Stem Cell Research and Therapy in the Islamic Republic of Iran: Pioneering in the Islamic World

Abstract

In the early 2000s, the Iranian stem cell research and technology had a relatively strong start that benefited from religious blessings, political and public support, as well as scientific endeavors on the part of non-governmental and public research organizations and universities. Later on, it developed a dynamic niche market of public, private start-up, and spin-off companies and organizations that pioneered in the Islamic world in terms of ISI papers, clinical trials, and cell therapy. However, at present, it faces new challenges stemming from the insufficient finance and a comprehensive law and regulation structure to keep its momentum. To remedy this situation, the scientific community and other stakeholders need to have a series of shared long-time goals and try to build consensus on how to achieve them through nationally approved policy documents.

Introduction

S ince the early 2000s, Iran has sought to build a new-found pride by starting a fresh move toward a knowledge society with the paradigm of advanced technologies. Recent statistics show that Iran, with a 20% annual growth rate in the publication of scientific papers, tops all other countries in the world [1]. Iran also has the highest tertiary growth enrolment rate in the Middle East. The total number of college students has grown 7 times during the last decade, amounting to more than 4.1million, representing more than a third of the country's 18–24 year-old population [2]. Meanwhile, R&D centers and graduate schools have recently flourished in multidisciplinary fields such as nanotechnology, biotechnology, and stem cell research and technology (SCRT).

Among these innovative fields, stem cell research and therapy, as a vital interdisciplinary scientific ground with rapid pace of advancement and drastic clinical promises, has attracted many graduate students and young scholars. The number of Iranian published papers in ISI scientific journals of the stem cell field, starting from 15 papers in 2004, has reached 145 papers in 2011, catching up with the long-time forerunner, Turkey, and forging ahead among the Muslim countries. Moreover, the number of registered stem cell clinical trials in Iran, with 31 cases, far exceeds those in any other Muslim nation such as Turkey (6 cases) and Egypt (5 cases), indicating that Iran is ahead of the Islamic world in the field of therapy-oriented stem cell research (Table 1).

Table 1.

Registered and Submitted Stem Cell Clinical Trials from Iran to NIH Clinical Trials Site

No.	Condition	Intervention	Control	Phase	Estimated enrollment	Clinicaltrials.gov identifier	Status	No. included patients
1.	Multiple sclerosis	Intravenous injection of mesenchymal stem cells	Yes	I/II	30	NCT01377870	Recruiting	6
2.	Avascular necrosis of femoral head	CD133+ cell infusion into the cored area	No	I	10	NCT01198080	Data analysis	12
3.	Myocardial infarction	1. Intracoronary injection of bone marrow-derived AC133+ cells 2. Intracoronary injection of bone marrow-derived MNC	Yes	II/III	100	NCT01187654	Recruiting	40
4.	Myocardial infarction	1. Intramyocardial injection of bone marrow-derived AC133+ cells 2. Intramyocardial injection of bone marrow-derived MNC	Yes	III	105	NCT01167751	Recruiting	80
5.	Peripheral vascular diseases ischemia	Intramuscular injection of bone marrow-derived mononuclear cells	No	I/II	20	NCT00677404	Completed	18
6.	Limbal stem cell deficiency	Transplantation of cultivated limbal epithelium on amniotic membrane	No	I/II	10	NCT00736307	Completed	10
7.	Liver cirrhosis	1. Portal vein infusion of bone marrow-derived AC133+ cells 2. Portal vein infusion of bone marrow-derived MNC	No	I/II	7	NCT00713934	Completed	7
8.	Facial deformities	Injection of autologous cultured fibroblast	Yes	II/III	40	NCT01115634	Data analysis	40
9.	Liver fibrosis	Combined pioglitazone plus autologous bone marrow mesenchymal stem cell transplantation	No	I	3	NCT01454336	Recruiting	3
10.	Hip osteoarthritis	Autologous chondrocyte intra-articular implantation	No	I	6	NCT01500811	Data analysis	6
11.	Hip osteoarthritis	Bone marrow-derived mesenchymal stem cell injection	No	I	6	NCT01499056	Data analysis	6
12.	Ischemic ulcer	Repeated bone marrow-derived mononuclear cells transplantation	No	I/II	14	NCT01480414	Recruiting	12
13.	Ankle joint osteoarthritis	Autologous mesenchymal stem cell transplantation	No	I	6	NCT01436058	Data analysis	6
14.	Knee joint osteoarthritis	Intra-articular injection of mesenchymal stem cells	Yes	II	40	NCT01504464	Recruiting	38
15.	Leg length inequality	Autologous transplantation of bone marrow-derived mesenchymal stem cells with retinal pigmented epithelium	No	I	6	NCT01210950	Data analysis	6
16.	Osteoarthritis	Autologous mesenchymal stem cell transplantation	No	I	6	NCT01207661	Completed	6
17.	Osteoarthritis	Autologous mesenchymal stem cell transplantation	No	I	5	NCT00550524	Completed	5
18.	Cerebral palsy	Intrathecal bone marrow-derived CD133 cells transplantation	No	I	8	NCT01404663	Recruiting	7
19.	Nonunion fractures	Autologous transplantation of bone marrow-derived mesenchymal stem cells	No	I	6	NCT01206179	Data analysis	6
20.	Bone cyst	Autologous transplantation of bone marrow-derived mesenchymal stem cells	No	I	6	NCT01207193	Data analysis	6
21.	Liver cirrhosis	1. Portal vein injection of bone marrow-derived AC133+ cells 2. Portal vein injection of bone marrow-derived MNC	Yes	I/II	30	NCT01120925	Recruiting	20
22.	Liver failure cirrhosis	Portal vein injection of progenitor of hepatocytes derived from mesenchymal stem cells	No	I/II	30	NCT00420134	Completed	30
23.	Liver failure cirrhosis	Autologous mesenchymal stem cells	No	II/III	30	NCT00420134	Completed	30
24.	Liver failure cirrhosis	Autologous mesenchymal stem cells	Yes	II	36	NCT00476060	Recruiting	30
25.	Vitiligo	Autologous transplantation of non-cultured melanocytes	No	II/III	100	NCT00631865	Data analysis	100
26.	Full-thickness articular cartilage defects	Autologous transplantation of bone marrow-derived mesenchymal stem cells	No	I	6	NCT00850187	Completed	6
27.	Homozygous familial hypercholesterolemia	Allogeneic transplantation of transdifferentiated or mesenchymal stem cells	No	I	1	NCT00515307	Completed	1
28.	Malignant infantile osteopetrosis	Hematopoietic stem cell transplantation	No	II/III	10	NCT01087398	Recruiting
29.	Ocular lesions of Behcet's disease	Autologous bone marrow-derived mesenchymal stem cells	No	I	6	NCT00550498	Completed	3
30.	Crohn's disease	Intravenous injection of mesenchymal stem cells	No	I	5	—	Submitted to ethics committee
31.	Amyotrophic lateral sclerosis	Intrathecal injection of autologous bone marrow-derived mesenchymal stem cells	No	I	10	—	Submitted to ethics committee
32.	Amyotrophic lateral sclerosis	Intravenous injection of autologous bone marrow-derived mesenchymal stem cells	No	I	10	—	Submitted to ethics committee
33.	Amyotrophic lateral sclerosis	Intraventricular injection of autologous bone marrow-derived mesenchymal stem cells	No	I	10	—	Submitted to ethics committee
34.	Cardiomyopathy	Autologous cardiac stem cells	No	I	20	—	Submitted to ethics committee
35.	Avascular necrosis of the scaphoid	Autologous bone marrow-derived mesenchymal stem cells	Yes	I/II	20	—	Submitted to ethics committee

MNC, mononuclear cells.

History

The history of stem cell research and therapy in Iran dates back to 1991, when the Hematology-Oncology and Stem Cell Transplantation Research Center affiliated to Tehran University of Medical Sciences, founded by Dr. Ardeshir Ghavamzadeh, began its therapeutic and research activities in the area of transplantation routines, including allogenic, autologous, and synergenic bone marrow transplantation (BMT) for various diseases, including cancers, nervous system disorders, and blood illnesses.

In 1999, a new chapter was turned when stem cell research in Iran began following the inauguration of the Stem Cell Center of the Royan Institute, an already prominent reproductive biomedicine clinic and research center that served as a nonprofit organization. Since then, the Royan Institute has acted as a major player for SCRT advancement. Its founder, the late Dr. Saeid Kazemi-Ashtiani, a technological entrepreneur, exhibited remarkable social entrepreneurship and advocacy for this field and helped, to a great extent, in informing the top religious and political authorities about the significance of the cutting-edge science of stem cells for the country. The Kazemi Award for Research Excellence in Bio-Medicine was established in 2010 to pay tribute to his legacy. This annual award honors scientists who dedicate their lives toward making advancements in relieving the pain of humans and in making extraordinary progress in the science of biomedicine. Till date, Professor Rudolf Jaenisch from MIT, United States (2010), and Professor Hans R. Schöler from Max Planck, Germany (2011), have received this award.

Stem Cell Research, Cloning, and Clinical Studies

A turning point for stem cell research in Iran occurred in 2004, when the first human embryonic stem cell (ESC) line, Royan H1, was produced in the Royan Institute [3].

With the first generation of the human ESC line, Iran ranked tenth among the countries with human ESC research and technology. In 2008, the first human-induced pluripotent stem cell (iPSCs) was established. This achievement, although not a breakthrough on its own, enabled the Iranian scientists to pursue many avenues of research into the methods of developing, expanding, and freezing pluripotent stem cells and generating therapeutic cells from these cells such as neural, pancreatic, heart, and liver cells. Currently, the Royan Stem Cell Bank, the first in the country, preserves 108 mouse ESC lines, 12 human ESC lines, and 106 human-iPSC lines from healthy and diseased individuals.

In 2006, the Royan Institute succeeded in generating Royana, the first cloned sheep in Iran and in the Middle East. Subsequently, Hanna, the fifth goat cloned in the world, and 2 other transgenic goats carrying human factor IX in their milk by transgenic somatic cell nuclear transfer were generated [4].

Recently, the research has focused on developing new ways in nanobiotechnology and tissue-engineering, transdifferentiation, and small-molecule modulation in regenerative medicine. In parallel with progress made in medical and stem cell research in Iran, required infrastructures for cell therapy such as Good Manufacturing Practice facilities were developed in the last few years to ensure the manufacture of sterile, potent, and uncontaminated products for clinical trials.

The first clinical trials, using autologous bone marrow-derived stem cell, was conducted in patients with myocardial infarction. This was followed by cell therapy trials in the kidney, vascular, liver, skin, and eye; bone diseases; and neurological disorders as well as progressively proceeding to the final phases of safety and efficacy.

As time passes, the number and complexities of clinical trials increase. Now, there are 31 registered clinical trials by the Royan Institute, Tehran University of Medical Science, Shiraz University, and Tarbiat Modares University. The strategy of intervention consists of autologous mesenchymal and hematopoietic stem cell injections for the patients with liver, bone, cartilage, lower limb ischemia, brain, and nerve system disorders (Table 1).

The stem cell transplantation has the advantage of benefitting from 4 cord blood banks hosted by the Royan Institute, the Royan Stem Cell Technology Company, the Iranian Blood Transfusion Center (IBTC), and the Hematology and Oncology in BMT.

Companies and Institutes

The SCRT was first focused on the R&D centers and universities of Tehran, Tarbait Modares, the Royan Institute, Tehran University, and the Pasteur Institute in Tehran. Then, it spread to major provincial universities of Isfahan, Mashhad, and Shiraz. Nowadays, the universities located in remote geographical places in the capital such as Uromieh, Kurdistan, Kerman, and Yazd are among the knowledge producers, attesting to the geographical diffusion of knowledge to a remarkable extent.

Diversification of the knowledge producers has also led to the emergence of a niche knowledge-intensive market in which some companies provide different products, cell lines, lab reagents, and other services for knowledge producers and cell therapy patients. Apart from incumbent institutes such as the Hematology and Oncology in BMT in Shariati Hospital and the Royan Institute, some new and energetic companies, mostly start-ups entities, which are established by the faculty members of publicly owned universities and nonprofit organizations venture into the market. Among them are the Stem Cell Technology Company, which focuses on tissue engineering, surgical techniques, and the Royan Stem Cell Technology Company, a spin-off of the Royan Institute, The Sina Cell is another company that offers clinical services and employs matrix-induced chondrocyte implantation for the patients with a defective knee. With direct support of the Iranian Council of SCRT (ICSCRT), the Iranian Stem Cell Donor Registry was established in 2009 in the Iranian Blood Transfusion Organization (IBTO). It is a national center for recruiting, training, registering, and maintaining hematopoietic stem cells from voluntary donors [4].

Religious Legitimization

Saving a life is given paramount importance in Islam, as the following verse from the Quran stresses: “And if any one sustains life, it would be as if he sustained the life of whole humankind” (Quran, 5–32). There are also Islamic injunctions that specifically promote education and research in the fields that alleviate the pains of humankind. fatwas (religious, legal edict), permitting medical research in Iran, emanate from such scientific friendly interpretations. The fatwa by Ayatollah Khamenei, the Supreme Leader, in 2002 on the admissibility of “the destruction of the left-over embryos from in-vitro fertilization cycle in order to collect stem cells for research” was received as a blessing for the stem cell community in Iran, because the fatwa not only permits human ESC research, but also, coupled with Ayatollah's other statements, refers to it as a religious obligation for researchers in the Shiite community.

This flexibility of the religious institutions vis-à-vis human ESC stems from the perception that the Shi'a, the dominant sect of Islam in Iran, allows adjustments to accommodate changes within Islamic beliefs, while the Sunni doctrine follows more strict traditions. This automatically allows the Iranian scientific community, in which the Shi'a prevails, to have a comparative advantage over those in the neighboring countries, as they are permitted to work with human ESC.

Governance, Oversight, and Coordination

Since the outset, SCRT has received the recognition of policy makers and R&D planners as being one of the national priorities in high technologies, inspired by the overarching policy document of “20-Year Vision.” Later, while some provisions of the national development plans were interpreted differently over time in the State's documents and white papers, the emphasis on the national scientific and technological progress remained intact, exhibiting a virtual consensus within the spectrum of the Iranian political elites on the significance of the role of science and technology, including stem cell research, in the nation's development.

The consistent support of the successive political establishments paved the way for the establishment of the ICSCRT in 2009 under the auspices of the Vice President for Science and Technology (VPST), mandated to draft the national stem cell research policy document, and set research priorities and appropriate financial resources.

The first achievement of the ICSCRT was the key policy document titled “Iranian Stem Cell Research and therapy Initiative (ISCRTI),” which was released in 2010. Pending the final approval by the Cabinet of Ministers in the next few months, the Initiative will shed light on the road of the SCRT in terms of strategies and targets.

Some of these goals have been already defined in other policy documents, and a few steps have been taken toward their achievement. The Iranian Stem Cell Donor Registry/Iranian National Cord Blood Bank was established in 2011 and is currently gathering blood samples. The Legal and Scientific Committees and working groups have been established with the aim of drafting specific laws and regulations and standard procedures that are expected to be ready by the year 2013, and, finally, there is an ongoing institution building process for financial endowments to be allocated to the manufacturers of lab instruments and reagents.

With regard to the legality and regularity aspects, the Ministry of Health and Medical Education is in charge of supervising stem cell clinical trials and therapy in Iran. This Ministry adopted 2 sets of procedures to monitor the whole process: The first procedure covers the monitoring process from the in vitro process to the end of the third stage of clinical trials, and the second procedure applies to the process that starts from the submission of the drug master file to the authorities and finishes by presenting the licensed product to the market (Fig. 1).

FIG. 1.

The process of monitoring and approval of stem cell research and therapy in Iran. Research pipeline from lab studies to distribution and the relevant monitoring authorities.

The first set of procedures is based on the decentralized decisions of the in-house ethics committees that is set up at all R&D centers and in universities in compliance with the directives of the Ministry of Health and Medical Education. The members of these committees are selected from the internal scientific staff and invited religious consultants. They fulfill their duties by relying on unified guidelines that are drafted and approved under the general title, “Specific National Ethical Guidelines for Biomedical Research.” The separated parts of the guidelines provide working models on clinical trials, genetic research, gamete and embryo research, and research on animals. Although there is no specific framework for stem cell research, it does not prevent the related committees from inferring and extracting their frameworks from the letter and spirit of the guidelines.

These guidelines were compiled in 2005 by a task force, including experts in religion, law, ethics, medicine, and related fields of science, initiated by the Ministry of Health and Medical Education. They have been developed to put into effect ethical codes in research and to protect different stakeholders' rights, including patient research participants, vulnerable groups, and animals. They are in accordance with the international frameworks such as the one by the World Medical Association of Helsinki and its following amendments. Similar acts and guidelines of other countries were also used as references for compiling the drafts.

Within the specific section on clinical trials in the drafts, some topics include the following: participants' rights, informed consent, ethical review committee's responsibilities, and compensation. They set restrictions on the trials, involving vulnerable groups, such as patients with mental disorders, children, pregnant women, neonates, and prisoners. Moreover, stem cell research and cloning for therapeutic purposes is permissible only during the first 2 weeks or 14 days of fetus development with all things duly considered and all possible precautions taken. Some of the principles recommended in the ethical guidelines for gamete and embryo research include (1) respect for human dignity and human rights; (2) voluntary and informed participation in research, which will not affect a patient's treatment; (3) respect for privacy and confidentiality; (4) equitable distribution of benefits and harms, especially in research, including clinical treatment; (5) prohibition of the production of hybrids using humans, animals, and human eugenics; (6) prohibition of the production of human embryos for research purposes; (7) use of only surplus in vitro fertilization (IVF) embryos, below 14 days, for research, which includes the destruction of embryos; (8) responsible people for the embryo being the donor, her partner, and recipients; and (9) all information regarding research and clinical care of the embryo being made available to responsible people [5].

The guidelines were communicated to universities and research centers after their adoption by the Policy-Making Council of the Ministry of Health and Medical Education, and several committee workshops and educational sessions are held by universities and research centers, through which the members become familiar with the guidelines [6,7].

With to the second procedure, it is not as clear as the first one; categorically, stem-cell-based products are still subject to the laws and regulations governing conventional drugs and medical products of the Food and Drug Organization (FDO), as there is no enacted law or well-defined regulatory framework that specifically deals with the practice of stem cell therapy. However, considering the challenges existing in the process of assessing the expected therapeutic benefits versus the potential risks in this field, the FDO has not yet reached the point of issuing any license or authorization for stem cell therapy in Iran.

International Cooperation

Stem cell research continues to grow in Iran. The number of participants at the Royan International Annual Congress on Stem Cell Biology and Technology has grown from 100 in the first congress in 2005 to more than 800 in the 7th congress in 2011. The Royan Annual International summer school on stem cells and developmental biology attracts hundreds of students, teachers, and young researchers every year. These congresses and summer schools introduce highly motivated young Iranian students and scientists to international research institutions. They provide not only the possibility of direct exchange of technical and intellectual information and allow scientific meetings, but are also forums for the exchange of information and personal ideas [8 –10]. Despite the difficulties arising from the international sanctions, the Iranian scientific community continues to enjoy a productive interrelationship with its foreign peers. The statistics provided by Web of Knowledge attests that out of 834 papers published by the Iranians, 56 papers have been coauthored by their American, 26 with British, 22 with Australian, and 20 with their German colleagues. Iranian scientists also actively participate in the international research projects such as the International Stem Cell Initiative (ISCI) [11], Asia Oceania Human Proteome Organization (AOHUPO), and Human ESC Membrane Proteome Initiative.

Troubles in Traversing the Valley of Death

As the Iranian stem cell scientific community gradually pushes ahead to focus on the final stages of research process and clinical trials, some problems loom ahead. The capital market is not ready to make sufficient investment in the form of seed money and venture capital. The public sector cannot handle the entire financial requirement, and the private sector does not show willingness to join in. Clinical trials are major undertakings, and the lack of required logistics has caused attritions and failure.

With regard to laws and regulations, as shown earlier, Iran currently provides a regulatory environment that is conducive to performing early-phase safety, proof of principle, and final testing clinical trials. The proposal for a clinical trial is submitted directly to the registered in-house ethics committees for approval without directly engaging the Ministry of Health and Medical Education regulatory committees. Nevertheless, clinical cell therapy needs the approval of the Ministry, which acts as the governing body, and the fact that it has not yet authorized any case of cell therapy adversely affects the research environment and creates ambiguity and confusion about the legal status of the current cellular transplantation in Iran.

As a result, there is a risk that Iran's stem cell scientific community slows down its activities in the advanced phases II and III of clinical trials and instead of trying to traverse the valley of death, shifts gears and goes backward to basic research.

Conclusions

Without a doubt, Iran's strength in the field of SCRT emanates in part from its favorable religious institutions and public support. The dynamic human capital, who are mostly in their thirties and forties, establish and run research organizations and universities and lead research teams, thus serving as another positive factor. Thanks to these factors, the SCRT has had a strong start in Iran, pioneering in the Islamic world.

To keep this momentum, however, the young stem cell community faces new challenges, stemming from the lack of sufficient finance and comprehensive laws and regulations. Obviously, there is a missing link in the system that prevents favorable factors such as consistent public-political support and religious blessing from being automatically translated into financial and legal instruments.

In the scientific community, many believe that that missing link is anticipatory/participatory governance through which a common perspective and agreed path toward it could emerge. As mentioned earlier, the long-awaited key policy document, “Iran Stem Cell Initiative,” is already drafted and expected to be approved in the next few months. Being just a step forward, this document is expected to ease the provision of financial means and legal structure and pave the way to form anticipatory/participatory governance and foresight bodies that will ultimately direct the stem cell research in Iran to a bright future.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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