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Prepared for 18th International Genetics Congress
Beijing, August 15, 1998, Revised September 9
Department of Genetics, University of Wisconsin, Madison, WI 53706, USA
This has been a great Congress, with state of the art science and intellectual ferment. All
of you in the audience have had the opportunity to share my excitement.
I regret not being here to give my talk at the scheduled time on August 10.
Unfortunately my flight was canceled so I arrived a day late. This Congress has therefore had
one feature that no other congress has had, having its introductory talk given at the end. I am
happy that Dr. Brenner was able to fill in for me on the first day. This is the second time that
Sydney and I have been on the same program, and on the earlier program he failed to appear.
So there is a certain symmetry in my absence.
I spent a month in China in 1983. How things have changed in those 15 years, in every
way, including genetics. At the time I especially treasured the opportunity to visit China’s
pioneer Drosophila geneticist, J. C. Li. Li did important work in the Morgan laboratory in the
United States and wrote several papers with C. B. Bridges. He was largely responsible for
introducing Drosophila research to China. At the time of my visit he was 89 years old, hale
and hearty and full of enthusiasm. His physique reflected his earlier career as a football player
at Purdue University. Until a few years before, he had bicycled to work and taught genetics
courses. I also met C. Y. Zhou, then 81 and a retired professor of agronomy. He was a
leading worker in plant genetics, having studied at Cornell with R. A. Emerson. Among
American universities, Columbia and Cornell were the two largest influences on early Chinese
genetics, which got off to a strong start.
I am particularly delighted to find Li’s student and my long time friend, C. C. Tan, on
this program. C. C. and I first met at the University of Texas 52 years ago. The story that I
heard is that in the early 1930s J. C. Li sent one of Tan’s papers to T. H. Morgan, who passed
it on to Theodosius Dobzhansky. Tan and Dobzhansky shared an interest in ladybird beetles,
and he and Morgan arranged for Tan to come to the United States. C. C. did widely
recognized work with Sturtevant and Dobzhansky on analysis of inversions in salivary gland
chromosomes and showed the correspondence of homologous gene positions in related
species. He also pioneered in transplanting eye-primordia, foreshadowing the later work of
Beadle and Ephrussi. At the University of Texas he gave a seminar on mosaic dominance in
ladybird beetles, which reminded us drosophilists of the phenotypes at the scute locus. C. C.
and I had dinner together in a Chinese restaurant, and he suggested that if he ordered the food
we would get more authentic Chinese dishes. Alas, no one in the restaurant could speak
Chinese! Between then and now, my life has been easy; his, alas, has not. But I am delighted
that a richly deserved honor, the Congress Presidency, has come his way at last. He celebrated
his 90th birthday anniversary this week. He has inspired a whole generation of Chinese
Genetics is a thriving subject in China, as this Congress has revealed. I trust the
Congress will be a stimulus for further work and further international cooperation. When I
was here in 1983, Chinese genetics had been through 25 disastrous years. After a strong start
in Mendelian genetics from 1920 to 1949, came a period of Lysenko’s influence from 1950 to
1957. This was followed by a period from 1958 to 1966 of co-existence of the two genetics,
which must have been terribly confusing for students. Then came the cultural revolution
from 1967 to 1976. Since 1976 the original genetic program has been gradually restored. It
was inspiring in 1983 to see the great zeal and enthusiasm, and especially the ability to do
good work without the sophisticated equipment that I was used to seeing at home.
It was a time of optimism, but people and laboratories were poor. For example,
researchers had to make their own enzymes and they did not have up-to-date equipment. I
was asked by several students to suggest problems that could be done inexpensively. One of
my suggestions has borne fruit. I had been interested in “the poor man’s genetics”, following
the Y chromosome by using surnames. I thought that China with its ancient records would be
a great place to use this technique to study population structure and migration. So I put Du
Roufu in touch with Luca Cavalli-Sforza and they have carried out an extensive collaborative
Genetics a twentieth century science, yet it was built on solid footings from earlier years.
The nineteenth century brought us Darwin’s theory of evolution; the shocked intellectual
world has never been the same. The century brought Galton’s introduction of quantitative
methods for studying inheritance and his approach to the separation of nature and nurture by
using twins. It brought Weismann’s distinction between germinal and somatic tissue. And, it
brought an understanding of chromosome behavior and meiosis. But, above all, it brought
Gregor Mendel and his experiments with garden peas, so simple and so beautiful, and so
Mendel was the hard-luck guy of nineteenth century biology, destined to have his work
misunderstood or ignored. This was true, not only in genetics, but in other fields, for example
meteorology and bee breeding. In meteorology his pioneering work, such as using the
recently developed telegraph to forecast weather for local farmers, as well as more basic work
on cyclones, was unrecognized in the larger world until after his death. In bee-breeding he
was frustrated by the queen bee’s stubborn refusal to mate except in the clouds. Mendel’s
later years were spent fighting administrative battles, and his research suffered — a
phenomenon not entirely unknown in our time. Alas, only after his death was he suddenly
transformed from an obscure Abbott to a scientific celebrity.
The science of genetics began with the triple rediscovery of Mendel’s rules, by three
scientists in three different countries. It was immediately apparent that Mendel’s factors
followed the rules that cytologists had recently worked out for chromosome behavior. Many
people must have seen the connection, but the ones who wrote about it most convincingly
were Boveri in Germany and Sutton in the United States. The chromosomal basis of heredity
was immediately accepted by almost all geneticists, although the definitive proof waited until
1916 for Bridges’ nondisjunction experiments.
It is convenient to divide twentieth century genetics into two periods, each about 50
years. A more precise dividing time between the old and the new genetics would be 1953, the
date of Watson and Crick’s great discovery. But I’ll speak in round numbers. In the first 50
years genetics was dominated by breeding experiments and the microscope — transmission
The second period started out by being dominated by microbes and molecules, tiny organisms
and enormous molecules. During the half-century, the techniques — beautiful, powerful
techniques —became increasingly chemical and the computer has played an indispensable
I would like to refer to the driving techniques of the two periods as the two M’s and the
two C’s. In the first period the two M’s were mating and microscopy. In the second period,
the two C’s were chemicals and computers.
On seeing the program of this Congress, I imagined myself as a Rip Van Winkle who
had gone to sleep in 1950 and had just awakened. (For those not acquainted with Western
lore, Rip Van Winkle was a character who slept for 20 years and awoke to a greatly changed
world.) I took a casual look at the program. Here is a short list of words -- mostly taken from
the program titles or suggested by them -- words that did not exist in 1950, or whose meaning
has greatly changed. I have put them in alphabetical order.
Anticipation (formerly an ascertainment concept, now cytological); apoptosis (now
studied genetically); BAC clones; Caenorhabditis elegans
, Zebrafish, Puffer fish,
(of course these species existed, but no western geneticist had heard of them,
although fugu was well known to Japanese); central dogma; clone (all sorts of new meanings);
coalescent; concerted evolution; cosmid (could anyone from pre-1950 guess the meaning?);
DNA amplification; double strand breaks; down regulation; endoplasmic reticulum; enhancer;
epigenetic (old word with a new meaning; maybe the new meaning is a mistake and another
word should have been employed); fingerprints (again a new meaning); fluorescent in situ
hybridization (better know as FISH); fragile chromosomes; genomics; HLA; Holliday
junction; homeobox; hybridization (another old word with a new meaning); junk DNA;
knockout; LINEs and SINEs; messenger RNA; molecular clock; mutators (actually mutator
genes were known but not understood); nucleosome; origin of replication; PCR; VNTR;
physical map; prion; promoter; pseudoautosomal; QTL; rDNA; restriction enzyme; retrovirus;
retrotransposon; signal transduction; synaptinemal complex; telomere (Muller had invented
the word, but the structure has been quite different from what he envisioned); transcription;
translation; transgene; transition; transversion; transposon; Xist.
I could go on, but I want to save time for saying other things. So let me return to the first
The First 50 Years
Soon after the discovery of the chromosomal basis of heredity, the role of sex
determination became an important issue. Did sex follow Mendel’s laws? It was immediately
apparent that it could be thought of as a repeated Mendelian backcross, but was there a gene?
A pair of heteromorphic chromosomes, called X and Y, clearly played a role in sex
determination, but the earliest workers had them confused. It was left to a bright young
woman, Nettie Stevens, to straighten it out. She showed clearly in an insect that the female has
two X chromosomes and the male an X and Y. But the generality was not clear. Doncaster,
studying moths, found genetic evidence for sex linkage, and the evidence pointed the other
way. It is not hard to image the confusion that ensued. The correspondence between
cytological behavior of X and Y chromosomes and the rules of sex-linked inheritance were
thrown into doubt. It was straightened out a few years later by the Morgan school, studying
sex-linkage in Drosophila, and by the realization that in lepidoptera the female sex is
Another early example of different conclusions reached by studying different organisms
arose with silkworm genetics, developed to a high point in Japan. As I mentioned, female sex
is heterogametic in moths. There was another difference, however. In Drosophila, sex is
determined by the number of X chromosomes and their relationship to the number of
autosomes; the Y is not involved. In the silkworm, the Y is the determining element.
American geneticists automatically assumed that humans would behave like big Drosophilas.
I recall a paper, which explained a curious human inheritance pattern by invoking the
Drosophila model of attached-X chromosomes. For all I know, Japanese geneticists reached
the opposite conclusion and preferred the Y chromosome determination. In any case, as
everyone in the room knows, the silkworm model was the one elected by mammals, and the
results in mice and men came as a major surprise to most western geneticists.
Many things that were thought to be understood have turned out to be different, or at
least more complicated. An example is Haldane’s rule, formulated in 1922. It says that, in
interspecies crosses whenever one sex is inviable or sterile, it is usually the heterogametic sex.
When I was in graduate school, I thought I understood the reasons. Now, as has been brought
out abundantly in this Congress, the better methods of analysis now available have shown the
story to be considerably more involved.
The first half-century was characterized by a futile search for the gene. Many
experiments were an indirect attempt to get at the nature of this elusive object — for example
by studying mutation. But most geneticists simply regarded the question as insoluble —
something for the future — and studied other problems.
I started graduate school in 1937. I well remember my feeling at the time, and I think it
was general, that it would be many years before we would know what the gene really is.
Certainly it would not happen in our lifetime. It seemed to be the most elusive of objects, and
many thought we would probably have to understand the full details of gene action before we
understood the gene itself. Hardly anyone thought of the gene as one-dimensional, although I
am informed that Koltsov suggested a double-helical structure.
Transmission genetics was essentially solved early in the century. The main principle, of
course, was Mendelism. Linkage was a conspicuous exception, but this was solved by the
Morgan school and Sturtevant’s construction of a linkage map. By the time of World War I,
geneticists knew all they needed to know to develop breeding methods. Transmission genetics
was a mature science; ready to be exploited. And it was exploited, in countless agricultural
Chromosome mapping became an important activity. In organisms with short life cycles
and large progeny numbers, such as Drosophila, progress was rapid. In the Orient the
silkworm was the center of mapping activity. Among plants, maize was the most completely
mapped. The Sixth International Congress of Genetics, held at Cornell University in 1932,
featured a living chromosome map of maize in which plants with mutant genes were planted
in rows corresponding to their chromosomal position. I recall a similar living map for the
morning glory, which was a feature of the first Japanese postwar genetics symposium in
1956. But progress in human gene mapping was essentially nil.
World War II brought a halt to genetics research in many countries. One of many tragic
examples occurred in Japan. Drosophila ananassae
was a favorite species there. A
substantial linkage map was constructed and this species had the interesting property of male
crossing over. Alas, despite four replicate cultures kept in widely different places, all the
strains were lost during the war. Dr. Moriwaki, who suffered the loss, was also the discoverer
in 1936 of cytoplasmic transmission of Leber’s optic atrophy, although of course he had no
way of knowing that the cytoplasmic elements were mitochondria.
During the first half-century, cytogenetics came into its own. Chromosome breakage and
the consequences thereof — inversions, translocations, deletions, and duplications — became
a part of the geneticist’s tool-kit . The finest development was in maize, culminating in
Barbara McClintock’s exploitation of the breakage-fusion-bridge cycle, with ramifications that
seemed incredible at the time but are now commonplace. Maize, because of its beautiful
pachytene chromosomes, was the species of choice in the United States. In the Orient,
Trillium was exploited. Drosophila got a big boost with the discovery of giant salivary gland
chromosomes. Cytogenetics was particularly pleasing to study, for you could draw a picture
of what ought to happen and it usually did.
Human cytogenetics was pitiful. The X and Y chromosomes had been identified, but
incredible as it now seems, the chromosome number itself was in doubt. I have the dubious
distinction of having studied with the man, T. S. Painter, who first reported the wrong number,
48, that dominated textbooks for a third of a century. Painter also made another mistake. C.
B. Davenport, praised for his genetic zeal and damned for his eugenic naiveté, had postulated,
as had several others, that Down’s syndrome is caused by trisomy. He obtained some cellular
material and asked Painter to look at the chromosomes. Painter looked and could find no
abnormalities. I have often wondered if this error delayed the discovery that trisomy is in fact
the cause. Let me quickly add, however, that Painter was really an excellent cytologist; the
problem was the inadequate techniques of the time. His luck changed in 1936 when he
showed that salivary gland chromosomes really were chromosomes, thus opening up the
fertile field of Drosophila cytogenetics, so richly exploited by Bridges, Muller, Sturtevant,
Dobzhansky, Lewis, and many others. How different it is now. Whereas in the early days you
couldn’t even count human chromosomes, now all you have to do is recognize different
colors. A child, unless color-blind, can do better than the most skilled cytologist of only a few
I am pleased that T. C. Hsu is attending this Congress. T. C. was a student of C. C. Tan.
He is the person who catalyzed the renewed study of human chromosomes by the discovery of
the chromosome-spreading effect of hypotonic solution. This led directly to the determination
of the correct number. In those early days we didn’t know what human chromosomes looked
like and one person showed a picture of what were presumably his own chromosomes, but
these turned out to be a contaminant from some other species. Contamination was common in
the early days of human cell culture.
Another aspect of cytogenetics, polyploidy, was widely exploited in the first half-century.
A large number of agricultural and ornamental plants turned out to be polyploid.
Allopolyploidy provided an easy way to obtain fertile hybrids between strains in which the
diploid hybrids were sterile. Colchicine and other polyploidy-inducing drugs made the task
easier. Increasingly this has become a part of the plant geneticist’s bag of tricks.
Mutation was first described by deVries in the early days of the century. His mutations
turned out not to be gene mutations, but rather to be segregants from complex cytogenetic
heterozygotes; but he had the right idea. For a quarter century, mutation was something
outside of experimental control, almost like radioactivity. Then in 1927, H. J. Muller and
simultaneously L. J. Stadler reported that ionizing radiation greatly enhanced the mutation
rate. Muller’s great contribution was not so much the idea of radiation mutagenesis, but rather
his developing a technique, the ClB
method, which permitted unambiguous quantitative
determination of mutation rates. With this discovery, mutation became an experimental
subject. Most of the studies were kinetic — effects of dose, dose-rate, and fractionation. And
such studies did not yield the hoped-for insight into the nature of the gene.
More surprising was the long interval before the discovery of chemical mutagens.
Looking back over the old literature, one sees several examples of what were probably
successful experiments, but the mind-set of the time was against it. The standard of proof was
set so high that few experiments met it. One of the early discoveries was Rapoport’s finding
that formaldehyde is mutagenic. I am happy to note that Svetlana Vasilieva, who is attending
this Congress, was once an assistant to Rapoport. The discovery of the mutagenesis of
mustard gas is a remarkable story. J. M. Robson in Edinburgh had noticed that mustard burns
resemble those caused by radiation. This suggested that mustard might be mutagenic, and this
possibility was discussed by H. J. Muller and Charlotte Auerbach while Muller was in
Edinburgh. Auerbach’s experiments were dramatically successful, and by this time Muller
had moved to the United States. He had learned of her results, but since they involved a war
chemical, they were regarded as a military secret. I remember visiting Muller during this
period. He asked me if I had learned of Auerbach’s work, obviously hoping to discuss it. I
had not heard of it and waited for him to tell me. He said no more and changed the subject,
leaving me puzzled. I realized that something was afoot, and discovered what it was only
after the end of the war when the results could be publicly discussed.
After the war, came what Muller, in his Pilgrim Trust lecture delivered in 1945, called
“the coming chemical attack on the gene”. And what a magnificent prophesy it was
Shortly before the end of the half-century a new element was introduced, the study of
microorganisms. Joshua Lederberg’s demonstration of recombination in E. coli
rush for the gold found in microorganisms. At the same time the phage group, with Delbrück
as its intellectual leader, became equally prominent. Benzer had mapped phage genes and
driven the subject into the ground, to a resolution comparable to the size of large molecules.
Fine-scale genetics and the chemistry of large molecules had met.
During the first 50 years the greatest beneficiary of genetics was agriculture. Plant and
animal breeders had long produced spectacular results by selection. One doesn’t have to
understand Mendelism to realize that “like begets like”. Cattle breeders selected for milk or
beef production, horse breeders produced draft horses, riding horses, and ponies; and dog
fanciers got carried away, producing all manner of bizarre objects. But with Mendelism came
the basis for dealing with single-gene traits, usually complicated by dominance, which
blending inheritance couldn’t handle. Also, quantitative genetics theory, based on Mendelism
and developed by Fisher and Wright made selection more quantitative, and more effective.
The most striking success story in the new world was hybrid maize. With Mendelism
came the understanding of inbreeding depression. There was debate, and still is, about the
possible role of overdominance, but the absence of this knowledge did not deter the rapid
practical progress. Breeders developed inbred lines, selecting them for ability to combine
with other inbreds to produce good hybrids. Since hybrid maize was introduced in the 1930s
the yield per hectare has increased by about 5-fold. Of course, part of this is due to better
management and agronomic practices, but more than half, estimated at about two thirds, is
I want to add that R. A. Fisher, in addition to setting forth the basis of quantitative
genetics in 1918, also introduced efficient statistical design for field experiments. I have no
idea how much the improvement of agricultural performance owes to this one man, but it
Another major advance in the first 50 years was bringing genetics into our understanding
of evolution. Darwin came close to saying it all, but the big gap was the nature of inheritance.
The combination of Darwin and Mendel led by the 1930s to the new synthesis. The
theoretical basis was laid mainly by Haldane, Fisher, and Wright. Fisher had already supplied
the answer to what had bothered Darwin and his critics, and perhaps led to the Lamarckian
views in the later editions of his book. In this sense the successive editions of “The Origin”
got worse and worse. At the center was the question of decaying variability. Under the
prevailing view of blending inheritance, variability is lost very rapidly, as with intense
inbreeding in Mendelian populations. With Mendelian inheritance, variability is conserved
and a very small input of mutation is sufficient. Although the amount of variability in natural
populations is an object of continuing study, it no longer seems mysterious.
The three pioneers provided a mechanistic theory of evolution, based on the solid
foundation of Mendelian inheritance, that permitted deductive conclusions and offered the
opportunity for tests. But there were rather few opportunities for real quantitative testing.
Haldane used data on the evolution of industrial melanism in moths to estimate the selection
intensity, but such good examples were few. The beautiful quantitative theory, developed by
the three pioneers and extended by Kimura, found its deepest use in the second 50 years after
the advances created the new science of molecular evolution.
What Might have been Discovered, but Wasn’t
Before moving to the second half-century, it might be of interest to note some things that
were not discovered until later that could very well have been found earlier. By this, I mean
that they did not require any techniques not available at an earlier time.
The admonition of Bateson and Bridges to “treasure your exceptions” was often stated,
but I now think, not followed often enough. Bridges, however, followed his own advice. His
use of non-disjunction to prove the chromosomal basis of inheritance is a classic, although by
1916 it was no longer needed. But it was a magnificent paper and was the very first article to
appear in the new journal, Genetics
Here are some things that were discovered later and might well have been found earlier.
Were they simply overlooked or ignored as uninteresting?
• Imprinting. One gene after another in humans has been found to show imprinting. It is not
surprising that this was not noticed in small human pedigrees. But it is
surprising that it
was not noticed in the mouse and other rodents, where careful breeding studies were
done? Differences in reciprocal crosses should have been easily noticed. Furthermore,
there was solid work on such phenomena in mealy bugs and Sciara. These were regarded
as curiosities rather than as possible leads to a deeper insight. Were geneticists simply too
wedded to Mendel’s rules, so that they regarded exceptions as uninteresting exceptions or
• Transposable elements. Early in the century, Emerson had observed variegated maize
kernels. Demerec had puzzling examples of instability in Drosophila virilis
. But none
of these studies attracted much attention. Demerec went on to other things and his earlier
• Meiotic drive: The abnormal segregation of the t-locus in mice was well worked out. But
the general view was that this was a rather uninteresting exception. Rhoades’ beautiful
analysis of meiotic drive in maize, produced by the formation of neo-centromeres was
largely ignored. Meiotic drive became a popular subject only later after it was found in a
number of other organisms, especially Drosophila.
• Anticipation. This was explained as a statistical artifact, due to ascertainment bias. This
still may a part of the explanation. But now we know that the phenomenon is real in
Huntington’s and several other diseases, caused by instability of trinucleotide repeats.
Although the cytological mechanism could not have been discovered then, the reality of
the phenomenon surely could have been. It was too easily explained away as an
• Gene conversion. Carl Lindegren’s work in yeast was laughed out of court and other
explanations were sought. For example, one could explain many of his results by
assuming polyploidy. So conversion was rejected by most geneticists of the time.
• Subdivision of the gene: C. P. Oliver found evidence for crossing over within the gene in
Drosophila. But ruling out mutation was very difficult until ways of recovering reciprocal
products were developed. The notion that the gene was indivisible was widely prevalent
and evidence for subdivision was resisted.
• Chemical mutagens. I have already mentioned the reluctance to accept data that hindsight
shows us were providing pretty good evidence
• Kin selection and parental expenditure: These were clearly understood by Fisher, and
Haldane alluded to kin selection, but neither chose to exploit it. These ideas, central to
modern theories of behavioral evolution, were clearly explained in Fisher’s book in 1930.
Yet it took many years for Hamilton to awaken interest in the subject.
• Antibiotic and pesticide resistance. Penicillin and DDT both were discovered and
exploited during World War II. Students of evolution could easily predict what would
happen, and some writers did, but there was no serious general discussion until later. And
there was no attempt at concerted action, nor is there much today.
• Recombination in bacteria. Early experiments to search for recombination in bacteria
failed because they were not designed to detect rare events. The ideas Lederberg
employed so successfully in 1946 could have been used earlier. But bacteria were widely
Why this blindness to phenomena that are such a large part of our current thinking? I
believe there are two major explanations.
First, there was a widespread search for and belief in generality. Some of the things that
led to this belief were the regular occurrence of Mendelian inheritance, the general similarity
of meiosis in the various species studied, the construction of gene maps on simple principles,
and the way in which the consequences of cytogenetic changes could be predicted. As a
result, geneticists were encouraged to believe in the complete generality of what had been
discovered in a few favored species. Generality was the Zeitgeist. Deviations from
conventional expectations were often attributed to viability differences or technical errors.
A second factor was noted by George Beadle. He mentioned what he regarded as a
curious preference for randomness. The symmetry and the random aspects of Mendelian
segregation and recombination were very seductive. An example is the acceptance of no
chromatid interference in meiosis. The evidence for this, mainly from studies of attached-X
chromosomes in Drosophila, was not very strong. Yet the conclusion was universally
Was this preference for generality, symmetry, and randomness good for the field or bad?
Probably both. Clearly it aided in working out general principles. Population genetics
advanced rapidly by making this assumption. Yet, I also suspect that a number of phenomena
not discovered until after 1950 might well have been found earlier, if geneticists had been
more willing to trust their data and treasure their exceptions.
In 1950 the gene was still elusive. Long before, Muller had told us what the gene has to
do. It has to carry information; it has to replicate itself with superb accuracy; but when there
are errors, it has to copy them with the same accuracy, that is mutate; and it has to exercise
control over development and physiology.
The Transition: A Remarkable Decade, 1945-1955
Biochemical genetics and the relationship between genes and enzymes was not new. It
had been started by Sir Archibald Garrod in his discovery of inborn errors of metabolism near
the turn of the century. But the work of Beadle and Tatum in Neurospora sent the subject off
on a new course. Sewall Wright once told me that he had thought of writing a book on
developmental genetics, based heavily on his guinea pig studies, but the Neurospora work
clearly told him that there was a new direction. The field of biochemical genetics was forever
changed, and he didn’t write the book.
In 1946 Joshua Lederberg, working with E. L. Tatum, discovered recombination in
bacteria The great resolving power that comes from having enormous numbers and the
capacity to select very rare events were immediately appealing. It was only a few years until
became the best understood of all organisms, completely eclipsing maize and
Drosophila. At the same time phage genetics also had an explosive growth.
While this was going on there was increasing evidence for DNA as the genetic material.
The evidence had already been strong from the Pneumococcus transformation studies in 1944,
but for some reason the experiments of Hershey and Chase in 1952 had a greater influence.
At the same time the chemistry of DNA was becoming much more solid. In particular, the
repeating tetranucleotide structure was found to be wrong, thus making DNA attractive as an
The stage was set, and in 1953 two clever model builders, Watson and Crick, hit on the
right structure. The very structure of DNA immediately shouted the answers to Muller’s
questions. The era of molecular genetics was born, courtesy of Watson and Crick. The gene
was no longer mysterious. It was something to be exploited. The central question of genetics
The Second Fifty Years
In rapid succession the role of RNA was clarified, the translation of linear DNA
information to linear amino acid sequences was worked out, and the genetic code was solved.
This is much too familiar to all of you for me to elaborate.
As attention shifted from information transfer to regulation of gene action, the
intellectually satisfying operon model of Jacob and Monod took center stage. It was so neat
that the genetics world elected it by acclamation. Geneticists began to think of applying the
results, and especially the techniques, of microbial genetics to the study of multicelluar
organisms. A familiar quip of the time was that all we know about differentiation is from
organisms that do not differentiate.
At that time everything seemed beautifully simple — replication, a universal code,
transcription, translation, a central Dogma. And then the complications set in. So genetics
was no longer a subject in which a few simple principles could explain everything. The devil
is in the details, and you had to know them.
Whereas the first 50 years was devoted to a failed effort to learn the nature of the
genotype by studying phenotypes, the second 50 years have been dominated by the using the
genotype to understand the phenotype. The study of genetic control of development is now in
In the first 50 years genetics was limited by the paucity of available techniques. It is
astonishing, nevertheless, to note how much was learned about Drosophila by the use of the
many special strains that were developed, particularly by Muller and Bridges. It is equally
astonishing how much Barbara McClintock could see by examination of chromosome
breakage and color patterns in the maize endosperm. But the techniques were few. With such
a limited bag of tricks, successful genetic experimentation depended on cleverness — and also
on a great deal of time and patience. The past 50 years have been characterized by a truly
astonishing cascade of new techniques.
The techniques are so good -- so efficient, so easy, and so accurate — that a beginning
student can sequence a gene, something that was a daunting task to the best team of experts
not long ago. I’ll not dwell on these techniques; they have been abundantly evident
throughout this Congress. The subject is technique-driven, but who can complain when the
We are just beginning to use molecular methods for genetic dissection of common
multifactorial traits. It is too early to guess just how soon this will be practically useful, but
the ultimate importance can hardly be in doubt. Yield factors in cereals and vegetable crops
have been identified. Soon they will be exploited. There is good progress in understanding
Molecular biology has brought a totally new subject, molecular evolution. The genetic
study of species differences used to be confined to those species that could be crossed. The
arguments of skeptics of the time who thought that chromosomal differences applied only
within a species or between very similar ones were difficult to counter. Geneticists had to rely
on a faith that the same principles that govern small difference also apply to large ones, but the
definitive, convincing proof was lacking.
Now, no such limitation applies. DNA comparison between widely different organisms
is now so commonplace that it is hard to realize that in the not distant past this was
impossible. Geneticists expected that homologous genes would be found between distantly
related species, and that the genes would have diverged in function. They expected that gene
duplication would lead to new functions, and that some duplications would mutate themselves
out of functional existence. But suspecting this and proving it are different things, and we had
to wait for appropriate molecular techniques.
Motoo Kimura dropped a bomb when he suggested that the great bulk of molecular
change is neutral, driven by mutation and buffeted about by random drift. The jury is still out
on the question of what fraction of genetic change follows this paradigm, but there is no doubt
that much does, especially in non-coding regions. From this has grown a workable molecular
clock and the possibility of far better phylogenetic analysis.
We have an abundance of genes that have hardly changed over very long periods,
maintained by purifying selection. We have genes that have changed much too rapidly to be
mutation-driven, and hence are the result of positive or stabilizing selection. And we have
junk, presumably mainly neutral. Traditionally, the study of evolution has dealt with form and
function, and that is still where much of the interest lies. But with a solid underpinning of
molecular change, the subject proceeds in a much more rigorous way. And molecular studies,
mitochondrial DNA in particular, are now clearing up a topic in which we are all interested,
Now researchers are chipping away, carving a sculpture out of a very hard marble block.
The two big problems — the nature of development and the nature of the mind — are being
subdued. I don’t know whether there will be beautiful, general theories to come out of this —
something really nice like Watson and Crick found — or whether it will be an accumulation of
more and more details. I’ll confess to a secret hope for the former.
The accomplishments of modern genetics are indeed astonishing, especially to one like
me who grew up in the classical period and is having a hard time growing out of it. Consider
Temin and Baltimore have revealed a new kind of virus, the retrovirus. It came as a
surprise, but is now a well understood extension of the Central Dogma. Retroposons are
turning up everywhere, and not only are they turning up now, they have long been a factor in a
long evolutionary history and have left their footprints. And, I needn’t remind you that the
HIV virus is a terrible scourge and a major challenge to our ingenuity.
We have also seen an important role for RNA, not only as a vehicle by which DNA
imposes its information on development. There is now good reason to think that there may
have been an RNA world, before this was replaced by our present, presumably more efficient
QTLs (quantitative trait loci) rely on an old idea —the use of linked markers to locate
genes of interest. The difference is again a matter of technique. QTLs can now be discovered
efficiently and these procedures have yielded results in several plants — tomatoes, maize, and
rice, to name three. This will also be useful in livestock breeding. And they will help unravel
the mode of inheritance of complex human conditions. Only a few months ago came a report
of a QTL associated with high intelligence, the first opening in the door to a detailed genetic
understanding of important human behavioral attributes.
One organism after another is having its DNA sequenced. Just last month the sequence
of Treponema pallidum
was reported. This is significant, not because of its size, for this is
a relatively small organism, but because it causes a major disease. And, more important, it
has resisted study by the ordinary methods of bacteriology. Sequencing will surely open up
new avenues. Very early in the next century the complete human sequence will be known.
What seemed like an unattainable end point of genetics in 1950, complete knowledge of the
individual genes and of the genome will soon be achieved. A major task in the century ahead
is to take this great store of information and make sense of it.
If I were talking in North America I would emphasize maize and wheat. But we are
meeting in Asia, where rice is the major food crop. Rice is a particularly inviting target for
sequencing. In the first place, it is an important crop, grown throughout the world. It feeds
countless people, and it is usually eaten by people rather than fed to livestock. The world
badly needs improved rice. Its great advantage for sequencing is its small genome size. It is
the smallest of the cultivated grasses. Its 12 chromosomes include 430 megabases of DNA,
only one sixth the number in maize, and far fewer than polyploid wheat. The green revolution
brought a large increase in rice yields, but recent progress has been slower. There is room for
great improvement by both standard breeding methods and by newer techniques. For
example, finding QTLs in wild relatives may provide a source of new, valuable genes. It can
certainly help in identifying potentially useful qualitative traits. Can we develop varieties that
perform well with less fertilizer and pesticides, and especially with less water, surely the most
important limiting factor? Japan, Korea, and China are deeply involved in the rice genome
project. Will the complete sequence provide a quantum jump in practical knowledge? I hope
so. Perhaps rice will provide the first chance to see just how practically useful the complete
So far gene therapy has not had much success. Its best chance is with certain kinds of
rare diseases. Then there is the practical problem that manufacturing chemists are not likely to
spend the necessary money for a rare disease. Nevertheless, there are bound to be modest
successes. And if we can repair the genes causing, for example, Tay-Sachs disease or cystic
fibrosis, people will begin to think of getting rid of them? I suspect that parents would
welcome this. I for one would be happy to live in a world in which these genes and many
other misery-causing ones had become extinct. Of course, we are not likely to prevent
The papers have been full of Dolly, the sheep that is said to be a clone derived from an
adult, differentiated cell. The evidence that this is a real result and not an error has been
strengthened by recent DNA analysis. But more impressive is the result of Dr. Wakayama,
who has produced several cloned mice including clones of clones. They promise an answer to
a host of interesting questions. Why does the success rate remain low? Is it technical
imperfections, or fundamental? How will imprinting affect the process? Is imprinting
preserved or erased in differentiated cells? Will these cells show the cumulative wear and tear
of aging? What happens to the inactive X in females? How soon will cloning high-
performing dairy cows be practical? Will society deal rationally with the ethical and religious
issues raised by possible human applications?
Genetics has pervaded almost every branch of biology. Does this mean that it will lose
its identity, as it spreads its tentacles in many directions? Will we no longer have genetics
departments? The next century will tell us.
Genetics and Society
The great advances in molecular genetics will surely have correspondingly great
consequences. Early in the next century the sequencing of the many genomes will be
complete. We can easily see the potential benefits -- more food, better diagnosis and
treatment of disease, better ways to identify people killed in accidents, better understanding of
complex traits such as intelligence and emotions. We can also anticipate problems. They are
being discussed ad infinitum
. Will the intrusion into privacy be a major threat to our
liberties? Will the possibilities be exploited to our detriment by industry or government? The
opportunity for good and bad are both great. Much can be foreseen and planned for, but much
cannot. Will societies accept this knowledge and use it wisely? As Hamlet said “That is the
In the twentieth century genetics has been the victim of two ruthless dictatorships. Hitler
carried racist eugenics to ridiculous and tragic extremes. Stalin enshrined Lysenkoist genetics,
again perverting our science and again producing tragic consequences. We can easily imagine
such extreme views in the future. But what those two regimes had in common was that both
were ruthless dictatorships. That is the problem. I recall hearing H. F. Kushner, speaking in
Japan in 1956, reporting inherited effects of blood transfusions. I am certain that he knew
better, for he was well known traditional geneticist in an earlier period. We can’t expect
scientists to behave honestly and rationally when a gun is pointed at their heads.
Chinese genetics has been through difficult times, but it is now on the upswing and
progress is very rapid. That is apparent throughout this Congress. At this Congress we had a
free and open discussion of the Maternal and Infant Care laws. I am aware of my limitations
in understanding another culture, with its long and magnificent traditions. I am also aware
that my own society is not above reproach, for example in its continued confusion over
therapeutic abortion. But I will venture three comments:
(1) The word “eugenics” now has so many different meanings, many of them highly
pejorative, that it has lost is usefulness. As Ren-Zong Qiu has pointed out, the Chinese word
yousheng can as well be translated “healthy child”. It would be good for something like child
health to be used rather than eugenics.
(2) The wording of the law and especially the English translation is open to various
interpretations. I hope it can be interpreted that there is informed consent and that acceptance
of counseling advice is not mandatory. At the same time the counseling should be as accurate
as possible in predicting the risk of children with various impairments.
(3) Finally the value of scientific contact and policy discussions among geneticists in all
countries can only be good, and I would encourage more. We have much to learn from each
other. This Congress is an important step. Let me add my belief that we should welcome
comments from Chinese geneticists on genetic practices in our society.
Of far greater urgency and much closer at hand than any consequences of changing gene
frequencies is the total world population. Unless the world-wide birth rate is brought into
some sort of balance with food supply and economic realities, we may not have the luxury of
worrying about our genetic constitution.
China has 22 percent of the world population but only 7 percent of the arable land, and this
land area is being reduced by erosion and diversion to other uses. There is certain to be
conflict between individual freedom to reproduce and the social necessity that reproduction be
limited. China is the first large nation to face this problem and act decisively. The rest of the
I have lived through 82 percent of the twentieth century. I have seen the tremendous
growth of our fundamental knowledge. I have seen what once appeared to be beautifully
simple -- Mendelism, linkage maps, the Watson Crick model, the genetic code -- grow in
depth and complexity. We hare developing the techniques to manage this complexity. But do
we have the individual and social will? The twenty first century will tell.
You young people in the audience have an exciting time ahead. I would like to start over
and join you, but I’m afraid that is not a viable option. I can hope, however, to see you again,
early in the next millennium at the next congress in Melbourne.
MEDICATION MANAGEMENT FOR A BIOPSYCHOSOCIAL PAIN /FATIGUE-MANAGEMENT PROGRAM Almost all the patients referred to my program are on a drug-management plan that is appropriate for medical management of pain in the absence of a behavioral program. But behavioral pain-management is so effective that it adds a new dimension to the management of chronic pain. It requires a separate approach to
Vatikanoko II. Kontzilioaz haratago gaurko kulturatik bi arotara, bi eoitara. are bizkorrago eta kementsuago jarrai -tzen du aurrera. 1. Mundu modernoarekin adiski- detu raino bakarrik iritsi zela. Eta erdibide-listaren artean, mundua tragikoki bana-tua zegoela, herrialde kolonizatuenzuen, eta erdizka bakarrik lortu; bitar-tean, ordea –Kontzilioko eta ondoren-go urteetan– kultu