Profile of Ding-Shinn Chen

Ding-Shinn Chen has used every strategy at his disposal to battle the worldwide devastation caused by hepatitis B. From public health strategies that lower the rate of hepatitis B infection to basic molecular research that solves the mysteries of how the virus causes disease, Chen, who was elected to the National Academy of Sciences as a foreign associate in 2005, has spent a career studying a virus that causes one of the world's most common disorders.

Worldwide, 350 million people are infected with the hepatitis B virus, one of five viruses that cause hepatitis that, in turn, increase the risk of chronic liver disease and liver cancer. Hepatitis B infection is especially prevalent in Southeast Asia and sub-Saharan Africa. Indeed, some of Chen's earliest work showed that hepatitis B infection in his homeland of Taiwan was far higher than in the West. Based on those findings, Chen worked to create a public health program in Taiwan that, for the past 23 years, has vaccinated nearly all of the newborns there against hepatitis B. The program already has reduced some forms of liver disease and, over the next several decades, should reduce it further or even eliminate it. Chen and his colleagues also have studied the molecular nuts and bolts of how hepatitis causes liver diseases. In his Inaugural Article (1), they report on a mechanism that may explain why hepatitis B causes liver cancer in males more than five times as often as females.

Chen is Dean of the National Taiwan University College of Medicine and Director of the National Taiwan University Center for Genomic Medicine. He is married, with a son, who works in the finance field, and a daughter, who is a protein biochemist at Taiwan's Academia Sinica.

The Science of Medicine

Chen was born in Ying-Ge, Taiwan, south of the country's capital, Taipei. His interest in medicine began in high school, when his mother became ill and required surgery. His subsequent encounters with physicians and other health care workers convinced him to enter a seven-year medical program directly after high school at National Taiwan University College of Medicine. In his third year, while studying physiology, microbiology, and other building blocks of medicine, Chen began to realize the important contribution research makes to medical knowledge and treatment.

Ding-Shinn Chen

“My classmates and I thought we should also contribute to the knowledge of the future,” he says. “I started to seek laboratories in my medical school which would allow a student to conduct some simple experiments.”

He found such a laboratory in his fourth year, working on a simple animal experiment to determine whether there was a difference in immunological behavior between C57 black and AKR white mice.

“We used, at that time, a sophisticated way to determine the antibody-forming cells in the spleen (now called B cells),” says Chen. “We injected sheep red blood cells into the mice and analyzed the number of antibody-forming cells. Then we treated the mice with the immune suppressant methotrexate, an anti-cancer drug, and repeated the experiment to see if there was a difference between the black and white mice.”

The study took Chen and a classmate two years to complete during summer vacations. “At that time, there was no computer system and you had to go to the library and look at the many, many volumes of Index Medicus to see the current state of knowledge on the topic and then design the experiment,” says Chen. “I thought it was a very good experience for a young student like me” (2).

Finding a Cause

After graduating from medical school and a year of compulsory military service, Chen began his residency in internal medicine in 1969. That was when his interest in hepatitis began. “At that time, internal medicine residency needed four years, and I started to think about which discipline I should choose after my training finished,” he says. “Although we already knew we had very prevalent liver disease in Taiwan, we didn't know almost 80–90% of it was caused by chronic hepatitis B infection. If you look at the world, many people have liver disease. In Taiwan, many had chronic liver disease and many had a big liver with advanced primary cancer in it. So I chose gastroenterology as my subspecialty, which, in Taiwan, includes hepatology and liver disease.”

After the discovery of the hepatitis B marker, now called hepatitis B surface antigen (HBsAg), by Baruch Blumberg in 1965, there was finally a way to identify and differentiate the etiology of liver diseases.

Chen and his mentor, J. L. Sung, found that across Taiwan, 15–18% of the population carried the antigen, much higher than the 0.1% carrier rate in Western countries. Even more interesting was that 90% of people with liver cancer had HBsAg in their blood, and 80% of people with liver cirrhosis had the antigen (3, 4). “That's a very important finding because it indicates that these two diseases are associated or closely related to chronic infection with the hepatitis B virus,” Chen says. “Then we started to look at how these people got infected.”

They concluded that many of the infections resulted from mother-to-infant transmission. The virus is very contagious and infective, so if the mother has it, the newborn with its undeveloped immune system will be exposed to it in the birth canal. “The infection occurs so early that the immune system does not recognize it as a bad one,” says Chen. “This is why people had so high hepatitis B carriage. Of the 15–18% with it, some will develop chronic liver disease and/or liver cancer. During the 1970s and '80s, we made clear the natural history and role of early infection in chronic hepatitis B carriers” (5–7).

After identifying the transmission routes of hepatitis B, Chen and his colleagues began looking for ways to prevent it. “Before the virus was discovered there was no treatment and no effective way of prevention,” explains Chen. “After Blumberg identified a specific marker, a lot of research went into the significance of the viral marker and the antibody to this antigen” (7, 8).

Professor Chen and his research group.

Once a vaccine was developed and ready for public use in the early 1980s, Chen and Sung wanted to use it to decrease chronic carriage of hepatitis B in Taiwan. “We persuaded the government to launch a program to control hepatitis B in our people,” recalls Chen. “We started to get in touch with the government around 1980, when the vaccine was just available. Finally, the government was convinced that the disease was very serious and prevention was worthwhile. So we got the budget and the system working and started the vaccinations. We were the first country in the world to initiate universal vaccination against hepatitis B in newborn babies. I still remember the first day of July 1984 when vaccinations began” (9).

Now, across the country, clinics vaccinate newborns as soon as possible. Doctors screen mothers to see whether they are carriers and measure how infectious they are before they give birth. “The exposure starts right during delivery, so we have to give the immunization as soon as possible,” Chen says. “It's usually given within one week after delivery. It's quite complicated, because there are two types of carrier mothers.”

One type is extremely infectious. Babies of these highly infectious mothers will make hepatitis B antibodies for themselves once given the vaccine, but because the virus already has infected them, doctors need to add protective antibodies produced by others to beat the virus, says Chen.

When the program started, it vaccinated approximately 400,000 babies per year. Taiwan's birth rate has since fallen, and it now vaccinates 210,000 per year. “This is something we promote a lot in Taiwan,” says Chen. “The coverage is very good, about 98% in cities and 96% over all of Taiwan.” The chronic carrier infection rate in people born since 1984 has dropped to 0.6% in Taipei City and to approximately 1% nationwide.

The hepatitis B vaccine was the world's first to fight cancer. Because liver cancer usually does not develop until an infected person's sixth decade, it will be awhile before Taiwan feels the full effects of the vaccination program. However, as an early proxy, Chen and other researchers have found that liver cancer already is appearing much less frequently in children (10). In addition, as they continue to track the vaccine's effects, they have found a drop in rates of liver disease in children born after the vaccination program's inception (11).

Solving a Mystery

While Chen was battling hepatitis B on the public health front in Taiwan, he conducted basic research to better understand, on a molecular level, the virus that causes the disease. The hepatitis B virus is a small, 3,200 bp, partially double-stranded DNA virus. It makes four proteins: three are structural, and one, called HBx, trans-activates genes in the host cell. Unusually for DNA viruses, it must undergo reverse transcription and may integrate into the host's genome. Chen discovered this integration while visiting Robert Purcell's laboratory in Bethesda, MD, in 1979 (12).

Chen once again has added to our understanding of hepatitis B with his Inaugural Article, which may have found the answer to a long-standing mystery: why hepatitis B causes liver cancer in males much more often than females, by a ratio of between 5 to 1 and 10 to 1. He and his colleagues find that it has to do with an interaction between one of the proteins that make up the hepatitis B virus and male hormones.

“We found that HBx protein will work with androgen receptor (AR) in the presence of the male hormone testosterone and increase liver cancer,” says Chen. “This HBx protein, the only nonstructural one of the virus, works in concert with androgen receptor and testosterone to promote carcinogenesis.”

Chen says the interaction between HBx and AR also explains why hepatitis B is so much more prevalent in men (1). “We have other studies showing that the genetic alterations of AR are very important in liver cancer in males,” says Chen. “But we did not know how this was related to hepatitis B. Now with the hepatitis B viral protein X working on AR, we have the connection.”

Specifically, Chen and his colleagues propose that the HBx protein works through a signaling pathway called c-Src. They suggest that HBx and c-Src interact with the AR and then enter the cell nucleus to activate some of the effectors that promote liver cancer. The pathway they have identified also may be involved in other diseases, says Chen. “In many diseases, especially infectious disease, males are usually more susceptible, or the disease will be severer than in females,” he says. “We think that perhaps this pathway will possibly explain the differences in other diseases as well.”

Chen also has studied hepatitis viruses C and D and the severe acute respiratory syndrome virus. In the early 1990s, he and his colleagues (13) developed a treatment for chronic hepatitis C that combines interferon-α and ribavirin, and this has become the standard treatment. He has also studied the replication cycle of hepatitis D, a shadow virus that depends on viral coat proteins from hepatitis B, and its role in liver disease (14–16).

Because hepatitis D is so small, some researchers do not believe it fulfills the criteria to be a virus, says Chen. “It cannot live by itself, and it always needs the hepatitis B virus surface antigen to form a viral particle. The virus is hiding with hepatitis B, so if there's no B, there will be no D. Although this phenomenon occurs in the plant kingdom, in the animal kingdom, this is the first one.”

However, the majority of his work has been, and will be, focused on treating and eliminating hepatitis B. “Right now, hepatitis B is still the most important viral infection for human beings,” says Chen. “In Western countries, the vaccines are very effective and you can control it more easily. But in the rest of the world, 500,000 to 1 million people are still dying of hepatitis B-related liver diseases every year, particularly in Asia and Africa. Regretfully, the countries with the highest scientific standards have shifted their interest to HIV, HCV, and other diseases, so hepatitis B is given less consideration. I think from a human point of view, we need to study more of hepatitis B.”

There is still a long way to go before hepatitis B-related diseases can be significantly minimized or eliminated (17). “If we keep using the vaccination, the diseases will be controlled, but that will be 30 or 40 years away,” says Chen. “People keep dying from this disease, and we can use this sad opportunity to study how this virus is causing disease. We still have a lot of uncertainties. This is my number one project.”

One technique he has planned to solve these questions is genomic medicine. “If you look at some families, many are hepatitis B carriers, and almost all the carriers died of liver cancer, yet other families do not show the same phenomenon, even though the family members are also hepatitis B carriers,” he says. “There must be some host factors or genomic differences that dispose them to this cancer or disease.”

As if those goals were not enough, he adds, “I will also keep an eye on hepatitis C. It's still important in Taiwan and worldwide.”