- Email: [email protected]
The Future of Molecular Medicine
Molecular Aspects of Medicine 22 (2001) 91±100 www.elsevier.com/locate/mam
Editorial
The Future of Molecular Medicine 4th Berlin Colloquium of the Gottlieb Daimler and Karl Benz Foundation in co-operation with the Max Delbr uck Center for Molecular Medicine (MDC), Berlin-Buch, on Wednesday, May 10, 2000 in Berlin at the Konrad Adenauer foundation, Tiergartenstr. 35, D-10785 Berlin The title of this symposium ``The Future of Medicine'' should have a questionmark because nobody can tell for sure how health and disease will be de®ned and diagnosed in the future. We do not know how patients will be treated and want to be treated ten or more years from now, though it seems likely that it will be a blending of modern practices and ancient traditions. In spite of all the progress we make in today's science we have to remember that there are certain kinds of so-called traditional ways of healing, that have persisted more or less unchanged for many centuries and are still in widespread use. Just think of traditional Chinese acupuncture or the Asian herbal called ``Barefoot Doctor's Manual'' that was published in England in the 1980s. In contrast to these eastern practices, western medicine is based on the rise of the natural sciences, and has changed enormously with them in the past and will probably change at even faster in the future. Modern medicine as we know it today in the western hemisphere started its development more than four hundred years ago. Historians place its beginnings at the period we call Renaissance. It was then that Paracelsus questioned the traditional authority of Galen and Avicenna by burning their books, and it was then that the ®rst anatomy theatres were established. After a long interruption in the history of mankind it ®nally became possible again for scientists to look inside the body to study the shape of organs and do anatomical studies. These early anatomists created the basis for modern medicine and prepared the stage for postmortem examinations that advanced the understanding of diseases in the following centuries. Scientists moved away from the traditional assumption that body ¯uids like gall and blood were responsible for sickness and disorders. In 1761 the Italian physician Giovanni Morgagni published a treatise that de®nitely established malfunctioning organs as the cause for diseases (Fig. 1). 0098-2997/01/$ - see front matter Ó 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 0 9 8 - 2 9 9 7 ( 0 1 ) 0 0 0 0 2 - 4
92
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
Fig. 1. In looking for the causes of disease in man scientists discovered layer after layer. In the 18th century they concentrated on organs, and in the 19th century they discovered cells to be linked with disease states. Today we ®nd the causes in molecules and genes.
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
93
In the coming centuries science advanced this point of view to another level and discovered that the state of body cells could be directly linked with disease states (Fig. 1). The great breakthrough was achieved by one of the famous founders of medicine in Berlin. I talk about Rudolf Virchow, who created what is called Cellular Pathology in 1858. Virchow identi®ed the function of cells as the basis of health and disease. At the same time the science of bacteriology started to develop, among others through the work of Louis Pasteur, who could demonstrate that germs cause the decay of organic substances. Already the days before Pasteur saw the rise of the science we call chemistry. It allowed to take a closer look at the substances that were then available as drugs. Many of the therapies that we still apply at the present time are based on ideas and insights that were made in the late 19th century on the basis of concepts that grew out of cellular pathology and went on to bring forward the science of biochemistry. The next generation of scientists did not stop at the level of cells. They opened and entered these basic structures of organisms to discover the other units of life that excite us today and that present us once more with a new science. I am talking about genes and the genomics that deals with them. With the ongoing genetic invasion of medicine it seems that we experience a paradigmatic shift that can be compared to the revolution connected with the name of Nicolaus Copernicus who forced us to leave the Geocentric World alone and learn to live in an Heliocentric World. This shift that removed the earth from the center of the cosmos was one of the most important events not only in the history of science but in the history of ideas in general. Till this time people thought they were right in the middle of the world and they thus could look at the rest as if it were on the outside. Then they realized that they were part of the world and all they could do was at the inside. And if you want to follow that analogy, we can say, that the pre-genomic medicine was looking at bodies and cells from the outside. One was looking at the organs without gaining a view on what was really happening at the genes and their information inside. Molecular genomic medicine reverses this situation. It looks from the inside, from the information molecules which are the origin of all cellular life, and then tries to compare this view with what goes at the outside in order to understand organs that are no longer functioning. Since this revolution has just begun it will be very exciting to see what its consequences will be. The future of medicine will heavily depend on it. Please, grant me permission at this point for a further excursion into the history of science and let me ask, how molecular genomic medicine did get started. You will not be surprised about my impression that Max Delbr uck was one of the important people that helped to found our area of research (Fig. 2). He worked in Berlin-Buch on the campus that is now named after him. Here he tried to establish an interdisciplinary approach combining physics and genetics aiming at explaining the phenomena of inheritance and of life. Delbr uck teamed up with the Russian geneticist Nicolai Timofeev Ressowsky, and they both tried to understand how radiation could in¯uence genetic material. They collaborated for a landmark paper that they published in 1935 with a third co-worker, the physicist K.G. Zimmer. It is entitled ``On the Nature of Gene Mutation and Gene Structure'' (Fig. 3) and it contains the then sensational suggestion that genes consist of atoms that combine in such a way that
94
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
Fig. 2. Max Delbr uck (1906±1981) in his caltech oce in the 1970s.
structures are produced that remain stable through several generations. Unfortunately the paper is written in German, but I nevertheless strongly recommend to you to take a look at it, since this essay exerted a considerable in¯uence on the history of molecular biology. It did so with the help of a world famous physicist who made decisive use of Delbr uck's suggestion of an atomic nature of the gene. I speak of the noble laureate Erwin Schr odinger (Fig. 4) who was forced to leave Berlin and Germany when the Nazis rose to power. In the late 1930s he settled in Dublin where he was asked to give lectures on the physical understanding of life. Schr odinger had read the 1935 paper by Delbr uck and his co-workers, and he actually used what he called ``Delbr uck's model'' to give the ®rst description of the molecular nature of the genes, and he wanted to use it to explain what he called the phenomena of life (Fig. 5). He presented his ideas in the now famous book ``What is life? The physical aspect of the living cell'' which was published at the end of the second world war and widely read ± among others by Francis Crick and James Watson, the well-known discoverers of the double helix. Crick ± like Delbr uck ± was a physicists, and we have to accept the fact that modern biology was not created by biologists but by physicists. These scientists were, of course, in¯uenced by one of the greatest minds of modern times, i.e. by Isaac Newton, whose ideas are still exerting their in¯uence. Newton had put forward the most successful theory in modern physics by showing that the same laws hold in
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
95
Fig. 3. The famous paper written in German that investigated ``The Nature of Gene Mutation on Gene Structure''.
heaven and on earth. Newton was able to explain the gravitational force, and with its help he recognized the causes for the tides of the ocean and he was able to derive the laws that govern the movements of the planets in the skies. He thus created one of
96
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
Fig. 4. Erwin Schr odinger (1887±1962) in a portrait from the 1940s.
the most successful theories of modern physics and by its triumph he painted a rather deterministic picture of reality (Fig. 6). After this breakthrough, sciences other than physics were looking for their Newton and so was biology hoping for a physical view of life. Delb uck's suggestions went into this direction, which was followed by the two persons I already mentioned, namely Watson and Crick, the famous couple who described the even more famous double helix in 1953. With Crick being a physicist the in¯uence of this science on the development of biological thinking cannot be overestimated. Remember that it was Crick who proposed the molecular dogma that is still on most scientist's mind. According to that dogma it is the genetic substance DNA that makes RNA which in turn makes protein which in turn makes function. This scheme was often misinterpreted as de®ning a certain kind of genetic determinism and I cannot help but feel that much of the opposition against biomedicine and molecular genetics is due to this false concept that seems to suggest that biology is fate. We have to remember that this deterministic concept of life was introduced into the life sciences by physicists. It is true that they provided us with an enormous improvement in methodology, but they are probably also responsible for the persisting misconception that life can be explained in a fully deterministic way. But life is full of surprises and the future of medicine is unknown. We do not know where it goes, there is a large degree of uncertainty. If we would know the future we would not have to do research. Nevertheless certain predictions are possible. Some people say that within ten years there will be a great number of genetic tests for diseases or disease susceptibilities, some of them are already available. It is
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
97
Fig. 5. The opening pages of Chapter 5 from Schr odinger's ``What is life?''.
an open question how much one can conclude for medical practice from these genetic tests but they will be developed and oered. It also will be very likely that we see the ®rst successful examples of gene therapy and the ®rst development of
98
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
Fig. 6. Two British natural philosphers and some consequences of their thinking.
corresponding protocols. The feasibility of this approach has already been shown in many instances. Though so far no patient has been cured by gene therapy despite all the activities, one can nevertheless still speculate that in about 20 years germ-line therapy may be possible in principal. Computer models for human and animal cells may be available in 30 years, individual genome sequencing with cheaper and faster methodology may be a reality and even clinical trials to prolong life may be feasible. Forty years from now there's a possibility that genome-based health care becomes a reality. Individualized prevention may be feasible. Modern medicine will then probably no longer want to wait for people to become sick but will instead try to look more closely at predisposing factors ± most likely genes ± in order to prevent the outbreak of a disease. Already today there are many examples that show how to go along that way. This will all be accompanied by a worldwide debate on how we apply our knowledge from genetic research if it provides us with the possibility to interfere with germ lines and to use embryonic stem cells for new therapies. Nobody is able to predict the future, as I mentioned, and we should look closer at topics that we have to deal with at the present time. Three of these topics are being discussed today and this kind of psychedelic picture of my view of molecular medicine may be an illustration on where we might go on in our discussions (Fig. 7). One topic is the question of what happens after the human genome is being sequenced. Today scienti®c and popular journals are full of reports that deal with the advances in this area at the present time. And they ask what happens after the genome sequence is complete? How do we deal with the data and how do we extract knowledge from that for a better practice of medicine? The second important topic, of course, is the question, what happens if we de®nitely identify a disease with a clear cut genomic or genetic origin. How can and will and should it be corrected? How do we interfere with the genome? One of the possibilities is gene therapy with the various methodologies available in this area. This will be the second topic we are discussing today. The third topic is probably the most controversial one. It has a lot of potential in many directions with respect to medical and non-medical use. I talk about embryonic stem cells research and it's medical applications, the handling of the germ line of animals and men, of interference with the germ line, of shaping the future evolution and ± as some people say ± may be the creation of new organisms better known by the term ``cloning''.
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
Fig. 7. An illustration of the molecular parts that play a role in the future of medicine.
99
100
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
Obviously already today there are many topics of great interest. The future of medicine will bring us even more food for thought and debate. I think science is ready for it and we are ready for science. Let ``The Future of Molecular Medicine'' begin. Detlev Ganten Max Delbruck Center for Molekulare Medicine (MDC), Department of Clinical Pharmacology, Freie Universitat Berlin, Robert-Rossle-Strasse 10, 13125 Berlin, Germany E-mail address: [email protected]
Editorial
The Future of Molecular Medicine 4th Berlin Colloquium of the Gottlieb Daimler and Karl Benz Foundation in co-operation with the Max Delbr uck Center for Molecular Medicine (MDC), Berlin-Buch, on Wednesday, May 10, 2000 in Berlin at the Konrad Adenauer foundation, Tiergartenstr. 35, D-10785 Berlin The title of this symposium ``The Future of Medicine'' should have a questionmark because nobody can tell for sure how health and disease will be de®ned and diagnosed in the future. We do not know how patients will be treated and want to be treated ten or more years from now, though it seems likely that it will be a blending of modern practices and ancient traditions. In spite of all the progress we make in today's science we have to remember that there are certain kinds of so-called traditional ways of healing, that have persisted more or less unchanged for many centuries and are still in widespread use. Just think of traditional Chinese acupuncture or the Asian herbal called ``Barefoot Doctor's Manual'' that was published in England in the 1980s. In contrast to these eastern practices, western medicine is based on the rise of the natural sciences, and has changed enormously with them in the past and will probably change at even faster in the future. Modern medicine as we know it today in the western hemisphere started its development more than four hundred years ago. Historians place its beginnings at the period we call Renaissance. It was then that Paracelsus questioned the traditional authority of Galen and Avicenna by burning their books, and it was then that the ®rst anatomy theatres were established. After a long interruption in the history of mankind it ®nally became possible again for scientists to look inside the body to study the shape of organs and do anatomical studies. These early anatomists created the basis for modern medicine and prepared the stage for postmortem examinations that advanced the understanding of diseases in the following centuries. Scientists moved away from the traditional assumption that body ¯uids like gall and blood were responsible for sickness and disorders. In 1761 the Italian physician Giovanni Morgagni published a treatise that de®nitely established malfunctioning organs as the cause for diseases (Fig. 1). 0098-2997/01/$ - see front matter Ó 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 0 9 8 - 2 9 9 7 ( 0 1 ) 0 0 0 0 2 - 4
92
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
Fig. 1. In looking for the causes of disease in man scientists discovered layer after layer. In the 18th century they concentrated on organs, and in the 19th century they discovered cells to be linked with disease states. Today we ®nd the causes in molecules and genes.
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
93
In the coming centuries science advanced this point of view to another level and discovered that the state of body cells could be directly linked with disease states (Fig. 1). The great breakthrough was achieved by one of the famous founders of medicine in Berlin. I talk about Rudolf Virchow, who created what is called Cellular Pathology in 1858. Virchow identi®ed the function of cells as the basis of health and disease. At the same time the science of bacteriology started to develop, among others through the work of Louis Pasteur, who could demonstrate that germs cause the decay of organic substances. Already the days before Pasteur saw the rise of the science we call chemistry. It allowed to take a closer look at the substances that were then available as drugs. Many of the therapies that we still apply at the present time are based on ideas and insights that were made in the late 19th century on the basis of concepts that grew out of cellular pathology and went on to bring forward the science of biochemistry. The next generation of scientists did not stop at the level of cells. They opened and entered these basic structures of organisms to discover the other units of life that excite us today and that present us once more with a new science. I am talking about genes and the genomics that deals with them. With the ongoing genetic invasion of medicine it seems that we experience a paradigmatic shift that can be compared to the revolution connected with the name of Nicolaus Copernicus who forced us to leave the Geocentric World alone and learn to live in an Heliocentric World. This shift that removed the earth from the center of the cosmos was one of the most important events not only in the history of science but in the history of ideas in general. Till this time people thought they were right in the middle of the world and they thus could look at the rest as if it were on the outside. Then they realized that they were part of the world and all they could do was at the inside. And if you want to follow that analogy, we can say, that the pre-genomic medicine was looking at bodies and cells from the outside. One was looking at the organs without gaining a view on what was really happening at the genes and their information inside. Molecular genomic medicine reverses this situation. It looks from the inside, from the information molecules which are the origin of all cellular life, and then tries to compare this view with what goes at the outside in order to understand organs that are no longer functioning. Since this revolution has just begun it will be very exciting to see what its consequences will be. The future of medicine will heavily depend on it. Please, grant me permission at this point for a further excursion into the history of science and let me ask, how molecular genomic medicine did get started. You will not be surprised about my impression that Max Delbr uck was one of the important people that helped to found our area of research (Fig. 2). He worked in Berlin-Buch on the campus that is now named after him. Here he tried to establish an interdisciplinary approach combining physics and genetics aiming at explaining the phenomena of inheritance and of life. Delbr uck teamed up with the Russian geneticist Nicolai Timofeev Ressowsky, and they both tried to understand how radiation could in¯uence genetic material. They collaborated for a landmark paper that they published in 1935 with a third co-worker, the physicist K.G. Zimmer. It is entitled ``On the Nature of Gene Mutation and Gene Structure'' (Fig. 3) and it contains the then sensational suggestion that genes consist of atoms that combine in such a way that
94
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
Fig. 2. Max Delbr uck (1906±1981) in his caltech oce in the 1970s.
structures are produced that remain stable through several generations. Unfortunately the paper is written in German, but I nevertheless strongly recommend to you to take a look at it, since this essay exerted a considerable in¯uence on the history of molecular biology. It did so with the help of a world famous physicist who made decisive use of Delbr uck's suggestion of an atomic nature of the gene. I speak of the noble laureate Erwin Schr odinger (Fig. 4) who was forced to leave Berlin and Germany when the Nazis rose to power. In the late 1930s he settled in Dublin where he was asked to give lectures on the physical understanding of life. Schr odinger had read the 1935 paper by Delbr uck and his co-workers, and he actually used what he called ``Delbr uck's model'' to give the ®rst description of the molecular nature of the genes, and he wanted to use it to explain what he called the phenomena of life (Fig. 5). He presented his ideas in the now famous book ``What is life? The physical aspect of the living cell'' which was published at the end of the second world war and widely read ± among others by Francis Crick and James Watson, the well-known discoverers of the double helix. Crick ± like Delbr uck ± was a physicists, and we have to accept the fact that modern biology was not created by biologists but by physicists. These scientists were, of course, in¯uenced by one of the greatest minds of modern times, i.e. by Isaac Newton, whose ideas are still exerting their in¯uence. Newton had put forward the most successful theory in modern physics by showing that the same laws hold in
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
95
Fig. 3. The famous paper written in German that investigated ``The Nature of Gene Mutation on Gene Structure''.
heaven and on earth. Newton was able to explain the gravitational force, and with its help he recognized the causes for the tides of the ocean and he was able to derive the laws that govern the movements of the planets in the skies. He thus created one of
96
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
Fig. 4. Erwin Schr odinger (1887±1962) in a portrait from the 1940s.
the most successful theories of modern physics and by its triumph he painted a rather deterministic picture of reality (Fig. 6). After this breakthrough, sciences other than physics were looking for their Newton and so was biology hoping for a physical view of life. Delb uck's suggestions went into this direction, which was followed by the two persons I already mentioned, namely Watson and Crick, the famous couple who described the even more famous double helix in 1953. With Crick being a physicist the in¯uence of this science on the development of biological thinking cannot be overestimated. Remember that it was Crick who proposed the molecular dogma that is still on most scientist's mind. According to that dogma it is the genetic substance DNA that makes RNA which in turn makes protein which in turn makes function. This scheme was often misinterpreted as de®ning a certain kind of genetic determinism and I cannot help but feel that much of the opposition against biomedicine and molecular genetics is due to this false concept that seems to suggest that biology is fate. We have to remember that this deterministic concept of life was introduced into the life sciences by physicists. It is true that they provided us with an enormous improvement in methodology, but they are probably also responsible for the persisting misconception that life can be explained in a fully deterministic way. But life is full of surprises and the future of medicine is unknown. We do not know where it goes, there is a large degree of uncertainty. If we would know the future we would not have to do research. Nevertheless certain predictions are possible. Some people say that within ten years there will be a great number of genetic tests for diseases or disease susceptibilities, some of them are already available. It is
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
97
Fig. 5. The opening pages of Chapter 5 from Schr odinger's ``What is life?''.
an open question how much one can conclude for medical practice from these genetic tests but they will be developed and oered. It also will be very likely that we see the ®rst successful examples of gene therapy and the ®rst development of
98
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
Fig. 6. Two British natural philosphers and some consequences of their thinking.
corresponding protocols. The feasibility of this approach has already been shown in many instances. Though so far no patient has been cured by gene therapy despite all the activities, one can nevertheless still speculate that in about 20 years germ-line therapy may be possible in principal. Computer models for human and animal cells may be available in 30 years, individual genome sequencing with cheaper and faster methodology may be a reality and even clinical trials to prolong life may be feasible. Forty years from now there's a possibility that genome-based health care becomes a reality. Individualized prevention may be feasible. Modern medicine will then probably no longer want to wait for people to become sick but will instead try to look more closely at predisposing factors ± most likely genes ± in order to prevent the outbreak of a disease. Already today there are many examples that show how to go along that way. This will all be accompanied by a worldwide debate on how we apply our knowledge from genetic research if it provides us with the possibility to interfere with germ lines and to use embryonic stem cells for new therapies. Nobody is able to predict the future, as I mentioned, and we should look closer at topics that we have to deal with at the present time. Three of these topics are being discussed today and this kind of psychedelic picture of my view of molecular medicine may be an illustration on where we might go on in our discussions (Fig. 7). One topic is the question of what happens after the human genome is being sequenced. Today scienti®c and popular journals are full of reports that deal with the advances in this area at the present time. And they ask what happens after the genome sequence is complete? How do we deal with the data and how do we extract knowledge from that for a better practice of medicine? The second important topic, of course, is the question, what happens if we de®nitely identify a disease with a clear cut genomic or genetic origin. How can and will and should it be corrected? How do we interfere with the genome? One of the possibilities is gene therapy with the various methodologies available in this area. This will be the second topic we are discussing today. The third topic is probably the most controversial one. It has a lot of potential in many directions with respect to medical and non-medical use. I talk about embryonic stem cells research and it's medical applications, the handling of the germ line of animals and men, of interference with the germ line, of shaping the future evolution and ± as some people say ± may be the creation of new organisms better known by the term ``cloning''.
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
Fig. 7. An illustration of the molecular parts that play a role in the future of medicine.
99
100
Editorial / Molecular Aspects of Medicine 22 (2001) 91±100
Obviously already today there are many topics of great interest. The future of medicine will bring us even more food for thought and debate. I think science is ready for it and we are ready for science. Let ``The Future of Molecular Medicine'' begin. Detlev Ganten Max Delbruck Center for Molekulare Medicine (MDC), Department of Clinical Pharmacology, Freie Universitat Berlin, Robert-Rossle-Strasse 10, 13125 Berlin, Germany E-mail address: [email protected]