take the safe route and undergo comprehensive genome analysis. This is despite the fact that many researchers think in their hearts, "Is it really necessary to go that far?"

No matter how much you investigate, the risk can never be zero. Ultimately, if it can be judged that the risk is sufficiently small compared to the benefit of the disease heading toward recovery, the decision will be made to proceed with treatment. Even so, we must recognize that if a problem should occur, criticisms such as "I told you so" or "It's a human experiment" will arise, and there is a risk that regenerative medicine will be set back.

Basic research needs to be carried out in parallel with the accumulation of clinical research. In the first place, why are these mysterious cells called iPS cells created? How is the process of differentiation induction into various tissues determined? Scientific clarification has not been completed. Listening to academic lectures at the International Society for Stem Cell Research (ISSCR), there are many presentations regarding these principles and mechanisms. If understanding of cell properties and differentiation methods progresses, techniques to reliably control them so that tumors do not occur should also come into view.

As an effective method for making cells of a certain quality available at even a slightly lower cost, there is a method of creating iPS cells in advance, performing strict quality checks, and then stockpiling them. These cells are for allogeneic transplantation. The "iPS Cell Stock" being developed by Professor Yamanaka and others at the Center for iPS Cell Research and Application (CiRA) at Kyoto University is based on this idea and is being developed with a national budget. iPS cells created in advance from blood cells of immune types common among Japanese people are stockpiled. These are less likely to cause rejection.

RIKEN Project Leader Takahashi is also using cells from CiRA's iPS cell stock in new clinical research starting in 2017. They are grown into retinal pigment epithelial cells when needed and transplanted into patients by injection. The cost of treatment is expected to be reduced by more than one order of magnitude compared to the first clinical study. Although still expensive, it is coming somewhat within reach. Keio University's spinal cord injury treatment and Kyoto University's Parkinson's disease treatment also use cells from CiRA's iPS cell stock.

However, only a handful of researchers can currently organize treatment plans so successfully. One reason is that the acquisition routes for the original cells, which are the raw materials for regenerative medicine cells including iPS cells, are extremely limited. Currently, CiRA is the only organization in Japan supplying iPS cells that can be used for the purpose of transplantation into humans in clinical research or clinical trials aimed at obtaining approval based on the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices (Pharmaceuticals and Medical Devices Act). iPS cells are created based on blood collected at a limited number of reliable institutions, including the Japanese Red Cross Society. Although the production system has been expanded by increasing Cell Processing Centers (CPC), it is considered difficult to meet all future needs. For example, there may be cases where human iPS cells are needed to experimentally administer cells to animals at the research stage. There are likely many needs for cells that are easier to obtain without requiring the high quality of CiRA. Overseas, private companies entered the cell supply business early on, and there are leading companies supplying clinical-grade iPS cells, such as Cellular Dynamics International (now FUJIFILM Cellular Dynamics) in the U.S. and Lonza in Switzerland. There are also many companies that create and sell other cells for regenerative medicine, such as mesenchymal stem cells, and they are expanding services by taking orders for cells in Japan as well. Unless such operators grow, the pace of treatment research will not increase easily.

If you trace the origin of cells purchased from private operators, you often end up with overseas tissue donors, and they are frequently not Japanese cells. This is true not only for regenerative medicine but also for cells used in drug discovery research to confirm the effects and safety of new drug candidates. In the U.S. and Europe, rules, quality control, and distribution mechanisms are in place to receive cell donations with the individual's consent, create iPS cells based on them, grow them into transplant cells, and sell them as cell products. These were established through cooperation between the public and private sectors as the "foundation" necessary to spread cell therapy in general, including gene therapy as well as regenerative medicine. Steady efforts have also been continued to obtain social consensus with the support of patient groups and others. On the other hand, in Japan, the cell business has a strong negative image because it is associated with organ trafficking, and it is difficult to spread due to ethical issues.

In 2017, it was discovered that cord blood from a bankrupt private cord blood bank had been leaked without the donors' knowledge and was being used at multiple clinics, attracting great attention. These clinics were performing treatments to transplant cord blood into patients for the purposes of cancer treatment and anti-aging. They had not submitted notifications to the Ministry of Health, Labour and Welfare based on the Act on the Safety of Regenerative Medicine, leading to the arrest of operators and doctors involved in the storage and distribution of cord blood. Cord blood is also used as a raw material for CiRA's iPS cell stock, but it is supplied from public cord blood banks authorized by the Ministry of Health, Labour and Welfare with the consent of donors, and is completely different from the private cord blood bank that caused the incident. However, some people confuse these or have a bad image of the use of cord blood, which is hindering sound regenerative medicine. There is no doubt that the need for cord blood as a raw material for cell therapy is high, and to dispel distrust, strict adherence to rules and transparency in the processes of cell acquisition, distribution, and administration are essential.

The Ministry of Economy, Trade and Industry (METI) established an expert study group and conducted a "Survey on the Acquisition of Raw Material Cells, etc." in 2015 to activate the securing and distribution of cell raw materials on par with the U.S. and Europe and to help promote regenerative medicine, and compiled a report. In this report, while considering the feelings and emotions of the public regarding the use of human cells, it stated that it is necessary to: (1) examine responses to the legal system, (2) improve social recognition, (3) undertake efforts to gain the understanding and cooperation of cell donors, and (4) respond to practical issues to ensure cooperation among cell donors and collection medical institutions. Subsequently, the Japan Agency for Medical Research and Development (AMED) has continued the study, implementing projects such as the "Project for Development of Evaluation Foundation Technology for Industrialization of Regenerative Medicine (Stable Supply Model Project for Human (Allogeneic) Somatic Stem Cell Raw Materials from Domestic Medical Institutions)," but the development of specific legal systems and practical mechanisms has not yet been completed.

While international competition in the development of new treatments such as regenerative medicine is intensifying, a situation where raw materials cannot be secured is disadvantageous. At a symposium of the 18th Congress of the Japanese Society for Regenerative Medicine held in Kobe City in March this year, voices calling for improvement of the current situation were heard one after another, such as "Peripheral blood mononuclear cells are difficult to purchase in Japan, so we are forced to import them from overseas to use in non-clinical trials and collect data" and "In the U.S., three major companies are selling them." The METI official who took the stage only responded by saying, "I want to consider it for about another year" and "First, I want to understand the actual situation."

Looking at the example of the UK, which leads the world in cell therapy research, the "Cell and Gene Therapy Catapult," operated with a national budget, plays a major role in connecting investors, companies, medical institutions, and patients. It is widely responsible for fostering companies that handle the supply chain from raw material procurement to the preparation of therapeutic cells, developing large-scale CPCs that can produce as many safe cells as needed for clinical trials, and mediating between companies/researchers and medical institutions nationwide. Each is operated and functioning under transparent rules, and the government is leading the way in quickly creating an environment where new treatments are easily accepted by the public.

Besides the issue of raw materials, there are several things to be resolved. When conducting clinical research for new treatments, patients who will be subjects must be recruited. Whether the research can be conducted without problems from ethical and safety perspectives is reviewed by a specialized committee. The Act on the Safety of Regenerative Medicine mandates review by a Certified Special Committee for Regenerative Medicine for relatively high-risk treatments and clinical research using iPS cells, etc., and review by a Certified Committee for Regenerative Medicine for relatively low-risk treatments and clinical research such as cosmetic surgery and cancer treatment conducted by private clinics using mesenchymal stem cells or immune cells.

These committees have conditions for members determined by type and have obtained certification, or a seal of approval, from the Ministry of Health, Labour and Welfare. Nevertheless, it is said that some committees are reviews in name only and easily approve the implementation of clinical research or treatment as long as a fee is paid. Although summaries of proceedings are published, the details of actual exchanges are unknown. According to an expert who attended a committee meeting, "It often ends without anyone saying a word." This could lead to a decline in trust in regenerative medicine itself. AMED and the Japanese Society for Regenerative Medicine are cooperating on a fact-finding survey project, and based on the results, they will consider ways to increase the effectiveness of reviews, such as reviewing the requirements for committee composition. Including both Special Certified and Certified Committees for Regenerative Medicine, there are more than 150 in Japan. It is impossible to establish a system where all of them possess quality and conduct solid reviews. One idea would be to consolidate them by region, such as at university hospitals where experts in medicine, law, and ethics are easily gathered.

Even if the safety and ethical issues seen so far are resolved, rapid technological progress always creates new challenges. A representative example is research to create germ cells such as eggs and sperm from iPS cells. In Japan, guidelines stipulate that when establishing fertilized eggs for research on assisted reproductive technology, the source eggs must only be surplus eggs collected for fertility treatment but left unused, or eggs obtained from ovaries removed due to illness that are not planned for use. They are difficult to obtain even in university laboratories, and eggs are shared from fertility clinics and other sources.

If iPS cells are differentiated into eggs or sperm and fertilized, it is technically possible to create fertilized eggs. The source material can be just a tiny amount of blood. A research group at Kyoto University is conducting related research with the aim of approaching the mechanism of the birth of life and helping to clarify the causes of infertility. Professor Mitinori Saitou, who leads the world in this field, succeeded in creating primordial germ cells, which are the basis of eggs and sperm, from human iPS cells. If human sperm and eggs can be obtained from iPS cells and fertilized eggs can be created from them, the clarification of abnormalities in the early growth process and the causes of diseases that appear with growth will accelerate. At that time, if genome editing can be applied to the created cells to modify targeted base sequences, new knowledge could be obtained all at once, potentially giving momentum to the development of treatments and prevention methods for intractable diseases.

On the other hand, there are voices concerned about the abuse of technology. Suppose it becomes possible to easily create fertilized eggs anytime, anywhere. If genome analysis is performed and sequences are found that could lead to even a slight risk of disease or "unfavorable" characteristics such as low specific abilities, they might be discarded without much resistance. It would be a problem if the selection of fertilized eggs, that is, the selection of life, were to be done very mechanically and easily.

Furthermore, in extreme cases, some people might think of experiments such as creating sperm and eggs from the iPS cells of the same person, creating fertilized eggs from them, and putting them into a woman's uterus to give birth to a child. This would result in the birth of a kind of human clone that has faithfully inherited the genetic information of only one person, which is not acceptable. Some kind of legal framework that comprehensively stipulates the state of cell therapy such as regenerative medicine and gene therapy, and reproductive medicine, is expected to be necessary eventually.

Building social consensus for cutting-edge technology and organizing and resolving ethical issues are extremely important, but in Japan, they tend to be neglected compared to technological development itself. In many cases, after a problem occurs, the Bioethics Specialist Committee of the government's Council for Science, Technology and Innovation hurriedly considers it and tries to reach a temporary conclusion in a short period. In the future, it will be necessary to consider issues while always engaging in dialogue with society, keeping an eye on global technological trends. It is essential not only to create "forms" such as committees and working groups but also to foster experts who can engage in in-depth discussions. Universities will be required more than ever to discover and nurture human resources with a broad perspective spanning medical sciences, law, life sciences, and social sciences.