Making a Deposit in Taiwan Biobank: How Safe Are Your Secrets?

What is a biobank? Why does Taiwan want to create one? And why has there been so much controversy?

In April of 2003, the completion of the human genome project marked the arrival of the "post-genome" era. Since then, a major focus of research has become the study of inherited genetic differences between groups and individuals.

To provide resources for research, many countries-including Japan, Sweden, Iceland, and the UK-have established biological databases or gene banks large and small.

And in this large-scale genetic war, Taiwan naturally cannot fall behind.

In 2004 the Executive Yuan announced that in order to ensure that Taiwan did not lose the genetic data collection race right from the start, the government would plan and promote the creation of Taiwan's own biobank.

The program's official launch followed in 2005, and it was incorporated into the NT$15 billion "Biomedical Technology Island Plan" (which also includes basic infrastructure for an integrated network of data on citizens' health as well as a system for clinical testing and research).

But Taiwan Biobank has not been favored by fate. While there are ambitious targets and blueprints, the whole project has wobbled unsteadily amidst a chorus of doubts. Over the past three years, we have only heard the sounds of the whistle calling "All aboard," but the biobank train has yet to get out of the station.

Why does Taiwan need a biological database? Is it just fashion? Or are there genuinely compelling reasons?

Y.T. Chen, director of the Academia Sinica's Institute of Biomedical Sciences (IBMS) and the man chiefly responsible for planning for Taiwan Biobank, points out that any specific ethnic group has unique characteristics in the gene pool. Although the world's 1.5 billion Chinese all trace their roots back to the same source, different groups have followed different historical paths, and local customs and habits vary widely, as do the natural environments where Han people live. The genes of people in Taiwan have therefore been through changes induced by circumstances, and variations in gene expression have developed. There is thus a genuine need to establish a biobank devoted to Taiwan itself.

This need is illustrated especially clearly with respect to the side-effects of medicines.

"The medications developed by the big pharmaceutical manufacturers in the US and Europe are designed for Caucasians," says Y.T. Chen. He cites carbamazepine (used for treating epilepsy and trigeminal neuralgia) as a case in point. About 5% of people in Taiwan are severely allergic to this drug, which can trigger symptoms of Stevens-Johnson syndrome. The problem lies with the HLA-B genotypes, of which there are more than 500 types. A relatively large proportion of Taiwan's population have the HLA-B*1502 genotype, and these people are 193 times more likely than the average to be allergic to carbamazepine.

With the decoding of human genes, a major focus of research today has become the study of genetic differences between individuals and groups.

Another reason for establishing Taiwan Biobank is the need for long-term cohort tracking studies, which can address polygenic or multifactorial diseases (diseases involving more than one gene or environmental factor). The database and tracking studies are each a reason for, and a product of, the other.

"This is a program that is in the best interests of the next generation," says Y.T. Chen. By following a cross-sectional sample of subjects over a long period (20 or 30 years), one can examine both innate genetic composition and acquired, lifestyle, and environmental risk factors, and discover what leads to various diseases. This is the basic blueprint for Taiwan's biological database.

Shen Chen-yang, a professor at the IBMS and co-director of the Taiwan Biobank plan, takes breast cancer as an example. Because female hormones stimulate cell growth and the thickening of the endometrium, women who begin menstruating earlier in life, continue menstruating later into life, or have no children, are high-risk groups for breast cancer because of longer exposure to the effects of hormones. However, clinical evidence from the US indicates that of every three women who are victims of breast cancer, two do not have any of the above risk factors. One can only surmise that genes play some role in either hindering or contributing to the onset of the condition.

There are also researchers who say that mild smokers (one to five cigarettes per day) who also carry the CYP1A1 Val allele have increased risk of breast cancer. This shows the interaction between genetic inheritance and the environment.

Taking lung cancer as another example, most people believe that smoking is a risk factor for lung cancer (the rate is ten times higher than among non-smokers). But in Taiwan, for every nine women with lung cancer, only one is a smoker. The unknown variable here could very well be genetic.

However, "The medical community cannot destroy the genes of a group of subjects in order to observe them," affirms Shen Chen-yang. "Therefore, there is no alternative method but to track a group of people continuously over a long period of time." This kind of research is not something that can be done in a single bound. For example, a study of the effects of smoking by two British researchers (Peto and Doll) took 15 years. And it took University of Texas professor R.P. Beasley 20 years to reach his conclusion that carriers of hepatitis B are 265 times more likely than average to get liver cancer.

The goal of Taiwan Biobank is to collect a large amount of genetic data about Taiwanese. "For epidemiology to be done scientifically, you need at least 200,000 people in order for the database to serve its intended function," says Y.T. Chen. Because in the past researchers did not have access to an adequate sample size, they could not tell the whole story of the interaction of inheritance and environment. Significant statistical correlations can only be achieved if you have a very large database.

By researching genes, the environment, and the interaction of genes and the environment, it is possible to discover which genes and which environmental factors are most important for us. When the time comes, the information can be used to develop medicines and gene therapies, or adopt preventive medical strategies (for example, genetic testing for drug allergies), and each patient can enjoy individualized, tailor-made medical treatment.

In recent years, genetic technology has developed rapidly around the world. Although this is exciting, it is also worrying. Because of numerous unknowns in genetic technology-such as the impact on the natural environment of gene transplants-it is as difficult to oversee as a wild horse. And the deeper the research progresses, the more unsettling it seems to get.

Terence Tai, convener of the ELSI (Ethical, Legal, and Social Issues) Committee of the National Research Program for Genomic Medicine, says that genetic research aimed at treating patients is often seen as more or less equivalent to testing of pharmaceuticals, and the physical data of participants is collected and retained for future research. The problem is, "It's not clear what kind of research will be done." Given the scattered nature of the personal data in genetic research, how should the ELSI and Institutional Review Boards (IRBs) in the relevant institutions fulfill their mission? It's a tough question.

Especially so given that the verbal battles over the human rights issues connected to genetic research have raged continuously without any clear result.

The November 1997 UN Universal Declaration on the Human Genome and Human Rights clearly states, "No research or research applications concerning the human genome, in particular in the fields of biology, genetics and medicine, should prevail over respect for the human rights, fundamental freedoms and human dignity of individuals or, where applicable, of groups of people."

Although Taiwan's gene database has been rechristened a "biological data bank," it has been unable to escape the concerns and fears aroused by the word "genetics." Thus, despite the fact that the IBMS has advanced from the phase of a "feasibility study" (August 2005 to January 2007) to that of a "guidance plan" (December 2005 to October 2009), and the governing agency at the central level has been changed from the National Science Council to the Department of Health, Taiwan Biobank has made only very limited progress.

Genes are composed of only the four "bases" A, G, C, and T, but they can combine into more than 3 billion DNA sequences. Breakthroughs in genetic research are solving many tough problems in the field of medicine, but are also raising fears of genetic discrimination, eugenics, and aggravation of class divisions.

The guidance plan includes four main areas: biomedical research (under IBMS), an information platform (Institute for Information Industry), biotech industrial development (Development Center for Biotechnology), and law and ethics (Foundation of Medical Professionals Alliance in Taiwan). Until the law and ethics structure is completed, all actions by the IBMS, from selecting research subjects to methods for physical testing, are open to suspicion and criticism.

The feasibility study was launched back in July of 2006. Through local meetings to explain the program, and seminars held in various hospitals or over the radio, recruitment of volunteers was conducted in the Chiayi area, and 1000 volunteers were found. They were then asked to fill in forms with basic demographic data, dietary habits, and subjective evaluations of physical condition. Next physical tests were carried out for waist size, hip circumference, body fat, blood pressure, pulse, lung function, bone density, and the like. Thus a foundational database was established. This was followed by an evaluation and improvement of the whole procedure, and an assessment of potential problems that might arise when the full program is formally initiated.

However, to date the biobank has not gotten approval from the Academia Sinica's IRB, and everything has stalled at the simulation stage described earlier. The most important job-the blood sampling program-has yet to get under way.

According to the original plan, blood samples were to be drawn starting in January of 2006. But as a result of opposition from human rights groups-even the method of recruiting volunteers has been controversial-the NSC had no better choice than to postpone the move. There are still a lot of things that could go awry between now and the end of 2009, when work is supposed to be completed on collection of blood samples from 15,000 people in three areas across Taiwan.

"Genes carry too much personal information. It's not the same as paying someone for a simple blood donation. In fact, it is absolutely impermissible to use any incentives to induce people to participate," says Liu Chung-yi, chairman of the Taiwan Association for Human Rights and an associate professor at NTU's Graduate Institute of National Development, staking out a hardline position. Offers of money or "free physical check-ups" to get people to participate are both "fraudulent" acts.

Blocked from providing any "inducements," the Academic Sinica is limited to giving each participant NT$300 for transportation. Even the possibility of sharing the results of the tests with donors is seen as a kind of "entrapment" by the TAHR.

Although Y.T. Chen finds this position to be somewhat incomprehensible, Liu Hung-en points out that in Japan, citizens are told clearly that "the results of the genetic analysis or blood analysis will not be revealed to the donor of the sample." This avoids giving people the false impression that participating in the database means getting a free physical or genetic exam. Thus, if the Academia Sinica provides the results to donors, are there not grounds to suspect that people have been induced to participate for the free physical exam? What would be the ultimate reason why individuals participate? It's not very easy to separate out specific motivations.

Another flashpoint of controversy is that Taiwan Biobank uses "ethnic groups" as the basis for cohort studies.

The plan calls for recruiting volunteers aged 40-70 for long-term tracking from three areas: Miaoli, with a high concentration of Hakka; Chiayi, with a high concentration of Minnan; and Hualien, with a large proportion of Indigenous peoples. These volunteers are to be tracked with biological tests (blood, urine) as well as questionnaires on eating habits, living environment, lifestyle, behavior, occupation, and medical history. By also studying the health of these participants, it should be possible to discover causal factors related to chronic illnesses like cancer, high blood pressure, or diabetes, as well as conditions that are unusually common locally (such as chronic hepatitis and cirrhosis of the liver).

All well and good from a scientific point of view. But the "ethnic" nature of the research plan still raises hackles, because, unlike traditional public health information, "It potentially affects not only the individual, but the entire ethnic group," says Shen Chen-yang.

Just as the word "eugenics" evokes memories of Nazi exterminations, in Taiwan, the words "ethnic group" can easily spark emotional responses and touch sensitive political nerves. This is hard to avoid even if one stresses that this is based on objective, reasonable science.

For example, a study of the SARS epidemic by Professor Marie Lin of Mackay Memorial Hospital's Immunohematory Reference Laboratory concluded that, as a result of differences in tissue antigens, Minnan and Hakka people were more susceptible to SARS infection, while immigrants who came to Taiwan from northern China after WWII were less susceptible. This conclusion was attacked for alleged "ethnic bias" or "ethnic divisiveness."

The fear of ethnic discrimination arises most readily among indigenous peoples. Liu Hung-en notes that the indigenous population is small (470,000), and they were severely oppressed in the past, so they have the greatest fear of being stigmatized. (For example, if indigenous people turn out to have a gene for susceptibility to alcoholism, they could be branded as "natural-born drunkards.") Researchers recruiting indigenous people must therefore not only seek the consent of the individual, but must get approval from the would-be volunteer's tribal council as well.

Responding to such concerns, Y.T. Chen says, "There are no grounds for fears of genetic discrimination." The genotypes of the four main races of mankind (Caucasian, Mongoloid, African, and Austronesian) have already been made public over the Internet. The American leader of the gene sequencing project Craig Venter has even put the map of his own genome on the Internet, inviting people to make good use of it.

Because genes are passed from generation to generation, they can be considered as a kind of enduring identity marker that crosses space and time. They involve not only the individual, but could reveal everything about the genetic condition, biology, psychology, or character, of a whole extended family or even ethnic group. If tests uncover genes for serious illnesses like Alzheimer's or muscular dystrophy, whole groups of people could face difficulties or discrimination in job-seeking, marriage, having children, or getting insurance. Therefore, the question has been raised: Is it enough just to get the consent of the individual?

A case related to these issues arose in Iceland. In 2000, a participant in the national health research database passed away, and his daughter, considering that she shared genetic characteristics with her father, and that therefore her personal health characteristics could be revealed to others, asked that her father's information be removed from the database. When she was refused, she sued the government for invasion of privacy. The case was decided in 2003, when Iceland's Supreme Court ruled against the government on the grounds that it had violated the clear guarantees of personal privacy contained in the constitution.

After this decision was handed down, more than 20,000 Icelanders chose to opt out of the database, virtually wrecking the government's plan to build a fully inclusive nationwide biobank.

The reason there has been so much controversy over Taiwan Biobank is that there are so many unknowns involved. This is especially the case where individual rights or interests collide with public health or the enforcement of government policy. For instance, in the future will genetic data, medical records, residential information, and insurance data be linked? If they are, what problems might arise? Just recently information held by the Center for Disease Control about patients with communicable tuberculosis leaked out over the Internet. Will airlines have the right (or obligation) to refuse such people? Could schools have the right to reject AIDS babies? Such questions make people more afraid than ever about the transparency of the management of genetic information in the future.

"The uses of DNA cannot be guaranteed," says Liu Hung-en. How can we be sure that the biobank will only be used for research purposes? If in the future a court seeks to check DNA in the database as evidence in a serious criminal case, could the Academia Sinica refuse?

Or, what if the accused in a paternity suit refuses to provide a DNA sample? Could the court subpoena the DNA of an accused person from the biobank? Such a case would involve not only the rights and interests of the child, and issues of inheritance, but could spark family feuding, so the effect on society should not be underestimated.

"Here you're building something which is clearly on a scale and impact of Taipei 101, but you're going about the whole thing as casually as if it were a temporary structure," says Liu Hung-en. Before you create the biobank, you have to think through and explain clearly any possible future complications, so that the public can understand. "You can't wait until after the building is finished before you start thinking about the impact on the local skyline or traffic conditions."

"You have to let the public know in advance: What is the overall plan for the biobank? What uses will it be put to in the future? How much power over the information are donors giving up when they agree to participate? You can't just muddle through on these things and fob people off with vague answers," argues Liu Hung-en. Given the current situation of a lack of transparency and openness, all critics can do is to blast away at every hypothetical threat they can imagine, even though this also may raise unnecessary fears.

From the point of view of the ordinary citizen, it is only natural to be worried about "Big Brother" having personal information, about discrimination and bias, and about the arrogance of technology that seeks to intervene in nature with artificial means. But from the point of view of scientists, for whom "there can be no progress without risk," knowledge per se is the highest value. As for how to best use such knowledge, or ensure that it is not improperly used, that is a technical problem for the follow-up stage, and should not be used as an excuse to delay research.

"A lot of countries started planning after we did, but got started before us," says Y.T. Chen with a note of urgency in his voice. It is not only advanced countries like the UK, Sweden, Iceland, and Japan that have biological databases, but even the PRC and Malaysia have set them up already. Meanwhile Taiwan Biobank is hung up on arguments over what Chen calls "peripheral details," and can't get out of the gate.

In fact, the forms and functions of the biological databases in all these countries vary considerably. The earliest one to be established, that of Iceland (founded in 1998), has also been the most contentious.

Iceland was the first country in the world to establish a "National Health Sector Database," as it was named. This country, whose residents are mainly descended from the Vikings, is an isolated island nation with a long-established national health insurance system and comprehensive medical records, making it extremely suitable for group-based research. The government initially planned to include the genes and medical records of all 300,000 citizens in the database, and passed legislation forcing citizens to specially apply if they wished to opt out. However, this idea was abandoned because the Supreme Court ruled this unconstitutional as an invasion of privacy. So the government has commissioned a private American company-deCode Genetic-to operate the system. About 100,000 persons, or a third of the total population, participate.

The model used in Japan is the one that differs most from that in Taiwan.

Data collected for the DNA Data Bank of Japan under the Individualized Medical Care Project focuses on 47 common diseases including diabetes, hepatitis, and hyperlipidemia. Through participating hospitals, samples of body fluids, clinical medical records, and information on living habits of 300,000 patients were collected for comparative studies. In other words, Japan's biobank uses physical exams of people who were already ill when the data was gathered, and does not recruit among the general population, nor is there is any ambition to do long-term tracking or to map out a comprehensive ethnic genome.

The biobank closest in form to that of Taiwan is probably the one in the UK.

The UK's database is managed by a non-profit organization, has no research institute of its own and does no research; it only supplies a research platform to which research institutions apply. Resources include physical exams, genetic data, and personal medical histories. After six years of preparation, in March of 2006 the UK formally opened the door to recruitment of volunteers between 45 and 69 years of age, with a target of 500,000.

Back in Taiwan, scientists are on the defensive. "Right now it is a total loss," says Liu Hung-en. Perhaps communicating with society is not something scientists are very good at, but since they now have to do it, they should work with outside groups and make information transparent and accessible to outsiders. Through university lectures, community education, legislative hearings, and so on, communication and debate can go forward on the basis of scientific methods and procedural justice. For instance, in the future which agencies or organizations should be able to use the biobank? How can we ensure that user rights are not excessive? Such questions affect the "public interest" nature of the database, and must be clarified as soon as possible.

"This isn't an issue of right or wrong," says Shen, "but a problem of choices that have to be made by society." Currently there is no consensus even on who should organize an external monitoring committee, so even this basic step has still not passed review with the Academia Sinica's IRB.

What will hapen now? Y.T. Chen states frankly, "If through a rational debate everyone believes that there is too much risk and that we shouldn't go ahead, then as a science researcher, all I can do is accept that." But he and other scientists are determined not to give up without a fight.

How can we break through the impasse between science and the rights and interests of the individual? It seems there are as yet no answers.