Ai Huisheng Microtransplantation

In 2011， a new treatment for leukemia was published on Blood， which is the most authoritative publication in the field of hematology globally and is published by the American Society of Hematology. Compared to traditional transplantation， this breakthrough new method was called microtransplantation. Ai Huisheng， head of the Department of Hematology and Transplantation of the Beijing-based Affiliated Hospital of the Academy of Military Medical Sciences， and his team， authored the article.

At the end of 2012， at the invitation of Blood， Ai became a member on its editorial board. Before Ai， only two people from the Chinese mainland had served on its editorial board， geneticist Chen Saijuan and stem cell biologist Cheng Tao.

For Ai， the invitation meant international recognition of his new treatment for leukemia， which he and his team have been researching and practicing for the past 16 years. Thomas Richard Spitzer， an expert on bone marrow transplants with Massachusetts General Hospital in the U.S.， believes that during the treatment process for leukemia， inducing stronger graft-versus-tumor （GVT） effects but without graftversus-host disease （GVHD） is extremely difficult， almost like searching for the Holy Grail. However， Ai and his team made difficult yet unique explorations. They have advanced from the traditional to mini， and then to microtransplantation， and achieved“magic results.”

From Big to Mini-transplantation

For a long time， leukemia was considered terminal. In the late 1970s， after American physician Donnall Thomas developed bone marrow standard transplantation between different individuals， the treatment for leukemia witnessed a historic breakthrough. In 1990， due to his contribu- tions to cell and bone marrow transplantation， “one of the greatest achievements in the field of treating cancer，” Thomas received the Nobel Prize in Physiology or Medicine.

By the mid-1990s， China’s hematopoietic stem cell transplantation was already mature. Beijing-based People’s Hospital and Affiliated Hospital of the Academy of Military Medical Sciences where Ai worked were the earliest medical institutions in the country to perform such surgeries. They employed myeloablative stem cell transplantation （AST）， which was widely used around the world then. This kind of transplant first “shatters” a patient’s immune system and medullary system through massive doses of chemotherapy and radiotherapy to destroy the patient’s hematopoietic and immunologic functions. Then， HLA （human leukocyte antigen） matched cells are transplanted to enable the growth of healthy cells in the patient’s body. The procedure proved extremely effective in treating leukemia.

Ai began to engage in leukemia clinic treatment and research in 1984. Born in 1958， he joined the army at age 16. In 1978， Ai， who loved to study， was admitted to Shanghai-based Second Military Medical University， as part of the first group of university students to enroll after the “cultural revolution” （1966-1976）. He graduated in 1983 and was assigned to work in Beijingbased Affiliated Hospital of the Academy of Military Medical Sciences. After a short time working in various departments， he settled in radiation and homeopathy department， the most revered in the hospital.

In the late 1980s， genotyping and immunophenotyping were already widely used to diagnose leukemia. However， China still used comparatively outdated microscopical and morphological diagnosis. In 1988， Ai began to research leukemia immuophenotype and genetic diagnosis， and participated in the formulation of related domestic medical guidelines. However， he soon realized that “even the best diagnosis casts little influence on the treatment.” After thinking for a long time， Ai decided to shift his research to “treatment”， especially treatment on patients with refractory leukemia or drug-resistant leukemia. After some time， new problems emerged. Although treatment had witnessed breakthrough and many patients found themselves in remission， the rate of relapse was still very high. Moreover， overdoses of chemotherapy and radiotherapy， plus complications after transplantation， were persisting problems globally. Many patients were either unable to endure the entire ordeal， or remained perpetually sick after transplantation.

In that era， Ai had already seen intensive studies progress in “immune and transplantation fields” globally. Animal experiments proved that only by eroding the immune system could donor cells survive transplantation. Contrasting international traditional transplants （which is known as“big transplantation”）， Ai decided to reduce the intensity of chemotherapy and radiotherapy， while reinforcing clearance on the immune system. And for donor cell engraftment， he chose peripheral blood stem cells， which proved more resilient.

This method was known as non-myeloablative stem cell transplantation （NST）， an effective method with lower toxicity， like a “mini-transplant”. In February 1998， Ai led his team in performing the first mini-transplant in Asia.

“That patient suffered from acute severe aplastic anemia resulting from hepatitis，” Ai explains. “Along with a pulmonary infection and severe psoriasis， he was exhibiting a persistant high fever and organ dysfunction.” Facing the severe situation， the whole department began discussing treatment. Because of the patient’s poor organ function， he was not suitable for AST and didn’t have enough time to wait for drugs to take effect. With the approval from his family， Ai tried NST.

On the seventh night after the surgery， the patient’s condition finally took a favorable turn. His white blood cell count， an important index to determine a person’s immune function， returned to 400/microliters from zero. On the eighth morning after the transplant， Richard Champlin， head of Stem Cell Transplant Department at U.S.-based MD Anderson Cancer Center， gave a lecture in China. The content happened to be about mini-transplantation， which had been performed on more than ten patients in America. Ai attended the lecture， but his mind was on his patient. Then， he received a message： “The patient’s white blood cell count has increased to 1，600/ microliters.”

Richard Champlin and Shimon Slavin， transplant specialist with International Center for Cell Therapy Cancer in Israel， are the first doctors in the world to perform mini-transplantation. Soon after， Ai and his team began as well， but used slightly different methods than his predecessors. For example， in terms of chemoprophylaxis on graft-versus-host disease （GVHD）， while the common international practice was to use mycophenolate mofetil （MMF） for 28 days， Ai used it for 120 days. To enhance antileukemia and anti-cancer effects， many foreign centers often employed donor lymphocyte infusion （DLI） after transplants， while Chinese hospitals transfused “G-CSF-mobilized” peripheral blood stem cells. At present， in terms of the time period for drug treatment， the international community has reached the consensus of about 80 days. However， although China has published experimental data and international articles on better recoveries and safer procedures by using “mobilized”peripheral blood stem cells， due to various reasons， 95 percent foreign blood centers are still using DLI.

After his three-plus decades of practicing medicine， the period Ai enjoyed most was exploring mini-transplantation， which was mostly painful yet still joyful. “I was in my early forties and a nobody，” he recalls. “At that time， experts active in blood and transplants were all supporters of the traditional practice. ‘How dare you change the standard transplant method which has been popular for decades！ Don’t you know the first Nobel Prize-winning hemotologist got it because of this method？’ I had no supporters at all.”

At present， more than 300 leukemia patients have received mini-transplantations in Ai’s hospital. Of them， about 33 percent were older than 50， making them ineligible to receive the traditional transplant. As Ai put it， sometimes the development of science spirals. Today， in international medical circles， the boundary between traditional transplantation and mini-transplantation is blurring. Minitransplantation has become mainstream treatment in Western countries. And in China， even experts and blood centers that opposed it vehemently years ago have begun to accept the practice.

Mini-transplantation on Radiation Sickness

In his hospital， Ai serves as director of both the Hematology and Radiation Therapy Departments. Each year， several hundred patients with blood diseases come through his departments， which helps the hospital accumulate abundant treatment experience. Ai considers his hospital the first in China to open a radiation therapy department， and due to their vast experience， his staff should always be well prepared for emergency treatment from radiation poisoning. The primary cause of death for patients who receive heavy doses of radiation is their loss of hematopoietic function， which remains a worldwide challenge.

Late on October 21， 2004， an ambulance from Shandong Province roared into the Affiliated Hospital of the Academy of Military Medical Sciences， and Ai was on board. He went along to pick up two patients who had received heavy doses of radiation. Aside from the potential risk from nuclear power plants， radioactive leaks and waste is the biggest cause of radiation poisoning. According to China’s Ministry of Environmental Protection， at present， there are about 20，000 uncontrolled radioactive sources in China. During the process of using radioactive material to preserve fresh vegetables， the two patients from Shandong made a terrible mistake. “After using the radioactive material， they thought they had put it away and began to carry vegetables，”Ai recounts. “They discovered the source was still open when they had almost finished their work， but it was too late.”

Ai’s hospital is the only one in China designated by the National Health and Family Planning Commission to treat patients with severe radiation poisoning. After receiving the two patients， the hospital immediately set up a rescue team and Ai served as the head of both the clinical treatment team and expert panel. The Gray（Gy） is a derived unit of ionized radiation dose， which is defined as the absorption of one joule of radiation energy by one kilogram of matter. When a person is exposed to radiation of less than six Gray， his or her chance of survival is still good after treatment. However， whole-body exposure of more than eight Gray is considered very severe. At that point， no one had survived radiation poisoning so severe： The patients from Shandong were exposed to 12 and 23 Gray， respectively.

Due to the heavy damage on the immune system from radiation， patients can hardly endure traditional transplants. Thus， hematopoietic stem cell transplantation for treating radiation sickness never succeeded. For the two patients， Ai hoped to use mini-transplantation， which he had been researching for nearly six years by then. Although this surgery had gradually become accepted for treating leukemia， it had never been used to treat radiation sickness.

Having no precedent， many experts in the rescue team were opposed to such risk. While the plan for treatment couldn’t be decided even after several heated discussions， the patients’ condition deteriorated. When Professor Ye Genyao， the first director of the Radiation Therapy Department， finally endorsed Ai， the decision was made. Ye was among the first group of medical experts on radiation therapy research and rescue in China， and had participated in many rescue efforts for patients suffering from radiation poisoning.

Just as everyone in the surgical team was in position for the procedure， Ai received a text message from his brother，“I’m afraid that grandma will not make it.”

Ai was born in a small village in Henan Province. Due to his parents’ busy work schedules， he was practically raised by his grandma and became greatly attached to her. “My grandma made an enormous influence on me. She is the one who taught me to be honest， upright， hardworking， and sincere. We were poor when I was a kid. Before leaving home for school every morning， she always gave me a roasted sweet potato， carefully peeled and wrapped up in paper，” Ai recalled.

Due to his busy work， Ai couldn’t visit her very often， who still lived in their hometown then. Thus， seeing the message， Ai froze. He ran to the restroom， locked himself in， and cried.

At 3：00 p.m. on October 28， the NST surgery was successful. Ten days after the surgery， the patients’ white blood cell count returned to normal range， and their hematopoietic function fully recovered. However， due to failures of other organs，the two patients were both dead within two months， which depressed Ai for a long time. “A doctor’s responsibility is to give his patients life，” he asserts. “In this case， although the transplants were successful and their hematopoietic function recovered， my patients didn’t survive and I felt very bad and even responsible.”

Although they didn’t survive， Ai and his team made major breakthroughs in treating patients with radiation sickness with hematopoiesis stem cell transplantation， and took a giant step forward in terms of curing patients with severe radiation poisoning. In 2006， at an international symposium for the 20th anniversary of 1986 Chernobyl nuclear disaster， his report on radiation therapy drew massive attention.

From Mini to Microtransplantation

Although his mini-transplantation has achieved important progress in the hematology diseases treatment， Ai doesn’t stop further exploring. Importantly， many problems in mini-transplantation remain unsolved. In 2001， Ai began to brainstorm new ideas. The key point of both traditional transplantation and mini-transplantation is guaranteeing a higher success rate for donor cells engraftment. So Ai raised new questions： Would it also be workable to transfuse a small amount of cells？ And would a small transfusion decrease or even avoid the occurrence of complications？

Animal experiments have proven his speculations workable. Since then， leading his team， Ai began systematic experiments and clinical research on microtransplantation. Later， Professor Thomas Spitzer explained Ai’s method in this way： Traditionally， a patient received fatal chemotherapy or radiation therapy before the transplant， in order to destroy leukemia cells and cancer cells and immunosuppressive host’s immunologic functions. This process is called myeloablative or nonmyeloablative conditions. In microtransplantation， patients only receive mild chemotherapy or targeted therapy on cancer cells. Their healthy immune system is kept， which allows a small amount of donor cells to get into their bodies. These cells not only produce a graft-versus-tumor effect， but also activate the patient’s immune system to identify and kill cancer cells. More importantly， this new technique can avoid some potential fatal complications such as graft-versus-host disease （GVHD） which often emerge during transplant.

In 2002， Ai’s hospital received a 75-year-old patient. She suffered from acute myelocytic leukemia developed from myelodysplasia syndrome， a kind of severe hematology disease， and associated with severe lungs infections. She had received plenty of chemotherapy and other treatments， but none of them produced satisfactory result. Ai suggested the microtransplantation plan， which was just experimental then. While the patient herself was very willing to have to try， her family was very hesitant. After heated discussions among family members， they finally agreed. And the old lady became the first clinical case for Ai’s microtransplantation.

One month after the microtransplant， the patient condition hadn’t improved obviously and she left hospital. The surprise came a year later. In May 2003， when SARS broke out， Ai received a call. He couldn’t believe his ears at first， because it was the woman who received the microtransplant. “She asked whether I was safe in the hospital during SARS， and she told me that she was recovering well and was in good health，” Ai reveals.

Ai and his team were overjoyed. After the epidemic was brought under control， they invited the woman to the hospital for a check-up， and were delighted to find that her leukemia was under control. Since then， microtransplantation gradually matured. Ai， who faced fierce criticism and doubt during his exploration of minitransplantation， once again fought alone. He and his team endured many hardships and they never asked for publicity. Most patients who ask Ai for the microtransplantation treatment learned about it from other patients who had received the surgery.

Until October 2010， when Blood published a research report by Ai’s team， microtransplantation was never announced to the public. In April 2012， Faculty of 1000， a website that publishes articles on biology and medicine from leading figures， also recommended this thesis and gave it a high rating， calling it a “thesis on tumors with the highest scientific value.” In October 2012， Journal of Clinical Oncology， a peer-reviewed authoritative medical journal published by the American Society of Clinical Oncology， published a second thesis on microtransplantation by Ai and his team. The journal also published commentary from bone marrow transplant expert Thomas Richard Spitzer on the same issue， who declared that Ai’s method would be a “new mode” in treating leukemia and tumors.

Unexpectedly， Ai didn’t hear objections from China’s blood circles this time. In 2013， led by Ai’s team， an international microtransplant coordination group was established. Nine authoritative blood institutes from China and a number of foreign blood research centers including Duke University and Cook County Hospital participated in the program. “In the past， we usually followed the lead of Western countries. This was the first time Western countries came to China and learned from us，” Ai grins. In December 2014， an annual symposium on stem cell transplantation and cell immunotherapy was held in Anderson Centers in San Francisco， U.S.A. Top global science researchers such as Dr. Champlin， Dr. Care Joune， and Ai attended and published important reports on progress in haploidtransplantation and cell immunotherapy. Ai and his microtransplantation were the toasts of the meeting.

During Ai’s studies in his early years and his work， Shen Beifen， his tutor during his post-graduate studies， who served as an academician with Chinese Academy of Engineering and expert on immunochemistry， influenced him a great deal. She is extremely strict. She checked one by one on the 100-plus samples Ai produced and used many methods to verify the accuracy and reliability of Ai’s experiments. Ai’s strict attitude on researching， leading a team， and clinical management comes from his tutor.

In his hospital， Ai is known as “chief judge” as well as “brother sharp”. His students， even those who were already experts in medical circles， are fearful of his words if they make a mistake. And he is strict. Everyone in the hospital knows that Ai’s cellphone is turned off when he comes to wards to check his patients. He also requires all doctors in his departments to come to check on their patients even on weekends and public holidays.

Ai loved to read as a kid， and he covered a broad range by adulthood， including history， literature， philosophy， and psychology. He is also a fan of kung fu novels by the renowned Chinese novelist Louis Cha Leung-yung. He often says that accumulation of medical knowledge takes a long time and medical practitioners should hone their skills with patience. He tells his students to learn more from other fields， and that they cannot be medical experts if they only learn medicine. When he served in the army， he worked as a radio technician. As a medical intern， he preferred cardiology. Finally， he chose radiation and blood diseases， his two least favorite departments of medicine initially. He has now been dealing with them for several decades. In the eyes of people close to him， Ai is stubborn， persistent and creative.

Some of his students also call him“naughty old boy.” Ai is now in his late fifties， and some of his friends recommended he study Buddhism and “mellow out”.“For me， I’m still too young to study Buddhism，” he chuckles. “In terms of both my work and life， I am still growing up.”