Biography of Zhu Chen

The alchemist's symbol for arsenic is a menacing coiled serpent, and perhaps rightly so. The element of arsenic has certainly earned a great deal of infamy from the reign of the Borgias to the novels of Agatha Christie, and in more recent times as a toxic contaminant of drinking water. But the symbolic serpent also coils around the staff of Aesculapius, an international symbol for medicine; arsenic the poison is also arsenic the healer.

Figure 1.

Zhu Chen

Indeed, writing in his Inaugural Article in this issue of PNAS (1) Zhu Chen of the Shanghai Institute of Hematology (Shanghai, China) describes arsenicals as among the oldest drugs known. Chen has been the principal figure behind the development of a radical approach to acute promyelocytic leukemia (APL) that combines the arsenic of traditional Chinese medicine (TCM) with Western medicine. His work in this area has provided a molecular rationale for an effective cancer therapy and led to his election to the National Academy of Sciences in 2003.

A Nontraditional Path

The beginning of Chen's academic career, a career that would bring arsenic to the forefront of modern cancer therapy, followed a route different from that of a Western scientist. Chen left academia at an early age. “I left primary school in Shanghai in 1966,” he said. “The so-called Cultural Revolution had begun, and, like most of my contemporaries, I went to work in the countryside and lost the opportunity to pursue studies in middle school and university.”

Chen's parents, however, encouraged him in his self-taught efforts to work through middle school and some of the university medical school subjects. His performance as both a farmer and a “barefoot” doctor was appreciated by the local people, whose recommendation to the admissions office of Shangrao Health School in Jiangxi helped Chen breach the political barrier to formal studies. He entered a two-year medical course at the school in 1975. This stood him in good stead for the end of the “revolutionary era,” when, in 1978, the postgraduate program was restored in China. “I finally set my feet on campus and started my career as a medical scientist working under hematologist Zhen-Yi Wang at Shanghai Second Medical University (SSMU), whose deep understanding of and achievements in biomedicine inspired me profoundly,” Chen said. During this period, Chen carried out research on several disparate diseases. He published procedures for detection and discrimination of hemophilia A carriers and variants of von Willebrand disease. He also focused on cell culture in leukemia (2–5).

After his graduate studies with Wang, Chen took an internship at Shanghai Rui-Jin Hospital, an affiliate of SSMU, where he worked from 1981 until 1984. He then relocated to the Central Hematology Laboratory at Saint-Louis Hospital (Paris), where he worked with Jean Bernard, Jean Dausset, Michel Boiron, Georges Flandrin, François Sigaux, and Laurent Degos of the University of Paris VII. “As a result, I realized the transition from hematologist to molecular biologist,” Chen said. He spent his first two years at Saint-Louis as a visiting intern. Between October 1985 and January 1989 he completed his Ph.D. and continued postdoctoral studies at the hospital until July 1989. By this time, Chen had published extensively on many different aspects of leukemia. He studied the rearrangement and expression of T cell receptor (TCR) genes in human leukemia and characterized part of the TCRã chain region (6–9).

An Ancient Cure for Today's Ills

Chen returned to China to take up a post at the Shanghai Institute of Hematology at Rui Jin Hospital in July of 1989. There he began studying APL, a subtype of acute myelocytic leukemia. He maintained his connections with his French mentors while developing fruitful collaborations with Samuel Waxman, Ryuzo Ohno, Hugues de Thé, Michel Lanotte, Arthur Zelent, and others in the United States, Japan, and Europe. The French connection led to a subsequent collaboration by Chen's team with de Thé and others, finally piecing together the complex picture of how chemistry might fight APL. Work by Hugues de Thé (Saint-Louis Hospital) and colleagues had revealed that the gene for the retinoic acid receptor α (RARα) is disrupted in the majority of APL patients and fused to a partner gene, PML, because of chromosome translocation t(15;17) (10–11). A parallel study by Chen in Shanghai produced the same result (12, 13). Previous research by Zhen-Yi Wang and colleagues had demonstrated that all-trans retinoic acid (ATRA) is successful in treating most APL patients by inducing differentiation in affected cells. This drug, combined with chemotherapy, results in 90% remission rates (14). By further analyzing the genetics and phenotype of APL, Chen's group identified the first variant chromosomal translocation t(11;17) with RARα fused to a distinct partner, PLZF, in a subset of APL that is resistant to ATRA. Chen and his collaborators carried out comparative studies between t(15;17) and t(11;17) that helped reveal a key mechanism in ATRA action: the modulation of aberrant RARα proteins and their coregulators (15–20).

Chen's experiences in France and subsequent collaborations taught him a great deal about Western medicine. However, much earlier Chinese studies caught Chen's eye and would ultimately lead to a pioneering fusion between the ancient and the modern. In the early 1970s, a group from Harbin Medical University (Nangang, China) investigated the medicinal properties of an arsenic-containing remedy that was traditionally used to treat a variety of diseases, including the fever we know as malaria. Through trials in more than 1,000 patients with different cancers, the Harbin team discovered that intravenous infusions of Ailing-1, a solution containing white arsenic and a tiny amount of mercury, produced complete clinical remission in two-thirds of a series of APL patients. The Harbin team found that the Chinese remedy produced a survival rate after 10 years of 9 in 32 cases (28%) (21).

Chen sought collaboration with the Harbin team, and in 1994 the researchers demonstrated that white arsenic in pure form, more precisely arsenic(III) trioxide, As2O3, produced the same positive results as the Harbin team had observed with Ailing-1 in the 1970s. Most importantly, Chen and his colleagues found that arsenic trioxide led to remission in APL patients for whom retinoic acid and chemotherapy had failed (22–24). Other researchers in the United States, Europe, and Japan subsequently corroborated these findings.

Figure 2.

Zhu Chen (second from left) with colleagues at the Shanghai Institute of Hematology.

Some researchers had suggested that similarities between the nature of remission in APL patients who received either arsenic trioxide or retinoic acid therapy could imply a similar mode of action. However, experiments Chen conducted from 1996 to 1997 (22–24) suggested otherwise. He demonstrated that As2O3 promoted both apoptosis and partial differentiation of APL cells. This finding was in stark contrast to the late postmaturation apoptosis seen in retinoic acid therapy. His team had further shown that arsenic compounds induce the degradation of PML-RARα oncoprotein in a way distinct from ATRA (23–25). Based on these findings, Chen and his colleagues hypothesized that the arsenic-containing remedies of TCM might improve the retinoic acid therapy. Perhaps, the reasoning went, the two combined might be even more effective in treating APL.

Chen and his colleagues have now tested their theory for the first time on a group of 61 newly diagnosed APL patients, and Chen reports the results in his PNAS Inaugural Article (1). The team randomized the patients into three groups; one received retinoic acid only, the second group received arsenic trioxide, and the third group received a combination of the two, during both induction and maintenance therapy. In addition, patients in all three groups received standard chemotherapy. The researchers determined the degree of clinical remission by hematological analysis and measurements of tumor burden, and they measured side effects through standard clinical examination.

Chen reports that clinical remission rates were high (more than 90%) in all three groups. However, symptoms were lessened and remission efficiency was higher in patients on the combination therapy. The researchers also saw higher survival rates during follow-up for those patients. Chen suggests that the two drugs work synergistically to promote apoptosis as well as degradation of the PML-RARα implicated in the pathogenesis of the disease.

Through research such as this, Chen and his colleagues have transformed leukemia therapy. He attributes their success to the synergy among Western medicine, retinoic acid, and the white arsenic of TCM. “Our new approach means we need not only kill malignant cells but also educate these cells to undergo differentiation, maturation, and cell death,” he explained. “We have demonstrated the new approach to APL works because it may cure the disease in the majority of patients.”

Extending the Therapy

Chen and his colleagues have also extended their research to include methylated metabolites of arsenic trioxide. Arsenic(III) ions are methylated in the liver to mono- and dimethylated metabolites, such as methylarsonic acid, methylarsonous acid, dimethylarsinic acid, and dimethylarsinous acid. Chen and his colleagues reasoned that such metabolites may be partly responsible for the potent therapeutic effects of arsenic trioxide. The researchers compared the potency of the arsenic(III) and trivalent metabolites using chemical precursors of methylarsonous acid and dimethylarsinous acid to induce differentiation, growth inhibition, and apoptosis. They found that methylarsine oxide and, to a lesser extent, iododimethylarsine were more potent growth inhibitors and apoptotic inducers than the original arsenic compound in NB4 cells, an APL cell line. They obtained similar results with K562 human leukemia and lymphoma cell lines and in primary cultures of chronic lymphocytic leukemia cells, but not with human bone marrow progenitor cells (26).

Ongoing studies at the Shanghai Institute of Hematology and elsewhere are aimed at trying to broaden the use of arsenic in cancer therapy still further. Arsenic trioxide looks promising, particularly in treating other hematological cancers, including acute T cell leukemia, multiple myeloma, and non-Hodgkin's lymphoma (27). Researchers are also testing arsenic against hepatocarcinoma and gallbladder cancer. According to Chen, researchers are seeing clinical effects, but nothing as dramatic as those with APL.

While Chen's work on arsenic trioxide is undoubtedly changing how APL is treated, it is also providing new insights into the pathogenicity of the disease. Chen's findings may also help investigators understand whether arsenic can cause bladder, lung, and skin cancer. Arsenic itself is not considered carcinogenic, but there is an association between chronic exposure to it and incidence of these cancers. The underlying mechanism has never been fully explained, because arsenic's carcinogenicity has not been demonstrated in vivo or even in cell cultures.

The key to Chen's success lies in his philosophy: “It is important to recognize that experimentation complements clinical research,” he said. “The clinical effect is the ultimate aim of experiments, while experiments provide the theoretical basis for a clinical trial.” Chen further emphasizes that teamwork has been important to his research. “Without the efforts of the whole staff of the Shanghai Institute of Hematology, we would not have achieved what we have today,” he said. “We are showing how a combination of Western biomedical sciences and oriental philosophy as well as medical practice could bring new benefit to cancer therapy.”