Editors: Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.
Leslie A. Platt
Executive Vice President, The Institute for Genomic Research, Maryland, USA
Modern genomic research is providing amazingly detailed information about how life works and is allowing scientists the world over to develop new insights into the processes underlying the existence of every species on Earth from birth through death. The potential for progress in expanding the base of scientific knowledge about life is staggering. Together with their colleagues around the world, scientists at The Institute for Genomic Research (TIGR) in Gaithersburg, Maryland, are engaged in a broad and ennobling enterprise that clearly is one of the major developments of our time. The existence of TIGR is itself an example of the fast pace and remarkable potential for scientific and technological progress in what TIGR's founder, Dr. Craig Venter, has called the new genome era. Just over one year old, this not-for-profit, independent research institution, devoted to accelerating the sequencing, mapping, and functional characterization of human, animal, and plant genomes, has established itself as a world leader in the application of DNA sequence analysis, gene expression, model organism studies, and comparative evolutionary biology.
By using the expressed sequence tag (EST) technique pioneered by Dr. Venter while he was at the National Institute of Neurological Disorders and Stroke, National Institutes of Health, TIGR scientists have dramatically increased the pace of human gene discovery and identification. The EST sequencing method constituted a strategic breakthrough for gene discovery by increasing the rate of discovery by up to 1000 fold. EST sequencing also resulted in a tremendous cost reduction for identifying and sequencing new genes. From the estimated cost of $5.00 - $15.00 per finished base pair at the initiation of the U.S. Human Genome Project, the technique utilized by Dr. Venter of single-pass EST sequencing has reduced the cost of identifying genes to less than $0.12 per base pair. Recognizing these improvements, laboratories around the world have rapidly turned to EST sequencing as a major focus of their genome efforts.
Beginning with the first results from the EST method in 1991, scientists at TIGR have published EST sequences from over 8,500 human genes and made the sequence data and computer analysis results available to the community through public computer databases. All cDNA clones from this work are available to the world scientific community from the American Type Culture Collection, the respected scientific tissue and clone distribution organisation.
Among the large numbers of new genes identified are new human receptors and transporters, all of which are immediate candidates for further investigation as targets for specific drug development. We are proceeding to characterize biochemically and pharmacologically selected protein products of these new genes. We have also identified many new transcription, translation and splicing factors, as well as structural proteins, enzymes, and cell-surface proteins. As these genes are further characterized, we expect that many will prove to be of medical interest.
By sequencing ESTs and cDNA libraries from many different tissues, we can construct expression profiles for many human genes simultaneously. Over 150 human cDNA libraries are currently being sequenced at TIGR. These data will allow us to compare systematically the levels of expression of thousands of genes across different tissues and developmental stages. We will be able, for example, to identify genes that are expressed specifically in pre-cancerous or metastatic tumour cells, and to use this information for early diagnosis of cancers.
TIGR scientists have also developed novel software for streamlining the quality control, analysis, and management of EST data. This software has now been adopted by several other high throughput sequencing labs. TIGR is currently developing the world's first gene expression and function database, which will be available to the world scientific community via international computer networks.
Through cDNA sequencing, we are approaching the goal of identifying the majority of human genes much more rapidly than originally anticipated. At the outset of the U.S. Human Genome Project, it was envisaged that sequencing of all human genes would be accomplished by the year 2005. TIGR anticipates that identification of the vast majority of human genes will occur within the next year.
Dr. Venter and TIGR are also determined to harness the tremendous energy of the worldwide genome research community in cooperatively advancing the knowledge base as rapidly as possible. This will be accomplished in part by TIGR's regular, systematic, and timely publication of its data in peer reviewed journals. It will also be accomplished by collaborative projects such as the exciting new undertaking announced by Dr. Venter at the International Genome Sequencing and Analysis Conference V in Hilton Head, South Carolina this past month. At the Conference, Dr. Venter outlined the Cooperative Human EST Assembly Project, whereby the vast and growing public store of overlapping EST data -- including especially redundant data -- may be saved and simultaneously made available, thereby rapidly enhancing the global knowledge base about human gene sequences.
Through this approach, Dr. Venter stated, it should be possible within two years to have 200% coverage of total human mRNA and within three to four years, it should readily be possible for the scientific community, working together and sharing its data, to have between 300-400% coverage. The result of this should be the elucidation of the coding sequences of all human genes by combining the pieces of the puzzle now being assembled through the separate efforts in research laboratories around the world. Indeed, as of October 1993, the known world collection of human ESTs is already over 130,000. This includes a significant number from Dr. Venter's laboratory at TIGR and a large number of ESTs from Dr. Matsubara and his team here in Japan, as well as those of a number of other laboratories around the world.
The fast pace and nature of progress at TIGR, and in the field of genomic research in general, raises serious questions about scientific, social, legal, and ethical concerns affecting all humankind. The questions arise because of the awesomeness of the power of the knowledge base about life now being assembled in the scientific research community. The most intimate details about who we are as individuals -- what makes us tick as living organisms -- may soon be readily accessible to governments, insurers, employers, and others. Should, for example, an employer have knowledge about a worker's genetic make-up which, in the view of the employer, makes the worker a poor job risk? What makes this an even more aggravating question to examine is that the answer is in all likelihood, "Sometimes yes, and sometimes no." That is, a genetic screen to detect the high probability of sudden heart attack or stroke would most likely be approved in the screening of airline pilots, but not in airline flight attendants. The choices we will soon face as a global society because of this knowledge must be accompanied by a process of education that will enable us to choose wisely.
TIGR is firmly committed to the belief that scientific progress, particularly in the context of genomic research, must be guided by ethical and legal principles, and has established a Department of Research Policy and Ethics, which I chair, to facilitate understanding and education on the important issues that arise in this area. The efforts of the Department of Research Policy and Ethics are directed to helping inform and guide critical public discussion about the implications and impact of modern genome research. Issues of concern in these areas include societal uses of genomic information, implications of genetic testing, genetic knowledge and reproductive choices, as well as confidentiality and access to life and health insurance. The Department is planning programs on gene patenting, the potential effects on national and worldwide healthcare systems, and religious and philosophical views concerning the pursuit and acquisition of human genomic information. By sponsoring conferences and symposia, as well as through publications and various research related activities, the Department will provide an important forum for discussion of these vital concerns.
This past September, TIGR co-sponsored with George Mason University in Fairfax, Virginia, an international conference on "The Ethical Implications of Human Genome Research." Keynote presentations were made by scientific leaders of the U.S. genome program and by a range of leading medical and lay commentators. This conference was a tremendous success and elicited an enthusiastic response from the participants.
As I mentioned earlier, one focus of the Department's efforts is to promote public dialogue about the purposes and results of modern genomic research. A second, equally critical purpose of the Department's activities is to assure an integrated empirical examination, from the outset of the work, of the ethical basis for the genomic research conducted at TIGR and elsewhere. TIGR believes that we will thereby be better able to fulfil our own moral responsibility, as well as to provide an example for others engaged in basic or applied genomic research, to integrate serious exploration of the impact of the research with the underlying scientific work. Today, we are at the brink of potentially the most profound revolution not only in the history of medicine and healthcare, but also in the development of our conceptions of what life is and what it means to be human. Genomic research is yielding information in previously unfathomable detail about the basic functions of life and who we are as individual human beings. The knowledge gained from research conducted at TIGR and in research laboratories around the world may be expected to facilitate the early diagnosis of diseases like cancer, to provide new methods of identifying individuals predisposed to diseases such as hypertension, heart disease and alcoholism, and to lead to the identification of genes responsible for the many thousands of genetic diseases. Such knowledge may also be used for nonmedical purposes, including among others, creation and maintenance of DNA profile databanks, which raises serious privacy issues with respect to access and potential use of individually identifiable genetic information for a variety of purposes, including genetic discrimination.
It is vitally important that a framework for use of the new knowledge growing out of various aspects of genomic research be developed in the context of ethical and legal principles formulated by well-informed leaders both in the scientific community and in the general population. We at TIGR believe that it is essential at the outset of the genome era to lay a course that helps men and women of goodwill from all parts of society come together to identify, elucidate, and wrestle with the ethical implications of modern genomic research. This will help us to set in motion the means by which philosophers, theologians, educators, political leaders, and scientists can join together to discuss their perspectives and understanding of fundamental questions newly relevant in the genome era and will also allow humankind to achieve the best possible use of the fruits of genomic research.
Tremendous developments in the prevention and therapy of human disease have already occurred as a result of genomic research. It can only be expected that these beneficial developments will continue to occur in the future at an even faster pace, and that issues raised by these developments will become increasingly prevalent in our society. We must consider, for instance, the legal and ethical aspects of providing newly available, genetic based treatment to disabled or diseased infants and fetuses. In addition, genetic diagnosis and therapy must be developed with due regard for the ethical tradeoffs and considerations inherent in the treatments. For example, a woman's right to genetic privacy must be balanced against her genetic progeny's right to know their genetic heritage. One must carefully evaluate the likelihood that the positive results desired from gene therapy will occur and must also consider the risks associated with such therapy. Other important issues involve the question of how scarce resources in both the areas of scientific research and medical development should be allocated. Whether or not the wondrous cures and treatments now within reach because of the progress in basic science will be actually achieved will depend in large part upon how well we answer these and similar questions. We must not let the potential now before us fail to be realized because we did not educate ourselves and our leaders on the critical issues that must be considered in the genomic era.
The American poet, Henry Wadsworth Longfellow, in his poem, "The Builders," said it this way:
In the elder days of Art,
Builders wrought with greatest care
Each minute and unseen part;
For the gods see everywhere.
Let us do our work as well.
Both the unseen and the seen;
Make the house where gods may dwell
Beautiful, entire, and clean.
We at TIGR, and all members of the scientific community -- whether involved in genomic research or in other areas -- must remember that having more knowledge of how life works does not diminish the importance of religious and ethical considerations about the meaning and sanctity of life. Unraveling the secrets of life, learning the mechanics, is only part of the story. Dealing with the power of this knowledge in an ethically appropriate manner will determine whether the promise for the alleviation of suffering and enhancement of the quality of life will be realized.
In this critical task we are not alone. We have the enormous resources of the wisdom of the great sages who have helped us in our moral dilemmas since time immemorial. Whatever our religious backgrounds or beliefs, we can all, I am certain, agree that it all comes down to doing unto others as you would have them do unto you. Respect for the sanctity of life must guide this process.
The daily advances in genome research will force us to make difficult ethical choices. Whether or not we have an appropriate framework for making the right choices will determine whether we realize the potential of this research for good, or unleash on the world, because of our hubris and failure to act responsibly, a tragic perversion.
We clearly have the responsibility to ensure that we continue along the path responsibly, knowing the tremendous tasks and potentially dramatic benefits that lie before us.
Most importantly, we must act quickly. The Japanese poet Narihira, over a thousand years ago, characterized well the circumstances in which we now find ourselves in these words:
I have always known
That at last I would
Take this road, but yesterday
I did not know that it would be today.
We are today -- at this Seminar -- on Narihira's road. This road can lead toward fantastic possibilities for humankind. Let us proceed wisely. Thank you.