REVIEWThe First Clinical Trial in Tohoku University Hospital
after The Great East Japan Earthquake:
The Heroic Efforts of My Friend, Professor Masashi Aoki
Hideyuki Okano

Department of Physiology, School of Medicine, Keio University, Tokyo, Japan(Received for publication on November 2, 2011)(Revised for publication on November 28, 2011)(Accepted for publication on December 16, 2011)

The Great East Japan Earthquake of 2011 seriously jeopardized our collaborative research with Professor Masashi Aoki (Tohoku University School of Medicine) on the development of new therapies for amyotrophic lateral sclerosis (ALS) using hepatocyte growth factor. After the earthquake struck, Professor
Aoki made a tremendous contribution to saving patients’ lives and to recovering from the disastrous
situation. Thanks to his strong leadership and support from many reliable colleagues, we could finally
start new clinical trials for ALS patients. In this article, I wish to introduce Professor Aoki’s heroic efforts. (Keio J Med 61 (1) : 3–9, March 2012)

Keywords: amyotrophic lateral sclerosis, hepatocyte growth factor, clinical trial, earthquake, supplies

Introduction

continuing his efforts to recover from the disaster. Although the expression may sound hackneyed, Prof. Aoki’s heroic work during these past 6 months has moved
many people’s hearts. I decided that I should write downthese details before my memory begins to fade, and I am
glad that I was asked to contribute to this special issueof the Keio Journal of Medicine on the Great East Japan
Earthquake.
Study on the Treatment of ALS and Regeneration of
the Injured Spinal Cord Induced by Hepatocyte Growth
Factor
Before embarking on topics related to the earthquake, I
would first like to introduce the study of neural regeneration that Prof. Aoki and I are engaged in. Our researchgroup at Keio University (including the Departments ofPhysiology and Orthopedic Surgery) has been conducting a collaborative study with Dr. Aoki’s group at Tohoku
University for more than 5 years with the aim of developing a treatment for ALS and achieving regeneration of
the injured spinal cord using hepatocyte growth factor(HGF). HGF is a physiologically active substance discov-

The Great East Japan Earthquake struck on March 11,
2011, and registered a magnitude (Mw) of 9.0, the strongest in Japan in recorded history. The giant tsunami that
followed the earthquake affected the Pacific coast of the
Tohoku and Kanto regions and brought a disaster of truly
unprecedented scale, with the loss of more than 15,000
lives. The damage to nuclear power plants caused by thetsunami induced extreme confusion in Japan, and its influence still continues to this day.
However, people living in the damaged areas are moving forward strongly and positively, attempting to restore
normalcy and to emerge from the heavy blow they havebeen dealt. This is also the case for medical researchers
and those engaged in medical care in the affected areas.
The achievement of Prof. Masashi Aoki of the Department of Neurology, Tohoku University School of Medicine, who has long been my collaborator, is truly remarkable: he has started the world’s first clinical trial on thetreatment of amyotrophic lateral sclerosis (ALS) while

Reprint requests to: Hideyuki Okano, MD, Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku,
Tokyo 160-8582, Japan, E-mail: hidokano@a2.keio.jp
Copyright © 2012 by The Keio Journal of Medicine
3

4

Okano H: Tohoku–Keio Collaboration before and after March 11, 2011ered by Nakamura, Ichihara and others in Japan in 1984,1
and its primary sequence was elucidated by gene cloning
in 1989.2 This physiologically active protein has a varietyof biological activities, including promotion of cell proliferation and migration, three-dimensional morphogenesis,
inhibition of cell death and promotion of angiogenesis,and hence it facilitates the protection, regeneration andrepair of various tissues and organs. A research groupfrom Osaka University and our own group at Keio University have both confirmed the therapeutic effects of
HGF gene transfer on ALS and spinal cord injury (SCI)
3, 4 and we initiated a preclinical study of recombinanthuman HGF protein provided by Kringle Pharma, Inc.
Dr. Aoki (then a lecturer) demonstrated the efficacy of recombinant human HGF (rhHGF) protein in rat models of
ALS (SOD1 G93A transgenic rat) 5, 6 that he himself had
developed and a rat SCI model (unpublished results). We
then succeeded in inducing dramatic functional recovery by administration of rhHGF in a model of SCI in thecommon marmoset, a small New World monkey.7 With
such an effective collaborative system in place, basic andpreclinical studies aimed at neural regeneration began toprogress relatively smoothly. At the same time, research
was gaining momentum to realize Japanese-originatedregenerative agents to treat SCI, cerebral infarction and
ALS, with the acceleration of existing basic studies on
central nervous system (CNS) regeneration using HGF,
anti-IL-6 receptor antibody and stem cell transplantation 8,9, 10. In 2008, a collaborative research team mainlycomprising our group at Keio University and a groupformed by Dr. Aoki made an application to the regenerative medicine field of the “Super Special Consortia for
Supporting the Development of Cutting-edge Medical
Care,” an initiative of the Cabinet Office, under the “Cutting-edge Medical Care Development Project for Central
Nervous System Regenerative Medicine − Mainly Spinal
Cord Injury,” which was adopted without problems. For
this research project, an industry–university collaborative team was established, consisting of members from
Osaka University; Kyoto University; the Central Institutefor Experimental Animals; Kringle Pharma, Inc.; Chugai
Pharmaceutical Co., Ltd.; Dainippon Sumitomo PharmaCo., Ltd.; Seikagaku Corporation; and San Bio, Inc. (andalso currently Teijin Ltd.), in addition to the core members from Keio University (Departments of Orthopaedic
Surgery, Neurosurgery, Neurology and Physiology) and
Tohoku University, and the team is engaged in the realization of CNS regenerative medicine.
Since the approval of the research proposal, a collaborative team consisting of the spinal cord regenerationgroup from the Departments of Orthopaedic Surgery andPhysiology, Keio University, and Dr. Aoki’s group has
been attempting to develop treatment for ALS and spinal cord injury with HGF “from bench to bedside” andbegan to tackle the difficult problem of how to overcome
the potential dangers to which the initiation and execu-

tion of the clinical trial could expose patients. The trial
was to be conducted not by a giant pharmaceutical company, but by a venture company, Kringle Pharma, Inc.,and as is the case for other bio-venture companies, thiscompany also has limited working capital, necessitating
considerable fund raising to actually conduct the trial.
While applying for public funds, asking venture capitalists for funding and approaching major pharmaceuticaland bioscience companies, we took the necessary steps
needed before actually conducting the trial, including
safety tests (toxicity test of intrathecal rhHGF and pharmacokinetics tests) in macaque monkeys, establishmentof the clinical trial system in Tohoku University and thefine tuning of clinical protocols. By utilizing the systemof the “Super Special Consortia for Supporting the Development of Cutting-edge Medical Care,” we obtained theinformation and know-how on what steps needed to betaken before the initiation of clinical trials and proceededto efficiently prepare for the trial. Early in 2011, we held apretrial consultation with the Pharmaceuticals and Medical Devices Agency (PMDA). In addition, during thisperiod, on February 1, 2011, Dr. Aoki became a professor in the Department of Neurology, Tohoku University,
succeeding Prof. Yasuo Itoyama, and this boosted ourmorale towards preparation for the trial. Furthermore, wecame out with a relatively good feeling from the pretrial
consultation with the PMDA and estimated that we could
start the trial in April 2011 if everything went smoothly.
Then, NHK (a broadcast station supported by the Japanese government) sought to interview us about these basic and preclinical studies and preparations for the clinical trial, and NHK news reported on the “Developmentof a new treatment for ALS patients in Tohoku University Hospital” on March 1, 2011. This generated a great
response from patients, and Prof. Aoki received manyinquiries. We felt energized and decided to make every
effort to conduct a successful clinical trial for ALS using
HGF and to start a clinical trial for spinal cord injury at
Keio University Hospital 1 year later. In addition to thestudy of HGF, we started another collaborative research
project with Prof. Aoki at the beginning of 2011 in which
we attempted to establish induced pluripotent stem (iPS)
cells from patients with rare familial ALS to elucidate
the pathogenetic mechanism of the disease, and had successfully established multiple iPS cell lines by the beginning of March. Everything was going well and nobody
expected that such a huge tragedy was about to occur.
March 11, 2011
A great earthquake struck east Japan at 2:46 pm on
March 11, 2011. At the time of the earthquake, I was in
Tsukuba City for a research meeting and a lecture. Because of the paralyzed communication system, I could
not easily contact my family or laboratory, and becauseof the suspension of train services, I hurried home in a

Keio J Med 2012; 61 (1): 3–9

taxi feeling rather uneasy. The highways were completely
blocked and I took Route 6 to Tokyo. Route 6 was heavily
congested and the taxi could move only very slowly. I was
relieved to learn while in the taxi that my family was safe,
but I also understood that the iPS cell culture room andflow cytometry facility on the 9th floor of our laboratory
might have received a devastating blow. The taxi could
not reach Tokyo even by midnight. From the radio in thetaxi, I learnt that the earthquake had struck just offshore
from the Tohoku district [with a magnitude (Mw) of 9.0,
it was the strongest in Japan in recorded history] and thata giant tsunami had struck the coast of Tohoku district
just a few minutes after the earthquake. Are my friends in
the Tohoku district, including Prof. Aoki, safe? What will
happen to the clinical trial for ALS that we had preparedso hard for? Can this country overcome and recover fromthe earthquake? I had various uneasy thoughts as I finallyreached home at dawn the following day.
March 12–14, 2011
The day after the earthquake, I went to the university
and found that the School of Medicine and the hospital
was having a really hard time coming to terms with theeffects of the earthquake of the previous afternoon. As
for my laboratory, the damage to the laboratory rooms on
the fifth floor was very slight, but I could not bear to see
the damage of the laboratory rooms on the ninth floor:
CO2 incubators had fallen down, and disease-specific iPS
cells cultured in the incubators, the frozen stock of which
had not yet been prepared, were completely dead. We lost
all the cells that were going to be used the following week
for comprehensive protein expression analyses after a
few months in culture and also the iPS cells establishedfrom patients with rare familial ALS in the collaborative
research with Prof. Aoki. I could barely bring myself toclear away the scattered pieces of broken glass and experimental equipment. Many precision instruments had
been damaged, and I was stunned by such an unexpected
setback. I wondered how soon we could restart the experiments. However, young staff members in the laboratory courageously worked hard to clean up the mess, andI decided to restart as soon as possible. With the scale ofthe damage being significant even in Tokyo, I began to
imagine how disastrous a situation my friends would befacing in Tohoku, so much closer to the epicenter of theearthquake and the consequent tsunami. I immediately
sent the following e-mail to three Professors at Tohoku
University: Prof. Masashi Aoki, Prof. Shin-ichi Izumi,
my contemporary from Keio University, and Prof. Noriko
Osumi, who had long been a collaborator:“Dear Prof. Aoki, Prof. Osumi and Prof. Izumi,
I am grieved from the heart at the sight of the terrible
events in Tohoku in the aftermath of the Tohoku-Pacific
Ocean Earthquake.
Are you doing okay?

5

Please let me know if I can help you in any way.
If you are too busy dealing with the events at hand,
don’t bother to reply to this mail.
Hideyuki Okano”
Despite the terrible circumstances, Prof. Osumi andProf. Izumi soon replied to my e-mail saying that they
were fine. However, I did not receive any news for a longtime from Prof. Aoki, making me feel more and moreanxious about him.
At last, on March 14, Prof. Aoki sent me the following
mail:“Dear Prof. Okano,Thank you for your e-mail.
There was serious damage in Miyagi Prefecture, but
fortunately, Tohoku University Hospital and the medical
office did not suffer much damage.
However, we cannot yet enter the research building
where the medical office is located. My family is alsofine, thank you.
All members of the medical staff are doing their best toadminister medical care under emergency conditions, butthere are serious shortages of medical supplies and food.
In particular, the medical system in coastal areas isdevastated, and physicians and nurses in the front line areshowing signs of fatigue.
We are waiting for medical (drugs) and other supplies
from the rest of the country. Thank you in advance foryour help.
Department of Neurology, Tohoku University
Masashi Aoki”
I thought that I had to help him at all costs! Therefore,
I made every effort to collect supplies for Tohoku University. However, the reality was harsh in that electricity
shortages became serious not only in the damaged areas,
but also in the Tokyo Metropolitan Area, due to the shutdown of nuclear power plants caused by the earthquake
and tsunami and problems in the power transmission system.
March 15–31, 2011
I maintained close contact with Dr. Hirofumi Kurokawa
of Tohoku University Graduate School of Medicine, who
had been in the Tokyo Office of Tohoku University since
before the earthquake, and we analyzed what supplies
were needed. However, because of the marked shortageof goods also in Tokyo, I could not collect enough supplies alone. Therefore, I asked members of the professoriate in Keio University School of Medicine for help, andeveryone willingly provided food and daily necessities.
I used a vacant room on the second floor of the Center
for Integrated Medical Research in the Shinanomachi
Campus as a stock room for supplies. The problem was
how to transport the supplies to Sendai, where Tohoku
University Hospital is located. Needless to say, parcel
delivery services to Tohoku had not at that point been

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Okano H: Tohoku–Keio Collaboration before and after March 11, 2011

Fig. 1 Supplies of foods and convenience goods transported from Keio to Tohoku.
(A) Supplies are about to leave Keio University on March 25, 2011. Mr. Hajime Kanbayashi kindly accepted our request to deliver
supplies from Shinanomachi Campus of Keio University to Tohoku University in one of his company’s trucks under very difficult
circumstances. (B) Supplies from Keio arrived at Tohoku University on March 25, 2011. Photograph provided by Dr. Hirofumi Kurokawa. (C) The disastrous situation of Minamisanriku on April 3, 2011. Photograph provided by Dr. Hirofumi Kurokawa. (D) Supplies
from Keio arrived at the temporary town hall in Minamisanriku on April 3, 2011. Photograph provided by Dr. Hirofumi Kurokawa.

restored, the Tohoku Shinkansen was paralyzed and only
vehicles with a special mission and a pass could run on
the highways to Tohoku. When searching for a solution,
I received a wonderful offer to transport the supplies to
Sendai from a transport company whose board of directors includes Heizo Takenaka, Director, Global Security
Research Institute, Keio University. Finally, on March 25,
we sent the first batch of supplies to Tohoku University,and the supplies arrived the same day (Fig. 1). I received
a polite email message of thanks from Prof. Masayuki
Yamamoto, Dean of the School of Medicine, Tohoku University, and from Dr. Hirofumi Kurokawa, and I felt atiny sense of accomplishment. On April 3, supplies from
Keio were further delivered from Tohoku University to
Minamisanriku, where the most devastating tsunami occurred, by Dr. Kurokawa. Thereafter, parcel delivery services were restored, and a total of three deliveries weremade from Keio University to Tohoku University.
During this period, however, Prof. Aoki, Tohoku University Hospital and other medical facilities in the Tohoku district were in a terrible crisis because of electricity shortages. It was a critical situation, particularly for
ALS patients requiring artificial respiration and for patients receiving hemodialysis. On March 15, Prof. Aoki

Keio J Med 2012; 61 (1): 3–9

7

Fig. 2 Supplies of foods and convenience goods were sent to Prof. Aoki from the Japan ALS Association.
See the text for details. Photographs provided by Prof. Masashi Aoki.

sent the following SOS e-mail to professors in the departments of neurology and to his acquaintances in schoolsof medicine and hospitals throughout the whole country.
“Here in Tohoku, core medical facilities such as Kesennuma City Hospital and Ishinomaki Red Cross Hospital,
which are disaster base hospitals in the coastal area, areon the brink of collapse, and supplies of medical equipment, milk powder and food as well as physicians havebeen sent from Tohoku University, but these are notenough at all. It was decided to shut down all wards of the
Sendai Koseinenkin Hospital (400 beds) in the city, andpatients are being transported to Tohoku University one
after another. Under such circumstances, our hospital has
no reserve power and we are becoming fatigued.
Today, two patients on ventilators, along with two staff
members, were transported from our department to Yamagata University by helicopter (a physician has to accompany patients during transportation, which places aheavy burden on us).
It would be very helpful if you could send us physician/nurse teams.
Department of Neurology, Tohoku University
Masashi Aoki”
I thought “Why can’t they use Self-Defense Force aircraft for medical use?” and I called a friend of mine who
was an executive at the Ministry of Defense and also a professor at the National Defense Medical College to request
help in the transportation of patients. He came forward
and said, “I would like to offer help in transporting patients; however, the Prime Minister is in command of the

Self-Defense Forces, and we cannot act alone.” Throughthe good offices of the staff of the Ministry of Health,Labour and Welfare and the Cabinet Office, a route tocontact the prime minister’s official residence was finallyestablished. Thereafter, Prof. Aoki directly called thePrime Minister’s official residence on several occasions
to request dispatch of the Self-Defense Forces. Every day,Prof. Aoki exchanged information closely with professors
at the departments of neurology and physicians of his acquaintance throughout the entire country; with officialsof the Ministry of Health, Labour and Welfare; and with
the Ministry of Defense and the Air Self-Defense Force.
As a result, it was quickly determined where and how
patients requiring artificial respiration were to be transported. This wonderful teamwork bore fruit, and many
patients with ALS and those in need of maintenance hemodialysis were transported uneventfully by the end of
March.
I heard that approximately 100 patients undergoing
maintenance hemodialysis at the Tohoku University Hospital and other facilities in Sendai were transported to
Hokkaido by the Self-Defense Forces on March 22 and23. I had to take my hat off to Prof. Aoki; as a new professor, he showed wonderful leadership skills.
April, 2011
With such extensive efforts being made by Prof. Aoki,
naturally, patient groups did not leave him alone. At the
beginning of April, the Japan ALS Association sent sup-8

Okano H: Tohoku–Keio Collaboration before and after March 11, 2011

Fig. 3 A press conference about approval for the initiation of the HGF clinical trial for ALS was heldon July 8, 2012.
From the left: Prof. Masashi Aoki, the author, Mr. Kunio Iwatani (the President of Kringle Pharma Inc.).
Photographs provided by Dr. Fuji Nagami of Tohoku University.

plies to Prof. Aoki (Fig. 2). I was moved to tears by amessage from Prof. Aoki saying “We are determined toprotect medical and health services for people in this areawith all our heart and soul. Thank you in advance foryour help.”
By April, most patients had been transported to safety,
and Prof. Aoki began to send me e-mails about our research. Signs suggesting that preparations for the HGF
trial could be resumed soon began to appear. Prof. Aoki
also began to send out the strong message, “I would liketo make this trial the core of the restoration of Tohoku
University.” I thought “All right, then, I also have to do
my best!” We decided to make every effort to overcome
the delay in our research and worked hard to resume research under almost normal conditions at the beginningof April, in the very laboratory rooms damaged by theearthquake.
June 2011 Onward
On June 3, Kringle Pharma, Inc., submitted notificationof a phase I trial plan of HGF treatment for ALS to thePMDA, and finally, at the beginning of July, the initiationof a phase I clinical trial was approved by the PMDA. On

July 8, in the Tokyo Office of Tohoku University, where
the control center for the transportation of supplies soonafter the earthquake was located, Prof. Aoki, the staff ofKringle Pharma, Inc., and I held a press conference about
the receipt of approval for the initiation of the HGF clinical trial (Fig. 3).
The purpose of this phase I clinical trial is to confirm
the safety and pharmacokinetics of single and multiple
dosing of recombinant HGF protein in ALS patients, andthe trial is planned to be conducted at Tohoku University
Hospital. Approval from the institutional review board of
Tohoku University Hospital was obtained soon after obtaining approval from the PMDA. Hereafter, we propose
to select patients fulfilling the trial entry criteria and toactually initiate the phase I trial. I told Prof. Aoki, “Weovercame the earthquake, and finally, we can start.” Heanswered, modestly as usual, “Yes, but the real fight begins only now.”
It is almost certain that we will face some difficulties
while carrying out the trial, as we did in recovering fromthe earthquake. However, I am sure that our wonderful
teams can overcome such difficulties.

Keio J Med 2012; 61 (1): 3–9

9Concluding Remarks

References

Focusing on the collaborative research with Prof. Aoki
at Tohoku University, I have described the effects of theearthquake and our recovery from it. We enthusiasticallyembrace the challenge of this research precisely because
neural regeneration as a medical treatment is a difficult
task that no one has yet successfully achieved. Successwill come with the integration of basic and clinical medical systems beyond the realm of universities, a smoothindustry–university cooperation system and ample publicfunds, which are available only in wealthy societies. Even
under normal circumstances, these are not easy tasks.
Naturally, the heavy blow of the earthquake was a great
setback, but on the other hand, it reiterated our faith in thecollaborative process and underlined our attitude of “notbowing to any hardship.” In addition, it was impressivethat a person who had just been appointed professor wasable to display such exemplary leadership. I have learned
much from Prof. Aoki, and I am grateful for the opportunity to tell this story of triumph over adversity.

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Acknowledgments
I wish to thank all my colleagues, especially Professor
Masashi Aoki, for the motivation to write this article, andDr. Hirofumi Kurokawa for generous supplies of photographs taken in Tohoku. The collaborative work on HGF
was carried out by the Department of Physiology and theDepartment of Orthopedic Surgery of Keio University
and the Department of Neurology of Tohoku University
and was supported by Grants-in-aid for Scientific Research from JSPS and the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT);the Project for Realization of Regenerative Medicine andSupport for the Core Institutes for iPS Cell Research from
MEXT; a Grant-in-aid for the Global COE program from
MEXT to Keio University; Research on Measures for Intractable Diseases from the Japanese Ministry of Health,
Labor and Welfare of Japan; and by “Super Special Consortia for Supporting the Development of Cutting-edge
Medical Care.”