I am grateful for the honor of giving this Keynote Lecture. It is a privilege to attend this conference in which we will consider the extraordinary impact that biotechnology has already had on our lives, an impact which will surely expand in the coming years.

Because of our inability to forecast the future, my talk will focus on how our experience with the development of biomedical science and biotechnology can help us to identify serious problems and seek solutions.

In tracing the foundations of biotechnology, as a biochemist, I have chosen an event that gave birth to modern biochemistry 101 years ago. It was in 1887 that Eduard Buchner accidentally observed that the juice of a yeast cell could convert sugar to ethanol. This discovery of cell-free fermentation disposed of a firm belief promoted by Luis Pasteur for 40 years that alcoholic fermentation is a vital operation of an intact cell. Forty years of enzyme fractionation that followed Buchner's discovery resolved this so called " zymase" activity into a dozen discrete enzymatic reactions. Alcoholic fermentation was now explained in molecular terms and the stage was set for the extraordinary advances of biomedical science in the second half of our century.

During the course of resolving the alcoholic fermentation in yeast juice, glycolysis by muscle extract was also resolved into its molecular components and astonishingly proved to be virtually identical to that in yeast. Conservation of mechanisms and molecules for a billion or more years of evolution in bacteria, fungi, plants and animals has since been observed in a large number of bioenergetic and biosynthetic pathways. Universality of biochemistry represents one of the great revelations of our century.

Unfortunately, attention to enzymology and biochemistry has been diminished by the advent of molecular biology and biotechnology. Because of this, we need to emphasize what the classic disciplines of enzymology and biochemistry have provided in conceptual and practical ways to the emergence of biotechnology. Enzymology solved chemical and biological problems and it made available polymerases, ligases and nucleases, essential for the invention of recombinant DNA and the practice of genetic engineering. Studies of replication, transcription and translation made it clear that one could rely on the universality of biochemistry to make bacteria, yeast and animal cells into factories for the production of precious proteins, hormones and vaccines.

Before I focus on the status of biotechnology, let me reflect first on the broader issues of the development of biomedical science in our century to judge where we may be heading in the next. We believe that by reducing life processes to a molecular basis, we can eventually achieve a more rational and richer appreciation of health and disease, and of our place in the living world.

The first two decades in our century were dominated by the microbe hunters, successful in finding the microbes responsible for the most dreaded scourges of many centuries: tuberculosis, cholera, and diphtheria. But other diseases for which no microbe could be found: scurvy, pellagra, beri-beri, proved to be due to the absence of trace substances in the diet, called vitamins. Microbe hunters were succeeded by the vitamin hunters. By the 1940s, most of the vitamins had been discovered but their biochemical functions remained obscure. It was then that I joined the enzyme hunters who showed how the vitamins attached to enzymes enabled them to perform the vital metabolic functions essential for growth and reproduction.

Enzyme hunters, have in recent decades been replaced by gene hunters: the genetic engineers and biotechnologists who identify and clone genes and introduce them into microbial, plant and animal cells to create factories for the massive production of hormones and vaccines for medicine and better crops for agriculture. Biotechnology has become a multi-billion dollar industry.

In view of the inexorable progress in science, we can expect that gene hunters will be replaced by those who apply the techniques of the enzyme and gene hunters to the function of the brain. Will they be called Head hunters?

The current age of gene hunting and biotechnology is undeniably the most golden, with its inexhaustible supply of genes and efficient techniques to track and capture them. We are participating in the most revolutionary advance in the history of biological and medical science. Its effects on medicine, agriculture and industry have not been exaggerated.

Much of life can already be understood in rational terms if expressed in the language of chemistry. It is an international language, a language without dialects, a language for all of time, and a language that explains where we come from, what we are, and where the physical world will allow us to go. Chemical language has great esthetic beauty and links the physical sciences to the biological sciences.

The importance of chemistry in biological phenomena was hardly noticed 60 years ago. Now we understand and examine genetics and heredity in simple chemical terms as DNA, that is easily analyzed, synthesized, and rearranged. Species are modified at will. It is no longer a question of whether we can determine the sequence of the three billion base pairs of the human genome, but rather who will do it first.

In this era of science, characterized by informational plenty, I have selected four among the many problems that warrant our concern, whether we be scientists, clinicians, or neither.

They are first, the antiscience and antitechnologic attitudes in society; second, the consequent lack of support for basic science; third, the commercialization of biotechnology; and finally, the possible abuses of genomic knowledge.

The first problem is the rising tide of public fear, distrust and rejection of science: chemical, biological or technological. It is evident that chemistry has had a poor image for some time, the image of biology has not been doing well either, and there are those who dwell on the failure of science to cure the ills of society.

As a result of an uninformed or misinformed public, we have the second problem: the lack of adequate financial support for basic science and the severe pressure to engage in targeted research.

It may seem unreasonable and impractical, even to scientists, to solve an urgent problem, such as a disease, by pursuing apparently unrelated questions in basic biology or chemistry. Yet, the pursuit of understanding the basic facts of nature has proven throughout the history of medical science to be the most practical and cost-effective route to successful drugs and devices.

The same is true in agriculture and industry. Invention is the mother of our necessities. Inventions only later become necessities. Fax machines were invented 40 years ago, but it took a deteriorated postal service among other factors to make them the necessities they are today. The lessons to be learned are crystal clear. It is crucial for a government, a society, a culture, a company, and a university, to understand the nature of the creative process and to provide for its support. No matter how counter-intuitive it may seem, basic research is the lifeline of practical advances in medicine and pioneering inventions are the source of industrial strength. The future is not predicted, it is invented.

Frequently, I hear the question whether a small country with many needs and limited resources can afford to invest significant sums in the training and sustenance of scientists to do basic research. My advice is simple: no country that aspires to enter the next century of science and technology can afford to be left behind. The consequences of not keeping up with the world pace in science are disastrous: a drain of the best brains to other countries and the dulling and discouragement of those who remain. Even more, with the departure of their best scientists and engineers, the exploitation of ideas and devices produced elsewhere in the world will be laggardly and ineffective. Governments encourage research that is oriented to practical objectives in medicine, agriculture and industry. However, goal-oriented research rarely achieves its goal, diverting the creative energies of scientists from making great inventions. Unlike a company, which needs to supply profitable products immediately, the government of a country can and must invest in the long-term future.

Scientific data are now instantly transmitted and assimilated worldwide, bringing scientifically disadvantaged countries to the forefront of this new knowledge and enabling them to contribute to it. The global involvement in genetic science from Afghanistan to Zaire has been promoted by UNIDO in workshops, fellowships and projects. A major example is ICGEB; the International Center for Genetic Engineering and Biotechnology initiated by UNIDO and based in Trieste and New Delhi. Their unique and extraordinary program, funded largely by Italy, deserves the support from the industrialized nations, but unfortunately still lacks it.

Before considering the third problem, the advantages and disadvantages of biotechnology, we should be clear that the hybrid term biotechnology embodies the danger of blurring the important distinction between biology and technology. Biology, in its broader context is a quest for knowledge about life. Technology, again in broad terms, is the engineering to apply that knowledge to practical ends, specifically to obtain marketable, profitable products. Both basic and applied science are absolutely essential, but they differ in their design, just as their practitioners, the scientists and engineers, differ in their temperaments and training. Biology and technology are interactive and interdependent.

The discoveries of recombinant DNA, cloning and genetic engineering were all made in academic laboratories. But these laboratories were then, and still are, ill-equipped to develop these discoveries, to bring them to the stage of large scale production and the ultimate marketing of efficacious, safe drugs and devices. The large pharmaceutical companies in the early '70's were not disposed to clone genes and isolate their utterly novel protein products: the rare hormones, cytokines and receptors, agents that could perform previously impossible functions as diagnostic and therapeutic agents. Proteins were strange entities to the pharmaceutical companies at that time. For these reasons, we needed the small biotech ventures to undertake the challenge to blend and innovate the biotechnologies. By their efforts, the discoveries in academic laboratories were advanced to the point where the big companies could conduct the large-scale development and production for clinical trials, obtain the regulatory approvals and carry out responsible marketing. There are now over 1200 companies in the U.S. employing 200,000 people directly and many more in related industries. Many of these biotech companies continue to represent attractive and practical means to discover and develop new drugs and devices to advance medicine and agriculture.

These technologies represent the greatest advances in the history of the biomedical sciences. Our capacity to isolate, analyze, synthesize and rearrange the genes of every organism - from viruses to human - will continue to revolutionize the practice of medicine and agriculture. Even greater, biotechnologies will advance our understanding of the basic chemistry of life that will lead to even more remarkable and unanticipated benefits.

Unfortunately, the public still remains concerned about the safety of genetic engineering and related biotechnologies. People are agitated by the doomsday scenarios of ethicists, environmentalists, and alarmists. Let me put it simply. After 25 years of work with recombinant DNA and genetic engineering, many millions of experiments have been performed by amateurs without supervision, as well as in the huge operations in highly sophisticated academic and commercial procedures. I am unaware of a single adverse result. Clearly safer than jaywalking or slicing bagels!

Now for the problems associated with biotechnology. I will focus on just two: the commercialization of biotechnology, and distortion of the academic mission.

Commercial ventures in biotechnology are very human. Whether the biotech enterprise is private or governmental, it is a human venture and as such, susceptible to a variety of mismanagements. With the goal to make money in a short time, there are, inevitably, instances of misrepresentation, litigousness and even fraud. It should be understood that biotech companies are not in business to do research and acquire knowledge for its own sake. Rather, they are in research in order to do business and to turn a profit. They possess neither the mandate nor the tradition to advance scholarship. Ventures must instead prove their profitability in the ebb and flow of financial markets and have to withstand abrupt changes in corporate management with a focus on a short-term goal. Litigation in biotechnology has engaged thousands of lawyers and has become a significant industry.

A second concern is that profit-driven ventures are more likely to promote secrecy and to subvert academic units with patent agreements. Joint ventures often demand exclusive access to discoveries and delay publications. Scientists, students, and academic resources dedicated to the commercial ventures are often diverted from basic, untargetted research to work on projects that are highly focussed and selected for the prospect of early profitability.

From a cultural standpoint, it has long been a matter of deep concern that our society is driven by a conflict between two cultures: The sciences and the humanities. I now see a third culture emerging with a profound impact on both: it is the new culture of technology. This new culture is evident from the profound impact of biotechnology on heredity, disease and human behavior on the one hand, and on the other, the pervasive influence of computers, transistors and lasers on all communication and in every aspect of our business and personal lives.

Finally, we have a fourth concern, about the use of genomics, the use of genetic knowledge. What uses and possible abuses will come from knowing the total sequence of each human genome? Let me say emphatically that knowledge always beats ignorance. Yet, even when we know the 3-billion-letter sequence that spells the average human genome, we will still need to identify the 0.1% of the differences among us in nucleotides, the 3-million differences that uniquely identify each of us. We will need to know whether these differences are benign or associated with a disease or a predisposition to a disease. In some cases, we may even identify differences among us in the genes that improve a function: sharper vision, an ear for music, and a sunny disposition.

By knowing the genetic basis of some devastating diseases, we have already helped many people to avoid them. Analysis of DNA in a legal matter is newsworthy, but not profound. What is profound is the applications of genomics to basic research in biomedical science. The advances from genomics are incalculable. Regarding personal genomic information, we need to be concerned about their abuse in matters of employment, insurance and personal affairs. These issues are being widely discussed and do deserve the most serious consideration.

There is a subtle issue that has not been discussed enough. It is the illusion created to justify and promote the large federal and industrial investments needed to complete the human genome project. The benefit from this new knowledge will be enormous, but I am concerned about the illusion that knowing the sequence of the genome will tell us all we need to know to understand the structure and function of an organism. That simply is not true. We will still be miles away from our goal of understanding the enormous variety of life processes at the basic level of proteins and other molecular details.

In conclusion, having discussed several problems, I want to finish on a very positive note. What deserves the most emphasis and what does unite us all in science is our unconflicted and overriding devotion to the culture of science? What is great about this culture is the discipline of science, not the people doing it. It is science that enables us, ordinary people doing ordinary things, when assembled, to reveal the extraordinary and awesome beauties of nature.

To my mind, science is the crown jewel of civilization. To quote the late Karl Popper, an eminent philosopher of science and society: "Next to music and art, science is the greatest, most beautiful and most enlightening achievement of the human spirit." I disagree only in placing science first.