Bioethics and the Impact of Human Genome Research in the 21st Century

6.7. The Policy and Ethics of Gene Chip Technology
pp. 104-109 in Bioethics and the Impact of Human Genome Research in the 21st Century

Author: Erin D. Williams (Executive Director, Foundation for Genetic Medicine, Inc. USA)

Editors: Norio Fujiki, Masakatu Sudo, and Darryl R. J. Macer
Eubios Ethics Institute

Copyright 2001, Eubios Ethics Institute All commercial rights reserved. This publication may be reproduced for limited educational or academic use, however please enquire with the author.

"Any sufficiently advanced technology is indistinguishable from magic." - Arthur C. Clarke

Rapid developments in technology are empowering the incorporation of genomics and genetics into clinical medicine, agriculture, and related research. Now that so many living beings' genomes have been sequenced (human, yeast, and rat, for instance), the newest set of technological tools is focused on helping us to understand the structure and function of genes. This is no simple task. Human beings' 46 chromosomes alone house 3 billion base pairs of DNA and encode about 60,000 to 80,000 proteins.

It is widely believed that thousands of genes and their products (i.e., proteins) interact in each living organism to help facilitate life's functions. However, traditional methods in molecular biology generally work on a "one gene in one experiment" basis, which means that studies cannot easily take multi-gene relationships into account, making the "whole picture" of gene function very difficult to obtain. In the past several years, a new technology, called DNA microarray has changed that, promising to display the whole genome on a single computerized cell, a DNA chip.

DNA chips give researchers a snapshot of the interactions among thousands of genes simultaneously, in a systematic grouping called an array. "DNA sequences, representing tens of thousands of genes, can be densely arrayed on glass or silicon surfaces. These DNA chips can be simultaneously probed to evaluate distinguishing genetic identities of individual persons," or to investigate how large numbers of gene expressions are coordinated or correlated in normal and diseased cells and tissues.

DNA chip research efforts are international in scope. In September of 2000, it was announced that the Japanese company Takara Shuzo Co., Ltd., negotiated a license to commercialize low and medium density DNA arrays in Korea, Taiwan, the People's Republic of China, Japan, and around the rest of the world. These types of efforts have already spurred the development of DNA chip technologies that facilitate the study of cystic fibrosis, heart, blood vessel and lung disease, human immunodeficiency virus (HIV), cancer, and single nucleotide polymorphisms (SNPs). They have been used more broadly as well, to study to arabidopsis, rat, yeast and E. coli genomes, mouse models, and others.

Ethical Issues Raised by DNA Chip Technologies
There are many types of issues raised by the use of DNA chip technologies. For the purposes of this discussion, I will focus on some of the most difficult ones: those raised in large-scale research efforts that compile information gathered from DNA chips and correlate it with tissue samples and clinical records. I will begin by suggesting a participant centered viewpoint from which to conduct the examination. Next, I will address the commonly examined questions of collection, storage, and use of tissue samples and related information. Finally, I will introduce a couple notions that, while not legally required, should be incorporated into research protocols: comprehensive mutual education and equity.

Viewpoint
It is easiest to begin to understand the scope of issues involved with DNA chip technologies by temporarily setting aside our respective roles as experts in our fields. Imagine for a few moments that you are playing another role, one that you have almost certainly already played at some point in your life: that of a patient.

Imagine that you are sitting in your doctor's office, and that she has just informed you that after her preliminary assessment, she would like to conduct some further tests. There are many possible reasons for your symptoms, she tells you. To help her pinpoint her diagnosis, she wants to order a biopsy. It will, among other things, help her rule out the possibility of cancer.

Cancer?
Hearing the word cancer in connection with you own body can have a profound effect. You may feel as thought you've just received a mild electric shock. Your mind may begin to spin; you may feel a bit nauseated. Your energy may sink to your feet as you begin to consider the impact that this will have on your life, on your family, and on your plans for the future.

It is in this context in the human experience that materials for research are often sought. Tissue samples are taken from people who have or may have cancer or some other disease or condition. Together with information generated from DNA chips and numerous other samples and medical records, this information can form a databank. These databanks and the commercial applications that emerge as a result of them can be quite valuable, particularly when they generate pharmaceutical successes.

Individuals' participation is essential to the success of these DNA-chip and associated databanking endeavors. Yet in exchange for contributing their tissue samples (which, as patients might remind us, are their blood, organs, skin, saliva, etc.) and their personal medical information, patients typically receive little if any compensation. In exchange, patients and their families may face difficulties procuring health and life insurance, obtaining employment and housing, and more. As scientists seeking to help people in need, as ethicists striving light the way, as patients seeking empowerment through action, and as human beings interconnected in the web of life, the time has come for us to recognize that we can do better.

Collection, Storage, and Use of Tissue Samples and Related Information
Studies involving human participants should, at a minimum, comply with institutional, local, state, and federal regulations. Protocols should be approved by an Institutional Review Board (IRB), or the equivalent. As is now required by the United States National Institutes of Health, principal investigators and IRB members should also have training in the protection of human research participants.

Scrupulously following the regulatory requirements is particularly important for those seeking to commercialize their patented discoveries. Potential funders wisely avoid investing in discoveries for which the patents may be rendered unenforceable. For that reason, a patent applicant should be aware that "a patent by its very nature is affected with a public interest." An applicant should also be aware that if s/he does not include all "information which is material to patentability" (which, in the interest of the public, should include any lapses in protection of research participants), then s/he may be deemed to have made an untruthful declaration on the application. This type of transgression may render the patent unenforceable, and is further punishable by fine or imprisonment. Leslie Platt, Principal at Ernst and Young, L.L.P. summarized:

The time has come, ladies and gentlemen. The patent office doesn't have the resources to check each applicant's homework, but Wall Street does. And if there hasn't been complete compliance, they'll know that the resulting patents may be rendered unenforceable. What does that mean? The good guys are going to win this one.

Therefore, both because it is ethically preferable and because it is in the enlightened self-interest of those conducting research, it is important to adhere to the highest legal and ethical standards when collecting, analyzing and banking human tissue and related data.

The prevailing body of human-participant oriented regulations focuses on protection issues. These laws cover topics including informed consent, recontact or follow-up protocols, and approaches privacy protection for information and tissue storage. The following is a summary of current requirements and recommendations in the United States.

Informed Consent
On occasion in the past, tissue samples have been acquired without their donor's express knowledge or permission. In fact, United States case law has supported the proposition that, even when tissue collected for clinical purposes is later used for research without obtaining the donor's express separate consent, the donor has no right to revenue generated from resulting discoveries. However, the opportunity and desire to obtain tissue samples without the express consent of donors is rapidly evaporating.

Like the studies themselves, at a minimum, informed consent should be designed and conducted in such a manner as to comply with all institutional, local, and federal regulations. It should accurately convey to the participants the physical, social, psychological, and other potential risks and benefits of the research. In addition, given the familial nature of genetic information, the informed consent process should account for the possible impact of studies on an individual's family members, seeking their involvement where appropriate.

For databanking projects, because the ultimate uses of participants' records, tissue samples, and related information are not yet known, informed consent should be layered or multilevel. Layered informed consent means that participants are asked in advance about their preferences as to the types of research that they do or do not want to support. The National Heart, Lung and Blood Institute (NHLBI) recommends this type of approach, suggesting that participants be given the option of consenting to participate on one of three levels:

in the current study only,

in the current study and other investigations with goals broadly related to the area of the original research, or

in the current study and any future investigations, regardless of their relationship to the original inquiry.

Using the layered approach to informed consent allows participants to select the scope of projects that can access their tissue samples and related information.

Recontact or Follow-up Protocols
In addition to being asked about future research protocols, during the informed consent process participants should also be asked whether they would like to be recontacted to enable follow-up and/or other research. Taking care of this detail in advance permits researchers to contact amenable participants. It also allows participants who would rather not be contacted with such offers to make that desire clear.

The protocol for recontact should be created with input from researchers and participants alike. It should be designed to help facilitate research while protecting the privacy of participants. For instance, interested researchers should not simply be handed the names, phone numbers and email addresses of people who have agreed to be recontacted. After proposed follow-up protocols have been vetted in IRBs and/or other appropriate forums, the trustee holding the participants' key coded information should discretely get in touch with potential participants and describe the researcher's invitation. Only after participants have agreed should their contact information be released to the researchers.

Approaches Privacy Protection for Information & Tissue Storage
The most comprehensive way for researchers to guard against breaches in privacy and confidentiality when conducting large-scale studies is simply not to store the information and/or tissue samples once the research has been conducted. While this approach may heighten individual privacy protection, it may also inhibit databanking, future research, and medical care. For those reasons, in large-scale efforts, non-storage is not likely to be the privacy-protection approach of choice.

At the other end of the spectrum from the not storing information lies collecting and storing personally identifiable data. As its name suggests, personally identifiable data could enable a person without prior knowledge of the data or their collection to deduce the identity of data-subjects. This type of information storage for genetic material stands largely at odds with North American society, which "traditionally places a high value on privacy, personal autonomy, and free will in decision-making."

Another data-storage approach is anonymization of the sample or information. Data is said to be truly anonymized if "a person without prior knowledge of the data or their collection can[not], from the data and any other available information (such as postal charts, or a casually held key-code, or a list of the people recruited to the study), deduce the personal identity of data-subjects." Data may be anonymized by not collecting or completely removing identifiers, by aggregating data into groups and ranges and not reporting individuals' identities, or by "micro-aggregating" the data into pseudo-cases representative of the real population.

Though much useful health research is conducted on anonymized data, the following are reasons why maintaining personal identifiability may be important:

to allow technical validation of reports, such as to confirm correspondence of various data with the data subjects, or even to verify the very existence of the identity of the subjects, in order to prevent scientific errors or fraud;

to avoid duplicate records or redundant cases, such as to be certain that two case reports are independent and not just the same case recorded in two files;

to facilitate internal scientific data-quality control, such as enabling working-back to original records and ancillary data;

to allow case follow-up if more evidence or confirmation are needed;

to check data-subject consent on records, or to examine Institutional Review Board stipulations or opinions in a case;

to allow tracking of consequences after some research intervention, to be able later, if necessary, to notify the patient or physician and recommend reexamination or other measures in-between research and health care; and

to ensure accurate correspondence in linking data on data-subjects, or groups, or specimens, among different files or databases, perhaps over a long period, even over decades, and possibly to follow-on to descendants.

An intermediate form of data storage that is neither readily personally identifiable nor truly anonymized, is key coding. Data is key coded if its personal identifiers have been removed but are still potentially traceable via a matching, separately held code. Key coded data can provide general anonymity for research participants without triggering any of the above risks of permanently anonymizing data. This type of system, if properly executed with files kept only on secured, non-Internet accessible computers, would likely be preferable to both participants and researchers, as it simultaneously protects privacy and enables follow-up research.

The following recommendations may be useful for successfully key-coding data. The National Heart Lung and Blood Institute recommends holding the identifiers close to the point of collection. The National Institute of Alcohol Abuse and Alcoholism assigns a key-coded pseudonym to all subjects and has the key securely held by an independent third party. The National Institute for Child Health and Human Development (NICHD) requires researchers wishing to perform secondary studies on data originally collected by other investigators under an NICHD grant to pay a fee. The original researchers then use the fee money to key-code the identifiers and to take other protective steps before sharing the data. Whatever specific measures are taken, effective key-coding requires identifiers to be locked up separately from data, linking codes to be safeguarded either by a reliable person or by a trusted intermediary, and, the process of linking back to the original data-subject to be carefully managed.

Ethical Requirements for DNA Chip and Databanking Efforts

Comprehensive Mutual Education
In DNA chip research, two types of education should take place before and during the project. First, researchers should learn about the populations they are likely to affect, seeking the expertise of research participants where possible. Second, researchers should invite those who are likely to be affected to learn about the proposed research. Throughout the educational processes, all parties should remain open to listen to, respect, and learn from one another. The clearly stated goal should be for all parties to work together to create a mutually beneficial research protocol with equitable and meaningful results.

After the above steps have taken place, researchers should work with participants to think through their studies from the participants' perspective. During this process researchers and participants may focus their attention on identifying and minimizing any risks or discomforts that the participants might experience, and helping to empower them as the ones who make the research possible. The creation of an open and ongoing dialogue should not only allay any unfounded fears of both participants and researchers, but should also help them to recognize and address emergent issues in a thoughtful and thorough manner.

Equitable Outcomes
Once researchers and participants have come to understand one another through comprehensive mutual education, it should be fairly easy for them to discuss equity issues. Equity issues are those that define the aims of research, seeking to structure it in such a way as to set agreeable goals, and to share the rewards of success among all those who contribute to it. The concept of equity has as its premise a recognition that both researchers and participants contribute to investigations in essential ways, and that therefore both researchers and participants should benefit from successful results.

When discussing equity issues, it is essential to note two facts. First, there are many types of equity and potential benefits to be shared, not all of which are financial. The participant population should have the latitude to define what types of benefits are important to them. Second, provisions should be made for similar types of equity-sharing arrangements with downstream databank users. For instance, in exchange for access to a databank, a researcher might agree to return a standard tithing amount of 10% of profits derived from that research to the communities that that created the databank.

One example of how an equitable arrangement might be reached was suggested in the creation of a participant committee charged with reviewing proposals and forming proper research agreements between one participant group and researchers. The resulting agreements would be structured so as to allow the participant group, in this case an American Indian Tribe, to ensure that research was conducted in a manner supportive of Tribal ideals, including, for instance, ensuring the maintenance of the sacred web of life for future generations. Some other provisions called for cultural sensitivity training, empowerment, Tribal benefit from intellectual property rights, and Tribal archiving and data ownership.

Another mechanism for giving back to the participant community might be the provision of free medicine and/or treatment to those involved, to their family members, or to others with similar conditions. Support groups might be created and sustained for people with the condition(s) being examined. An office might be created to answer questions, make referrals, host a website, and send regular newsletters to keep the community informed about current research endeavors and promising results. These are only a few of the possibilities. Working together, researchers and participants can craft any number of creative mechanisms for sharing equity.

Please send comments to Email < asianbioethics@yahoo.co.nz >.

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