Therefore,  ΔG = (i σ P ) h 2 , where   (i σ P(0) )  =  S  previously. [ 14 ]   : 1710–181


The text above noted that successive  ΔG  declines because the "input" [the  phenotypic variance ( σ 2 P  ) ] is reduced by the previous selection. [ 14 ] : 1710–181   The heritability also is reduced. The graphs to the left show these declines over ten cycles of repeated selection during which the same selection pressure is asserted. The accumulated genetic advance ( ΣΔG ) has virtually reached its asymptote by generation 6 in this example. This reduction depends partly upon truncation properties of the Normal Distribution, and partly upon the heritability together with  meiosis determination ( b 2  ) . The last two items quantify the extent to which the  truncation  is "offset" by new variation arising from segregation and assortment during meiosis. [ 14 ]   : 1710–181  [ 27 ]  This is discussed soon, but here note the simplified result for  undispersed random fertilization (f = 0) .


Thus :  σ 2 P(1)  = σ 2 P(0)  [1 − i ( i-z)   1 / 2   h 2 ] ,  where  i ( i-z) = K = truncation coefficient  and   1 / 2   h 2  = R = reproduction coefficient [ 14 ] : 1710–181  [ 27 ]  This can be written also as  σ 2 P(1)  = σ 2 P(0)  [1 − K R ] , which facilitates more detailed analysis of selection problems.


Here,  i  and  z  have already been defined,   1 / 2   is the  meiosis determination ( b 2 ) for  f=0 , and the remaining symbol is the heritability. These are discussed further in following sections. Also notice that, more generally,  R = b 2  h 2 . If the general  meiosis determination ( b 2  )  is used, the results of prior inbreeding can be incorporated into the selection. The phenotypic variance equation then becomes:


σ 2 P(1)  = σ 2 P(0)  [1 − i ( i-z) b 2  h 2 ] .


The  Phenotypic variance  truncated by the  selected group  (  σ 2 P(S)  ) is simply  σ 2 P(0)  [1 − K] , and its contained  genic variance  is  (h 2 0  σ 2 P(S)  ). Assuming that selection has not altered the  environmental  variance, the  genic variance  for the progeny can be approximated by   σ 2 A(1)  = ( σ 2 P(1)  − σ 2 E )   . From this,  h 2 1  = ( σ 2 A(1)  / σ 2 P(1)  ) . Similar estimates could be made for  σ 2 G(1)   and  H 2 1 , or for  σ 2 a(1)  and  h 2 eu(1)  if required.


The following rearrangement is useful for considering selection on multiple attributes (characters). It starts by expanding the heritability into its variance components.  ΔG = i σ P  ( σ 2 A  / σ 2 P  )  . The  σ P  and  σ 2 P  partially cancel, leaving a solo  σ P . Next, the  σ 2 A  inside the heritability can be expanded as ( σ A  × σ A ), which leads to :


ΔG = i σ A  ( σ A  / σ P  )  =  i σ A  h  .


Corresponding re-arrangements could be made using the alternative heritabilities, giving  ΔG = i σ G  H  or  ΔG = i σ a  h eu .


This traditional view of adaptation in quantitative genetics provides a model for how the selected phenotype changes over time, as a function of the selection differential and heritability.  However it does not provide insight into (nor does it depend upon) any of the genetic details - in particular, the number of loci involved, their allele frequencies and effect sizes, and the frequency changes driven by selection.  This, in contrast, is the focus of work on  polygenic adaptation [ 62 ]  within the field of  population genetics . Recent studies have shown that traits such as height have evolved in humans during the past few thousands of years as a result of small allele frequency shifts at thousands of variants that affect height. [ 63 ] [ 64 ] [ 65 ]


The entire  base population  is outlined by the normal curve [ 59 ] : 78–89   to the right. Along the  Z axis  is every value of the attribute from least to greatest, and the height from this axis to the curve itself is the frequency of the value at the axis below. The equation for finding these frequencies for the "normal" curve (the curve of "common experience") is given in the ellipse. Notice it includes the mean ( μ ) and the variance ( σ 2 ). Moving infinitesimally along the z-axis, the frequencies of neighbouring values can be "stacked" beside the previous, thereby accumulating an area that represents the  probability  of obtaining all values within the stack. [That's  integration  from calculus.] Selection focuses on such a probability area, being the shaded-in one from the  selection threshold (z)  to the end of the superior tail of the curve. This is the  selection pressure . The selected group (the effective parents of the next generation) include all phenotype values from  z  to the "end" of the tail. [ 66 ]  The mean of the  selected group  is  μ s , and the difference between it and the base mean ( μ ) represents the  selection differential (S) .  By taking partial integrations over curve-sections of interest, and some rearranging of the algebra, it can be shown that the "selection differential" is  S = [ y (σ / Prob.)]  , where  y  is the  frequency  of the value at the "selection threshold"  z  (the  ordinate  of  z ). [ 13 ] : 226–230   Rearranging this relationship gives  S / σ = y / Prob. , the left-hand side of which is, in fact,  selection differential divided by standard deviation —that is the  standardized selection differential (i) . The right-side of the relationship provides an "estimator" for  i —the ordinate of the  selection threshold  divided by the  selection pressure . Tables of the Normal Distribution [ 49 ]   : 547–548   can be used, but tabulations of  i  itself are available also. [ 67 ] : 123–124   The latter reference also gives values of  i  adjusted for small populations (400 and less), [ 67 ] : 111–122   where "quasi-infinity" cannot be assumed (but  was  presumed in the "Normal Distribution" outline above). The  standardized selection differential ( i )  is known also as the  intensity of selection . [ 14 ] : 174, 186


Finally, a cross-link with the differing terminology in the previous sub-section may be useful:  μ  (here) = "P 0 " (there),  μ S  = "P S " and  σ 2  = "σ 2 P ".


The  meiosis determination (b 2 )  is the  coefficient of determination  of meiosis, which is the cell-division whereby parents generate gametes. Following the principles of  standardized partial regression , of which  path analysis  is a pictorially oriented version, Sewall Wright analyzed the paths of gene-flow during sexual reproduction, and established the "strengths of contribution" ( coefficients of determination ) of various components to the overall result. [ 27 ] [ 37 ]  Path analysis includes  partial correlations  as well as  partial regression coefficients  (the latter are the  path coefficients ). Lines with a single arrow-head are directional  determinative paths , and lines with double arrow-heads are  correlation connections . Tracing various routes according to  path analysis rules  emulates the algebra of standardized partial regression. [ 55 ]


The path diagram to the left represents this analysis of sexual reproduction. Of its interesting elements, the important one in the selection context is  meiosis . That's where segregation and assortment occur—the processes that partially ameliorate the truncation of the phenotypic variance that arises from selection.  The path coefficients  b  are the meiosis paths. Those labeled  a  are the fertilization paths. The correlation between gametes from the same parent ( g ) is the  meiotic correlation . That between parents within the same generation is  r A . That between gametes from different parents ( f ) became known subsequently as the  inbreeding coefficient . [ 13 ] : 64    The primes ( ' ) indicate generation  (t-1) , and the  un primed indicate generation  t . Here, some important results of the present analysis are given. Sewall Wright interpreted many in terms of inbreeding coefficients. [ 27 ] [ 37 ]


The meiosis determination ( b 2 ) is   1 / 2   (1+g)  and equals   1 / 2   (1 + f (t-1) )  , implying that  g = f (t-1) . [ 68 ]  With non-dispersed random fertilization, f (t-1) ) = 0, giving  b 2  =   1 / 2  , as used in the selection section above. However, being aware of its background, other fertilization patterns can be used as required. Another determination also involves inbreeding—the fertilization determination ( a 2 ) equals  1 / [ 2 ( 1 + f t  ) ]  . Also another correlation is an inbreeding indicator— r A  =  2 f t  / ( 1 + f (t-1)  ) , also known as the  coefficient of relationship . [Do not confuse this with the  coefficient of kinship —an alternative name for the  co-ancestry coefficient . See introduction to "Relationship" section.] This  r A  re-occurs in the sub-section on dispersion and selection.


These links with inbreeding reveal interesting facets about sexual reproduction that are not immediately apparent. The graphs to the right plot the  meiosis  and  syngamy (fertilization)  coefficients of determination against the inbreeding coefficient. There it is revealed that as inbreeding increases, meiosis becomes more important (the coefficient increases), while syngamy becomes less important. The overall role of reproduction [the product of the previous two coefficients— r 2 ] remains the same. [ 69 ]  This  increase in  b 2  is particularly relevant for selection because it means that the  selection truncation of the Phenotypic variance  is offset to a lesser extent during a sequence of selections when accompanied by inbreeding (which is frequently the case).


The previous sections treated  dispersion  as an "assistant" to  selection , and it became apparent that the two work well together. In quantitative genetics, selection is usually examined in this "biometrical" fashion, but the changes in the means (as monitored by ΔG) reflect the changes in allele and genotype frequencies beneath this surface. Referral to the section on "Genetic drift" brings to mind that it also effects changes in allele and genotype frequencies, and associated means; and that this is the companion aspect to the dispersion considered here ("the other side of the same coin"). However, these two forces of frequency change are seldom in concert, and may often act contrary to each other. One (selection) is "directional" being driven by selection pressure acting on the phenotype: the other (genetic drift) is driven by "chance" at fertilization (binomial probabilities of gamete samples). If the two tend towards the same allele frequency, their "coincidence" is the probability of obtaining that frequencies sample in the genetic drift: the likelihood of their being "in conflict", however, is the  sum of probabilities of all the alternative frequency samples . In extreme cases, a single syngamy sampling can undo what selection has achieved, and the probabilities of it happening are available. It is important to keep this in mind. However, genetic drift resulting in sample frequencies similar to those of the selection target does not lead to so drastic an outcome—instead slowing progress towards selection goals.


Upon jointly observing two (or more) attributes ( e.g.  height and mass), it may be noticed that they vary together as genes or environments alter. This co-variation is measured by the  covariance , which can be represented by "  cov  " or by  θ . [ 43 ]  It will be positive if they vary together in the same direction; or negative if they vary together but in opposite direction. If the two attributes vary independently of each other, the covariance will be zero. The degree of association between the attributes is quantified by the  correlation coefficient  (symbol  r  or   ρ  ). In general, the correlation coefficient is the ratio of the  covariance  to the geometric mean  [ 70 ]  of the two variances of the attributes. [ 59 ]   : 196–198   Observations usually occur at the phenotype, but in research they may also occur at the "effective haplotype" (effective gene product) [see Figure to the right]. Covariance and correlation could therefore be "phenotypic" or "molecular", or any other designation which an analysis model permits. The phenotypic covariance is the "outermost" layer, and corresponds to the "usual" covariance in Biometrics/Statistics. However, it can be partitioned by any appropriate research model in the same way as was the phenotypic variance. For every partition of the covariance, there is a corresponding partition of the correlation. Some of these partitions are given below. The first subscript (G, A, etc.) indicates the partition. The second-level subscripts (X, Y) are "place-keepers" for any two attributes.


The first example is the  un-partitioned  phenotype.


The genetical partitions  (a)  "genotypic" (overall genotype), (b)  "genic" (substitution expectations) and  (c)  "allelic" (homozygote) follow.


(a)

 r

 G

 X
 Y

 =

 c
 o

 v

 G

 X
 Y

 σ

 G

 X

 2

 σ

 G

 Y

 2

 {\displaystyle {r_{G_{XY}}}={{cov_{G_{XY}}} \over {\sqrt {\sigma _{G_{X}}^{2}\sigma _{G_{Y}}^{2}}}}}


(b)

 r

 A

 X
 Y

 =

 c
 o

 v

 A

 X
 Y

 σ

 A

 X

 2

 σ

 A

 Y

 2

 {\displaystyle {r_{A_{XY}}}={{cov_{A_{XY}}} \over {\sqrt {\sigma _{A_{X}}^{2}\sigma _{A_{Y}}^{2}}}}}


(c)

 r

 a

 X
 Y

 =

 c
 o

 v

 a

 X
 Y

 σ

 a

 X

 2

 σ

 a

 Y

 2

 {\displaystyle {r_{a_{XY}}}={{cov_{a_{XY}}} \over {\sqrt {\sigma _{a_{X}}^{2}\sigma _{a_{Y}}^{2}}}}}


With an appropriately designed experiment, a  non-genetical  (environment) partition could be obtained also.


There are several different ways that phenotypic correlation can arise. Study design, sample size, sample statistics, and other factors can influence the ability to distinguish between them with more or less statistical confidence. Each of these have different scientific significance, and are relevant to different fields of work.


One phenotype may directly affect another phenotype, by influencing development, metabolism, or behavior.


A common gene or transcription factor in the biological pathways for the two phenotypes can result in correlation.


The metabolic pathways from gene to phenotype are complex and varied, but the causes of correlation amongst attributes lie within them.


Multiple phenotypes may be affected by the same factors. For example, there are many phenotypic attributes correlated with age, and so height, weight, caloric intake, endocrine function, and more all have a correlation. A study looking for other common factors must rule these out first.


Differences between subgroups in a population, between populations, or selective biases can mean that some combinations of genes are overrepresented compared with what would be expected. While the genes may not have a significant influence on each other, there may still be a correlation between them, especially when certain genotypes are not allowed to mix. Populations in the process of  genetic divergence  or having already undergone it can have different characteristic phenotypes, [ 71 ]  which means that when considered together, a correlation appears. Phenotypic qualities in humans that predominantly depend on ancestry also produce correlations of this type. This can also be observed in dog breeds where several physical features make up the distinctness of a given breed, and are therefore correlated. [ 72 ]   Assortative mating , which is the  sexually selective  pressure to mate with a similar phenotype, can result in genotypes remaining correlated more than would be expected. [ 73 ]


The  history of genetics  dates from the  classical era  with contributions by  Pythagoras ,  Hippocrates ,  Aristotle ,  Epicurus , and others. Modern genetics began with the work of the  Augustinian friar   Gregor Johann Mendel .  His works  on pea plants, published in 1866, provided the initial evidence that, on its rediscovery in 1900's, helped to establish the theory of  Mendelian inheritance .


In  ancient Greece , Hippocrates suggested that all organs of the body of a parent gave off invisible “seeds,” miniaturised components, that were transmitted during sexual intercourse and combined in the mother's womb to form a baby. In the  Early Modern  times,  William Harvey 's
book  On Animal Generation  contradicted  Aristotle's theories of genetics and embryology .


The 1900 rediscovery of Mendel's work by  Hugo de Vries ,  Carl Correns  and  Erich von Tschermak  led to rapid advances in genetics. By 1915 the basic principles of Mendelian  genetics  had been studied in a wide variety of organisms — most notably the fruit fly  Drosophila melanogaster . Led by  Thomas Hunt Morgan  and his fellow "drosophilists", geneticists developed the  Mendelian  model, which was widely accepted by 1925. Alongside experimental work, mathematicians developed the statistical framework of  population genetics , bringing genetic explanations into the study of  evolution .


With the basic patterns of genetic inheritance established, many biologists turned to investigations of the physical nature of the  gene . In the 1940s and early 1950s, experiments pointed to  DNA  as the portion of chromosomes (and perhaps other nucleoproteins) that held genes. A focus on new model organisms such as viruses and bacteria, along with the  discovery of the double helical structure of DNA  in 1953, marked the transition to the era of  molecular genetics .


In the following years, chemists developed techniques for sequencing both nucleic acids and proteins, while many others worked out the relationship between these two forms of biological molecules and discovered the  genetic code . The regulation of  gene expression  became a central issue in the 1960s; by the 1970s gene expression could be controlled and manipulated through  genetic engineering . In the last decades of the 20th century, many biologists focused on large-scale genetics projects, such as sequencing entire genomes.


The most influential early theories of heredity were that of  Hippocrates  and  Aristotle . Hippocrates' theory (possibly based on the teachings of  Anaxagoras ) was similar to Darwin's later ideas on  pangenesis , involving heredity material that collects from throughout the body.  Aristotle suggested  instead that the (nonphysical)  form-giving principle  of an organism was transmitted through semen (which he considered to be a purified form of blood) and the mother's menstrual blood, which interacted in the womb to direct an organism's early development. [ 1 ]  For both Hippocrates and Aristotle—and nearly all Western scholars through to the late 19th century—the  inheritance of acquired characters  was a supposedly well-established fact that any adequate theory of heredity had to explain. At the same time, individual species were taken to have a  fixed essence ; such inherited changes were merely superficial. [ 2 ]  The Athenian philosopher  Epicurus  observed families and proposed the contribution of both males and females of hereditary characters ("sperm atoms"), noticed dominant and recessive types of inheritance and described segregation and independent assortment of "sperm atoms". [ 3 ]


In 1000 CE, the  Arab physician ,  Abu al-Qasim al-Zahrawi  (known as Albucasis in the West) was the first physician to describe clearly the hereditary nature of  haemophilia  in his  Al-Tasrif . [ 4 ]  In 1140 CE,  Judah HaLevi  described dominant and recessive genetic traits in  The Kuzari . [ 5 ]


The preformation theory is a developmental biological theory, which was represented in antiquity by the Greek philosopher  Anaxagoras . It reappeared in modern times in the 17th century and then prevailed until the 19th century. Another common term at that time was the theory of evolution, although "evolution" (in the sense of development as a pure growth process) had a completely different meaning than today. The preformists assumed that the entire organism was preformed in the  sperm  (animalkulism) or in the  egg  (ovism or ovulism) and only had to unfold and grow. This was contrasted by the theory of  epigenesis , according to which the structures and organs of an organism only develop in the course of individual development ( Ontogeny ). Epigenesis had been the dominant opinion since antiquity and into the 17th century, but was then replaced by preformist ideas. Since the 19th century epigenesis was again able to establish itself as a view valid to this day. [ 6 ] [ 7 ]


In the 18th century, with increased knowledge of plant and animal diversity and the accompanying increased focus on  taxonomy , new ideas about heredity began to appear.  Linnaeus  and others (among them  Joseph Gottlieb Kölreuter ,  Carl Friedrich von Gärtner , and  Charles Naudin ) conducted extensive experiments with hybridisation, especially  hybrids  between species. Species hybridisers described a wide variety of inheritance phenomena, include hybrid sterility and the high variability of  back-crosses . [ 8 ]


Plant breeders were also developing an array of stable  varieties  in many important plant species. In the early 19th century,  Augustin Sageret  established the concept of  dominance , recognising that when some plant varieties are crossed, certain characteristics (present in one parent) usually appear in the offspring; he also found that some ancestral characteristics found in neither parent may appear in offspring. However, plant breeders made little attempt to establish a theoretical foundation for their work or to share their knowledge with current work of physiology, [ 9 ]  although  Gartons Agricultural Plant Breeders  in England explained their system. [ 10 ]


Between 1856 and 1865,  Gregor Mendel  conducted breeding experiments using the pea plant  Pisum sativum  and traced the inheritance patterns of certain traits. Through these experiments, Mendel saw that the genotypes and phenotypes of the progeny were predictable and that some traits were dominant over others. [ 11 ]  These patterns of  Mendelian inheritance  demonstrated the usefulness of applying statistics to inheritance. They also contradicted 19th-century theories of  blending inheritance , showing, rather, that genes remain discrete through multiple generations of hybridisation. [ 12 ]


From his statistical analysis, Mendel defined a concept that he described as a character (which in his mind holds also for "determinant of that character"). In only one sentence of his historical paper, he used the term "factors" to designate the "material creating" the character: " So far as experience goes, we find it in every case confirmed that constant progeny can only be formed when the egg cells and the fertilising pollen are off like the character so that both are provided with the material for creating quite similar individuals, as is the case with the normal fertilisation of pure species. We must, therefore, regard it as certain that exactly similar factors must be at work also in the production of the constant forms in the hybrid plants."(Mendel, 1866).


Mendel's work was published in 1866 as  "Versuche über Pflanzen-Hybriden" ( Experiments on Plant Hybridisation )  in the  Verhandlungen des Naturforschenden Vereins zu Brünn (Proceedings of the Natural History Society of Brünn) , following two lectures he gave on the work in early 1865. [ 13 ]


Mendel's work was published in a relatively obscure  scientific journal , and it was not given any attention in the scientific community. Instead, discussions about modes of heredity were galvanised by  Darwin 's theory of  evolution  by natural selection, in which mechanisms of non- Lamarckian  heredity seemed to be required. Darwin's own theory of heredity,  pangenesis , did not meet with any large degree of acceptance. [ 14 ] [ 15 ]  A more mathematical version of pangenesis, one which dropped much of Darwin's Lamarckian holdovers, was developed as the "biometrical" school of heredity by Darwin's cousin,  Francis Galton . [ 16 ]


In 1883  August Weismann  conducted experiments involving breeding mice whose tails had been surgically removed. His results — that surgically removing a mouse's tail had no effect on the tail of its offspring — challenged the theories of pangenesis and  Lamarckism , which held that changes to an organism during its lifetime could be inherited by its descendants. Weismann proposed the  germ plasm  theory of inheritance, which held that hereditary information was carried only in sperm and egg cells. [ 17 ]


Hugo de Vries  wondered what the nature of germ plasm might be, and in particular he wondered whether or not germ plasm was mixed like paint or whether the information was carried in discrete packets that remained unbroken. In the 1890s he was conducting breeding experiments with a variety of plant species and in 1897 he published a paper on his results that stated that each inherited trait was governed by two discrete particles of information, one from each parent, and that these particles were passed along intact to the next generation. In 1900 he was preparing another paper on his further results when he was shown a copy of Mendel's 1866 paper by a friend who thought it might be relevant to de Vries's work. He went ahead and published his 1900 paper without mentioning Mendel's priority. Later that same year another botanist,  Carl Correns , who had been conducting hybridisation experiments with maize and peas, was searching the literature for related experiments prior to publishing his own results when he came across Mendel's paper, which had results similar to his own. Correns accused de Vries of appropriating terminology from Mendel's paper without crediting him or recognising his priority. At the same time another botanist,  Erich von Tschermak  was experimenting with pea breeding and producing results like Mendel's. He too discovered Mendel's paper while searching the literature for relevant work. In a subsequent paper de Vries praised Mendel and acknowledged that he had only extended his earlier work. [ 17 ]


After the rediscovery of Mendel's work there was a feud between  William Bateson  and  Pearson  over the hereditary mechanism, solved by  Ronald Fisher  in his work " The Correlation Between Relatives on the Supposition of Mendelian Inheritance ".


In 1910,  Thomas Hunt Morgan  showed that genes reside on specific  chromosomes . He later showed that genes occupy specific locations on the chromosome. With this knowledge,  Alfred Sturtevant , a member of Morgan's famous  fly room , using  Drosophila melanogaster ,  provided the first chromosomal map of any biological organism. In 1928,  Frederick Griffith  showed that genes could be transferred. In what is now known as  Griffith's experiment , injections into a mouse of a deadly strain of  bacteria  that had been heat-killed transferred genetic information to a safe strain of the same bacteria, killing the mouse.


A series of subsequent discoveries (e.g. [ 18 ] ) led to the realization decades later that the genetic material is made of  DNA  (deoxyribonucleic acid) and not, as was widely believed until then, of proteins. In 1941,  George Wells Beadle  and  Edward Lawrie Tatum  showed that mutations in genes caused errors in specific steps of  metabolic pathways . [ 19 ]  This showed that specific genes code for specific proteins, leading to the " one gene, one enzyme " hypothesis. [ 20 ]   Oswald Avery ,  Colin Munro MacLeod , and  Maclyn McCarty   showed in 1944  that DNA holds the gene's information. [ 21 ]  In 1952,  Rosalind Franklin  and Raymond Gosling produced a strikingly clear x-ray diffraction pattern indicating a helical form. Using these x-rays and information already known about the chemistry of DNA,  James D. Watson  and  Francis Crick  demonstrated the molecular structure of  DNA  in 1953. [ 22 ]
 [ 23 ]  Together, these discoveries established the  central dogma of molecular biology , which states that proteins are translated from  RNA  which is transcribed by DNA. This dogma has since been shown to have exceptions, such as  reverse transcription  in  retroviruses .


In 1947, Salvador Luria discovered the reactivation of irradiated phage [ 24 ]  leading to many further studies on the fundamental processes of repair of DNA damage (for review of early studies, see  [ 25 ] ). In 1958, Meselson and Stahl demonstrated that DNA replicates semiconservatively, leading to the understanding that each of the individual strands in double-stranded DNA serves as a template for new strand synthesis. [ 26 ]  In 1960, Jacob and collaborators discovered the operon which consists of a sequence of genes whose expression is coordinated by operator DNA. [ 27 ]   In the period 1961 – 1967, through work in several different labs, the nature of the genetic code was determined (e.g.  [ 28 ] ).


In 1972,  Walter Fiers  and his team at the  University of Ghent  were the first to determine the sequence of a gene: the gene for  bacteriophage MS2  coat protein. [ 29 ]   Richard J. Roberts  and  Phillip Sharp  discovered in 1977 that genes can be split into segments. This led to the idea that one gene can make several proteins. The successful sequencing of many organisms'  genomes  has complicated the molecular definition of the gene. In particular, genes do not always sit side by side on  DNA  like discrete beads. Instead,  regions  of the DNA producing distinct proteins may overlap, so that the idea emerges that "genes are one long  continuum ". [ 30 ] [ 31 ]  It was first hypothesised in 1986 by  Walter Gilbert  that neither DNA nor protein would be required in such a primitive system as that of a very early stage of the earth if RNA could serve both as a catalyst and as genetic information storage processor.


The modern study of  genetics  at the level of DNA is known as  molecular genetics , and the synthesis of molecular genetics with traditional  Darwinian   evolution  is known as the  modern evolutionary synthesis .


The  adaptor hypothesis  is a theoretical scheme in molecular biology to explain how information encoded in the  nucleic acid sequences  of  messenger RNA  (mRNA) is used to specify the amino acids that make up  proteins  during the process of  translation . It was formulated by  Francis Crick  in 1955 in an informal publication of the  RNA Tie Club , and later elaborated in 1957 along with the  central dogma of molecular biology  and the  sequence hypothesis . It was formally published as an article "On protein synthesis" in 1958. The name "adaptor hypothesis" was given by  Sydney Brenner .


Crick postulated that there must exist a small molecule to precisely recognise and bind the mRNA sequences while amino acids are being synthesised. The hypothetical adaptor molecule was later established to be a hitherto unknown nucleic acid,  transfer RNA  (tRNA).


In 1953, English biophysicist Francis Crick and American biologist  James Watson , working together at the  Cavendish Laboratory  of the University of Cambridge, worked out the correct description of the  structure of DNA , one of the major genetic materials. [ 1 ]  In their follow-up paper the same year, they introduced the concept of genetic information alongside the notion that DNA and protein cloud be related. [ 2 ]  By 1954, it was becoming to be understood that  DNA , RNA (only messenger RNA was understood at the time, but only as a vague nucleic acid, and identified as such only in 1960 [ 3 ] ) and proteins were related as components of the same genetic information pathway. However, the structure of RNA and details of how these biological molecules related and interact with each other were still a mystery, especially on how proteins could be synthesised from nucleic acids. [ 4 ]  Watson called this problem "the mysteries of life" in his letter to Crick. [ 3 ]  Watson and  Alexander Rich  discussed in the  PNAS , saying, "We shall not be able to check a structural relationship between RNA and protein synthesis or between RNA and DNA until we know the structure of RNA." [ 5 ]


Evidences had been accumulating since the 1940s that protein synthesis occurs simultaneously with increased level of RNA in the cytoplasm. [ 6 ] [ 7 ] [ 8 ]  The relationship between DNA and RNA for protein synthesis was first hypothesised by French biologist André Boivin and Roger Vendrely in 1947. They wrote in  Experientia  (later renamed  Cellular and Molecular Life Sciences ): "Through catalytic actions the macromolecular desoxyribonucleic acids govern the building of macromolecular ribonucleic acids, and, in turn, these control the production of cytoplasmic enzymes. In truth, the enzymic equipment results simultaneously from the effect of ribonucleic acids (catalytic action) and from the effect of substrates (mass action). [ 9 ]


Alexander Dounce , of the  University of Rochester Medical Center  in New York, came close to the correct interpretation of protein synthesis from RNA. [ 10 ]  In 1952, he proposed the first notion, naming it the "nucleic acid template hypotheses," [ 11 ]  that proteins were made from RNA, rather than from DNA. However, since the exact chemical structure of DNA or RNA was not known at the time, he suggested erroneously that proteins and RNA have complimentary sequences, as he described in  Enzymologia : "the specific arrangement of amino acid residues in a given peptide chain is derived from the specific arrangement of nucleotide residues in a corresponding specific nucleic acid molecule." [ 12 ]  It was met with criticism in  Nature  the next year, [ 13 ]  to which Dounce defended his hypothesis:


In the hypothesis proposed by me, ribonucleic acid was deliberately chosen as the template, since it seems probable from a number of considerations and experimental investigations that protein syn- thesis may occur in cytoplasm as well as in nuclei. There can be no objection at the present time to assuming that the genes are templates, but it is not necessary to assume that the genes act directly as templates for protein synthesis. [ 11 ]


Dounce was also close to a correct and fundamental explanation of the gene protein relationship, as he said: "the relationship between plasma genes and nuclear genes [postulated by  Sol Spiegelman  and  Martin David Kamen  in 1946 [ 14 ] ] could be explained by the template sequence deoxyribonucleic acid - ribonucleic acid - protein, with the additional postulate of a co-existing independent ribonucleic acid synthesis with ribonucleic acid acting as its own template." [ 11 ]  The correct interpretation of genetic information transfer (DNA → RNA → protein) developed by Crick in 1957 became the  central dogma of molecular biology . [ 15 ] [ 16 ]


Soviet-American physicist  George Gamow  was the first to come up with a coherent scheme for protein synthesis from DNA. [ 17 ]  Based on the  Watson-Crick model , he envisaged that the DNA itself is a direct template for protein synthesis. [ 18 ]  Assuming that the four  bases  of DNA could produce 20 different combinations as triplets, he suggested that the different amino acids must correspond to a twenty-letter alphabet of the nucleotide sequence. [ 19 ]  In such configuration, the DNA directly produces proteins from the free molecules of amino acids. [ 20 ]  In the 13 February 1954 issue of  Nature  he explained:


It seems to me that such translation procedure can be easily established by considering the ' key-and-lock ' relation between various amino-acids, and the rhomb-shaped 'holes' formed by various nucleotides in the deoxyribonucleic acid chain... One can speculate that free amino-acids from the surrounding medium get caught into the 'holes' of deoxyribonucleic acid molecules, and thus unite into the corresponding peptide chains. [ 21 ]


Watson, then at the California Institute of Technology in Massachusetts, also thought up the issue. [ 22 ]  Unlike Gamow, he realised the possible importance of RNA as an intermediate stage in protein synthesis. [ 3 ]  He initially imagined that DNA was first converted by chemical reaction to RNA, but then changed his view to DNA as a template for RNA synthesis. [ 22 ]  This latter model, which he called "not ugly" was starting to become more convincing. In a letter to Crick on 11 December 1954, discussing how RNA could be produced from DNA since they contain fundamentally similar nucleotide compositions, he wrote: "I suspect the answer is staring us in the face." [ 22 ]


To solve the riddle of protein synthesis, Gamow (as the Synthesiser) created an informal team of scientists which he called the RNA Tide Club in 1954. As his prediction to denote 20 amino acids, the club could have only 20 members, with the designated officers: Crick (as the Pessimist), Rich (the Lord Privy Seal) and Watson (the Optimist) among them. It was meant partly to be humorous. [ 23 ]


Coming across Gamow's paper, Crick immediately noticed some issues in the scheme. The first was that he and Watson never had before counted the 20 amino acids or the possible 20 nucleotide triplets [ 19 ]  (although Gamow was subsequently proven to be correct and his model was the first prediction of the  genetic code [ 17 ] [ 23 ] ). The other issue was that RNA and protein synthesis appeared to exclusively take place in the cytoplasm, and not in the nucleus, indicating that DNA to protein pathway requires just not direct chemical binding, but some kind of mediator must be involved. [ 10 ]


Crick began to think of a solution to this problem in the line of Watson's idea that the role of RNA was overlooked. He rejected Gamow's assumption that molecules like amino acids that are too different chemically from nucleic acid that it would be structurally impossible to bind to DNA. Instead, he visualised a certain kind but unknown molecule that linked nucleic acids and carry amino acids to  ribosomes  to form peptide chains. [ 3 ]  As he discussed it with his colleague Sydney Brenner about the features of such molecule, Brenner was impressed with the idea and named the concept as the "adaptor hypothesis". [ 24 ]  The adaptor was then a hypothetical molecule that apparently help in an indirect interaction between DNA, RNA and amino acids during protein synthesis. [ 3 ]  As Crick explained:


I don't think that anybody looking at DNA or RNA would think of them as templates for amino acids were it not for other, indirect evidence... [In one possible scheme] each amino acid would combine chemically, at a special enzyme, with a small molecule which, having a specific hydrogen-bonding surface, would combine specifically with the nucleic acid template, This combination would also supply the energy necessary for polymerisation. In its simplest form there would be 20 different kinds of adaptor molecule, one for each amino acid, and 20 different enzymes to join the amino acid to their adaptors, Sydney Brenner, with whom I have discussed this idea, calls this the "adaptor hypothesis", since each amino acid is fitted with an adaptor to go on to the template... The adaptor hypothesis implies that the actual set of twenty amino acids found in proteins is due either to a historical accident or to biological selection at an extremely primitive stage." [ 24 ]


Crick admitted that he had no way knowing what kind of chemical substance was an adaptor, but then prudently suggested that it was composed of nucleotides, a sort of RNA, that had common features of both DNA and RNA. [ 3 ]  He even speculated that "insulin, for example, are probably RNA-made proteins. Perhaps a special class of DNA-made proteins exists, almost always in small quantities (and thus normally overlooked). [ 24 ]


The template could consist of perhaps a single chain of RNA…Each adaptor molecule containing, say, a di- or trinucleotide would each be joined to its own amino acid by a special enzyme. These molecules would then diffuse to the microsomal particles and attach to the proper place on the basis of the RNA by base-pairing.


The article circulated to the members of the RNA Tie Club in January 1955 as "On Degenerate Templates and the Adaptor Hypothesis: A Note for the RNA Tie Club" is described as "one of the most important unpublished articles in the history of science", [ 25 ] [ 26 ]  and "the most famous unpublished paper in the annals of molecular biology." [ 27 ]


The adaptor hypothesis was fully formalised in 1957. Crick presented the elaborate explanation in a lecture titled "Protein synthesis" on 19 September 1957 at the  Society for Experimental Biology  symposium on the Biological Replication of Macromolecules, held at  University College London .


The lecture was further expanded and published as "On protein synthesis" in 1958, which science historian  Horace Freeland Judson  remarked: "The paper permanently altered the logic of biology." [ 28 ]  This is because it was the first comprehensive insight into genetic information (later called the central dogma of molecular biology), protein synthesis (known as the  sequence hypothesis ), the role of RNA (the adaptor hypothesis) as well as the existence of genetic code. [ 3 ]


The adaptor hypothesis was framed to explain how information could be extracted from a  nucleic acid  and used to put together a string of amino acids in a specific sequence, that sequence being determined by the nucleotide sequence of the nucleic acid (DNA or  RNA ) template. Crick proposed that each amino acid is first attached to its own specific “adaptor” piece of nucleic acid (in an  enzyme-catalysed  reaction). The order of assembly of the amino acids is then determined by a specific recognition between the adaptor and the  nucleic acid which is serving as the informational template. In this way the amino acids could be lined up by the template in a specific order. Coupling between adjacent amino acids would then lead to the synthesis of a polypeptide whose sequence is determined by the template nucleic acid.


Crick's  thinking behind this proposal was based on a general consideration of the chemical properties of the two classes of molecule — nucleic acids and proteins. The amino acids are characterised by having a variety of side chains which vary from being  hydrophilic  to  hydrophobic : their individual characters reside in the very different properties these side chains have. By contrast, a nucleic acid is composed of a string of nucleotides whose sequence presents a geometrically defined surface for  hydrogen bonding . This makes nucleic acids good at recognising each other, but poor at distinguishing the varied side chains of amino acids. It was this apparent lack of any possibility of specific recognition of amino acid side chains by a nucleotide sequence which led Crick to conclude that amino acids would first become attached to a small nucleic acid — the adaptor — and that this, by base-pairing with the template (presumably as occurs between DNA strands in the double helix), would carry the amino acids to be lined up on the template.


Gamow was not entirely wrong. Although his concept about the direct synthesis of amino acid from the DNA double strands was proven false, his prediction on the nature of amino acids and how they were coded by the DNA sequences (triplet nucleotides) were confirmed the key components of protein synthesis. [ 17 ]  This broad concept is now known as the genetic code. It was Crick, along with J.S. Griffith and  Leslie Orgel  (member of the RNA Tie Club), describing the 20-amino acid prediction as the "magic number," introduced the proper concept in 1957:


[The] order of the amino acids is determined by the order of the nucleotides of the nucleic acid. There are some twenty naturally occurring amino acids commonly found in proteins, but (usually) only four different nucleotides. The problem of how a sequence of four things (nucleotides) can determine a sequence of twenty things (amino acids) is known as the 'coding' problem. [ 29 ]


As Crick was lecturing on his hypothesis, such adaptors do exist in nature was already discovered by the team of  Mahlon Hoagland  and  Paul Zamecnik , whose paper was published the following year in March 1958. [ 30 ]  These “soluble RNAs” are now called  transfer RNAs  and mediate the translation of  messenger RNAs  on  ribosomes  according to the rules contained in the  genetic code . Crick imagined that his adaptors would be small, perhaps 5-10 nucleotides long. In fact, they are much larger, having a more complex role to play in  protein synthesis , and are closer to 100 nucleotides in length.


Richard Altmann  (12 March 1852 – 8 December 1900) was a  German   pathologist  and  histologist  from  Deutsch Eylau  in the  Province of Prussia .


Altmann studied medicine in  Greifswald ,  Königsberg ,  Marburg , and  Giessen , obtaining a doctorate at the  University of Giessen  in 1877. He then worked as a  prosector  at  Leipzig , and in 1887 became an  anatomy  professor (extraordinary).  He died in  Hubertusburg  in 1900 from a nervous disorder.


He improved fixation methods, for instance, his solution of  potassium dichromate  and  osmium tetroxide . [ 1 ]   Using that along with a new staining technique of applying acid- fuchsin  contrasted by  picric acid  amid delicate heating, he observed filaments in the nearly all cell types, developed from granules. [ 1 ] [ 2 ]   He named the granules "bioblasts", and explained them as the elementary living units, having  metabolic  and  genetic  autonomy, in his 1890 book " Die Elementarorganismen " ("The Elementary Organism"). [ 3 ] [ 4 ]   His explanation drew much skepticism and harsh criticism. [ 5 ]  Altmann's granules are now believed to be  mitochondria . [ 6 ] [ 7 ]


He is credited with coining the term " nucleic acid " in 1889, replacing  Friedrich Miescher 's term "nuclein" when it was demonstrated that nuclein was acidic. [ 8 ]


William Thomas Astbury   FRS  (25 February 1898 – 4 June 1961) was an English  physicist  and  molecular biologist  who made pioneering  X-ray diffraction  studies of  biological molecules . [ 1 ]  His work on  keratin  provided the foundation for  Linus Pauling 's discovery of the  α-helix . He also studied the structure for  DNA  in 1937 and made the first step in the elucidation of  its structure .


Astbury was the fourth child of seven, born in  Longton, Stoke-on-Trent .  His father, William Edwin Astbury, was a  potter  and provided comfortably for his family. Astbury also had a younger brother, Norman, with whom he shared a love of music. [ citation needed ]


Astbury might well have become a potter but, luckily, won a scholarship to  Longton High School , where his interests were shaped by the Headmaster and second master, both  chemists . After becoming  head boy  and winning the  Duke of Sutherland 's gold medal, Astbury won the only local  scholarship  available and went up to  Jesus College, Cambridge . [ citation needed ]


After two terms at Cambridge, his studies were interrupted by service during the  First World War . A poor medical rating following  appendectomy  resulted in his posting in 1917 to  Cork ,  Ireland  with the  Royal Army Medical Corps . He later returned to Cambridge and finished his last year with a specialization in  physics .


After graduating from Cambridge, Astbury worked with  William Bragg , first at  University College London  and then, in 1923, at the  Davy-Faraday Laboratory  at the  Royal Institution  in  London . Fellow students included many eminent scientists, including  Kathleen Lonsdale  and  J. D. Bernal  and others. Astbury showed great enthusiasm for his studies and published papers in the journal  Classic  Crystallography , such as on the structure of  tartaric acid .


In 1928, Astbury was appointed  Lecturer  in Textile Physics at the  University of Leeds .  He remained at  Leeds  for the remainder of his career, being appointed  Reader  in Textile Physics in 1937 and  Professor  of Biomolecular Structure in 1946.  He held the chair until his death in 1961.  He was elected a Fellow of the  Royal Society  (FRS) in 1940. [ 2 ]  He is commemorated by the Astbury Centre for Structural Molecular Biology at  Leeds . [ 3 ]


In later life he was given many awards and honorary degrees.


At  Leeds  Astbury studied the properties of fibrous substances such as  keratin  and  collagen  with funding from the  textile industry . ( Wool  consists of keratin.) These substances did not produce sharp patterns of spots like  crystals , but the patterns provided physical limits on any proposed structures.  In the early 1930s, Astbury showed that there were drastic changes in the diffraction of moist wool or hair fibres as they are stretched significantly (100%). The data suggested that the unstretched fibres had a coiled molecular structure with a characteristic repeat of 5.1 Å (=0.51 nm). Astbury proposed that (1) the unstretched protein molecules formed a helix (which he called the α-form); and (2) the stretching caused the helix to uncoil, forming an extended state (which he called the β-form). Although incorrect in their details, Astbury's models were correct in essence and correspond to modern elements of  secondary structure , the α-helix and the β-strand (Astbury's nomenclature was kept), which were developed twenty years later by  Linus Pauling  and  Robert Corey  in 1951.  Hans Neurath  was the first to show that Astbury's models could not be correct in detail, because they involved clashes of atoms. Neurath's paper and Astbury's data inspired  H. S. Taylor  (1941,1942) and  Maurice Huggins  (1943) to propose models of keratin that are very close to the modern α-helix.


In 1931, Astbury was also the first to propose that mainchain-mainchain  hydrogen bonds  (i.e., hydrogen bonds between the backbone  amide groups ) contributed to stabilizing  protein structures . His initial insight was taken up enthusiastically by several researchers, including  Linus Pauling .


Astbury's work moved on to include X-ray studies of many proteins (including  myosin , epidermin [ 4 ]  and  fibrin ) and he was able to deduce from their diffraction patterns that the molecules of these substances were coiled and  folded . This work led him to the conviction that the best way to understand the complexity of living systems was through studying the shape of the giant macromolecules from which they are made – an approach which he popularised with passion as 'molecular biology'. His other great passion was classical music and once said that protein fibres such as keratin in wool were 'the chosen instruments on which nature has played so many incomparable themes, and countless variations and harmonies' [ 5 ]  These two passions converged when in 1960 he presented an X-ray image taken by his research assistant Elwyn Beighton of a fibre of keratin protein in a lock of hair that was said to have come from Mozart – who was one of Astbury's favourite composers. [ 6 ]


But proteins were not the only biological fibre that Astbury studied. In 1937  Torbjörn Caspersson  of Sweden sent him well prepared samples of  DNA  from calf thymus. The fact that DNA produced a diffraction pattern indicated that it also had a regular structure and it might be feasible to deduce it. Astbury was able to obtain some external funding and he employed the crystallographer  Florence Bell . She recognised that the "beginnings of life [were] clearly associated with the interaction of proteins and nucleic acids". [ 7 ]  Bell and Astbury published an X-ray study on  DNA  in 1938, describing the nucleotides as a "Pile of Pennies". [ 8 ]


Astbury and Bell reported that DNA's structure repeated every 2.7 nanometres and that the bases lay flat, stacked, 0.34 nanometres apart. [ 9 ]  At a symposium in 1938 at  Cold Spring Harbor , [ 10 ]  Astbury pointed out that the 0.34 nanometre spacing was the same as amino acids in polypeptide chains. (The currently accepted value for the spacing of the bases in B-form of DNA is 0.332 nm.)


In 1946 Astbury presented a paper at a symposium in  Cambridge  in which he said: "Biosynthesis is supremely a question of fitting molecules or parts of molecules against another, and one of the great biological developments of our time is the realisation that probably the most fundamental interaction of all is that between the proteins and the nucleic acids." He also said that the spacing between the  nucleotides  and the spacing of  amino acids  in proteins "was not an arithmetical accident".


Astbury and Bell's work was significant for two reasons. Firstly they showed that X-ray crystallography could be used to reveal the regular, ordered structure of DNA – an insight which laid the foundations for the later work of  Maurice Wilkins  and  Rosalind Franklin , [ 1 ]  after which the structure of DNA was identified by  Francis Crick  and  James D. Watson  in 1953. Secondly, they did this work at a time when most scientists thought that proteins were the carrier of hereditary information and that DNA was a dull monotonous molecule of little interest other than perhaps as a structural component. In 1944, Astbury was one of the few scientists to recognise the importance of work done by the microbiologist Oswald Avery and his Rockefeller colleagues Maclyn McCarty and Colin Macleod. Avery and his team had shown that nucleic acid could pass on the property of virulence in pneumococcus and thus offered the first strong evidence that DNA might be the hereditary material. [ 11 ]


Astbury described Avery's work as 'one of the most remarkable discoveries of our time' [ 12 ]  and it inspired him with the vision that, in the aftermath of World War 2, he would established a new department at Leeds that would become a national centre to blaze the trail for the new science of molecular biology. Writing to the Vice-Chancellor of the University of Leeds in 1945 he declared that 'all biology, is now passing over into the molecular structural phase...In all branches of biology and all universities this thing must come to pass and I suggest that Leeds should be bold and help to lead the way.' [ 13 ]


Sadly, not everyone shared his dream. The University Senate allowed him to establish a new department but would not allow him to use the phrase 'molecular biology' in the title due to opposition from senior biologists who felt that, as a physicist, Astbury was encroaching without invitation on intellectual territory that they rightfully considered to be their own. The Senate also granted him premises but these were a far cry from what he had hoped for. His new department was housed in a Victorian terraced house that required substantial conversion, with uneven floors that made delicate scientific equipment wobble, a faulty electrical supply and unreliable plumbing that sometimes led to flooding. To add to his woes, the Medical Research Council rejected his application for funding.


Despite these set-backs, two important developments took place in Astbury's new department. The first was the elucidation of the mechanism by which thrombin acts as a protease to catalyse the formation of the major component of blood clots, the insoluble protein fibrin, from its soluble precursor fibrinogen by Laszlo Lorand, a young PhD student who had fled his native Hungary to join Astbury. Lorand's work was a major discovery in our understanding of the process by which blood clots form.


The second development was a series of new X-ray photographs of B-form DNA taken in 1951 by Astbury's research assistant Elwyn Beighton which the historian of science, Professor Robert Olby has since said was 'clearly the famous B-pattern found by Rosalind Franklin and R. Gosling'. Olby was referring to an X-ray image of B-form DNA that was taken a year later by Rosalind  Franklin  and her PhD student  Raymond Gosling  at King's College a year later which came to be known as 'Photo 51' Despite its modest name this image was to play an important role in the story of DNA and a plaque on the wall outside King's College, London hails it as 'one of the most important photographs in the world'. This is because the image shows a striking cross-shaped pattern of black spots made by X-rays as they are scattered by the DNA fibre and when James Watson was first shown Franklin and Gosling's picture, this cross-shaped pattern made him so excited that he said 'my mouth fell open and my pulse began to race', [ 14 ]  because he knew that only a molecule coiled into a helical shape could scatter X-rays to give this particular pattern.


Franklin and Gosling's 'Photo 51' provided one of several important clues to Watson and Crick -but Astbury's response to Beighton's very similar X-ray images of DNA could not have been more different. He never published them in a journal or presented them at a scientific meeting. Given that Astbury was such a renowned expert in X-ray studies of biological molecules this apparent neglect of such an important clue may seem surprising. One explanation is that, although Astbury recognised the importance of DNA, he did not understand that biological information was carried in the one-dimensional sequence of bases within the molecule but rather, that it resided in subtle and elaborate variations in its three-dimensional structure. Far from making his jaw drop and his pulse race, the revelation that DNA was a simple a twisting helix would therefore have been a disappointment but it is intriguing to speculate on how differently history might have unfolded had Astbury shown Beighton's image to his friend and colleague the eminent US chemist and Nobel Laureate, Linus Pauling when he visited Astbury at his home in Headingley, Leeds in 1952. Pauling was, at that time, Watson and Crick's greatest rival in trying to solve the structure of DNA and was desperate to obtain a good quality X-ray diffraction image of DNA. In 1952, he had already proposed an incorrect model of DNA based on Astbury and Bell's early work but had Astbury shown Pauling these new images taken by Beighton, it might well have been Caltech, Pasadena and not Cambridge, UK that is today remembered for the discovery of the double-helix. Despite this missed opportunity, Astbury, together with Florence Bell, had made a major contribution by showing that the methods of X-ray crystallography could be used to reveal the regular, ordered structure of DNA.


But perhaps Astbury's greatest scientific legacy was his rather unusual overcoat. In the late 1930s Astbury and his collaborators A.C. Chibnall and Kennet Bailey showed that by chemical treatment, the molecular chains of soluble seed proteins could be refolded to make them into insoluble fibres. The company ICI was so interested in this idea that they built a pilot production plant in Scotland to a new textile fibre called 'Ardil' that was produced by deliberately altering the molecular structure of the main soluble protein component of monkeynuts to refold it into an insoluble fibre in the hope of using this as a cheap and abundant substitute for wool as a raw material in the textile industry. To demonstrate the feasibility of this idea, ICI made an entire overcoat from Ardil which Astbury regularly sported to lectures and in the end, although Ardil did not prove to be the salvation of the British textile industry, it did serve as a powerful illustration of Astbury's conviction that not only could we solve the structure of giant biomolecules such as proteins and DNA using X-rays, but that we might also then deliberately manipulate these structures for our own practical purposes.


This was an idea which truly came of age in the mid- to late 1970s with the rise of recombinant DNA technology by which time Astbury was dead but as his friend and colleague, J.D.Bernal wrote in an obituary to him, 'His monument will be found in the whole of molecular biology'. [ 15 ]


Astbury was known for his unfailing  cheerfulness ,  idealism ,  imagination  and  enthusiasm . He foresaw correctly the tremendous impact of  molecular biology  and transmitted his vision to his students, "his euphoric evangelizing zeal transforming laboratory routine into a great adventure". [ 16 ]  Astbury's enthusiasm may also account for an occasional lack of scientific caution observable in his work; Astbury could make speculative interpretations sound plausible.


Astbury was an excellent writer and lecturer; his works are characterized by remarkable clarity and an easy-going, natural manner. He also enjoyed music, playing both piano and violin.


Astbury met Frances Gould when he was stationed in Cork, Ireland with the  Royal Army Medical Corps  during  World War I . They married in 1922 and had a son, Bill, and a daughter, Maureen.


Oswald Theodore Avery Jr.  (October 21, 1877 – February 20, 1955) was a Canadian-American physician and medical researcher.  The major part of his career was spent at the  Rockefeller Hospital  in New York City.  Avery was one of the first  molecular biologists  and  a pioneer in  immunochemistry , but he is best known for  the experiment  (published in 1944 with his co-workers  Colin MacLeod  and  Maclyn McCarty ) that isolated  DNA  as the material of which  genes  and  chromosomes  are made. [ 4 ] [ 5 ] [ 6 ]


The  Nobel laureate   Arne Tiselius  said that Avery was the most deserving scientist not to receive the Nobel Prize for his work, [ 7 ]  though he was nominated for the award throughout the 1930s, 1940s, and 1950s. [ 8 ] [ 9 ]


The  lunar crater   Avery  was named in his honor.


Oswald Avery's grandfather was Joseph Henry Avery. [ 10 ]  He was a papermaker, and he was in charge of the papermaking at Oxford University. [ 10 ]  He discovered a way to make thin paper that could be printed on both sides. This paper was used to make Oxford Bibles. [ 10 ]


Avery's father, Joseph Francis Avery, born in 1846 in Norwich, Norfolk, became a Baptist minister after coming under the influence of C. H. Spurgeon, a Baptist Evangelist. [ 10 ]  He married his wife, Elizabeth Crowdy, in 1870, and spent three years in England, where he would continue his pastoral service as a Baptist. [ 10 ]  After this, he would move to Halifax, Nova Scotia with his wife, against the wishes of his friends, believing it to be the Will of God. [ 10 ]  He remained as a pastor for 14 years in Halifax before traveling to the Mariner's Temple in New York City, where he would preach to a rowdy and poverty-stricken crowd. [ 11 ]  While here, he would publish an edifying pamphlet entitled "The Voyage of Life", edited the church publication Buds and Blossoms, and patented and attempted to sell a preparation known as "Avery's Auraline", though it would gain little success. [ 12 ]  When their home burned to the ground in December 1890, the Baptist community of New York banded together to help pay for the expenses, including one John D. Rockefeller. [ 12 ]  He would die in 1892, leaving his wife Elizabeth Avery a widow. [ 13 ]


Avery's mother, Elizabeth Crowdy, was the beating heart and soul that made her husband's church the community center it was. [ 14 ]  After Joseph Francis Avery's death, she would continue editing the publication Buds and Blossoms. [ 14 ]  She would also continue to work with the Baptist City Mission Society, where she would come into association with a number of wealthy people, including the Sloans, the Vanderbilts, and the Rockefellers. [ 14 ]


Oswald had two siblings - an older brother Ernest and a younger brother Roy. [ 14 ]  Ernest was a gifted child, but became ill at a young age. [ 14 ]  Roy followed his brother Oswald in the field of bacteriology. [ 5 ]  He eventually taught at Vanderbilt Medical School in Nashville, Tennessee. [ 5 ]


Oswald Avery was born in  Halifax, Nova Scotia , in 1877 to Francis Joseph Avery, a Baptist minister, and his wife Elizabeth Crowdy. The couple had immigrated from Britain in 1873. Oswald Avery was born and grew up in a small wooden row house on Moran Street in the  North End of Halifax , now a designated heritage building. [ 15 ]  When Avery was 10, his family moved to the Lower East Side of  New York City . Oswald Avery began participating in church activities at a young age. [ 16 ]  He and his older brother Ernest learned how to play the cornet from a German musician who played at church. [ 16 ]  Soon, both were playing at church themselves. [ 16 ]  The brothers played on the steps of Mariners' Temple to attract worshippers. [ 17 ]  Both earned a scholarship to the National Conservatory of Music. [ 16 ]  Ernest became sick and did not continue, but Oswald pushed onward. [ 18 ]  He became talented enough to play with the National Academy of Music in Antonin Dvorak's Symphony No. 5, From the New World, under direction of Walter Damrosch. [ 18 ]


Oswald Avery began at Colgate University in 1896. [ 18 ]  Even though Colgate was a Baptist school, there were signs of rebellion against orthodoxy during Avery's time at the university. [ 18 ]  In Avery's senior year, he and a few of his classmates asked their philosophy professor to create a metaphysics class that would allow them to explore the credibility of the Christian faith. [ 19 ]  Avery's senior year was entirely electives, but he did not choose to take a single science elective, even though many were offered. [ 20 ]  Avery made exceptional grades throughout his years at Colgate. [ 20 ]  He received 8.5 out of 10 or above in all courses his freshman year and 9 out of 10 or above his sophomore through senior year. [ 20 ]  Avery's top grades were in his public speaking courses, in which he never received lower than a 9.5. [ 20 ]  He even tied for first with his friend Emerson in an oratorical contest. [ 20 ]  Avery earned his undergraduate degree in humanities at  Colgate University  and was a member of the Class of 1900. [ 21 ] [ 20 ]


Oswald Avery began medical studies at  The College of Physicians and Surgeons  at Columbia University in New York later in the year of 1900. [ 20 ]  At the college, he made good grades in all of his courses, except bacteriology and pathology. [ 22 ]  He graduated with a medical degree in 1904, and then he began to practice general medicine.' [ 23 ]  Avery did not like dealing with patients who have chronic diseases that he was unable to fix. [ 23 ]  He practiced medicine until 1907 when he began working as an associate director to Benjamin White in Hoagland Laboratory. [ 24 ]


At Hoagland Laboratory, he began by studying the bacteriology of yogurt and other fermented milk products and their effects on gut bacteria. [ 25 ]  He recorded his findings in "Observations on Certain Lactic Acid Bacteria of the Bulgaricus Type". [ 26 ]  During the years 1909 through 1913, he performed medical research with bacteriological, immunological, and chemical approaches. [ 26 ]


For a period of time, White came down with  tuberculosis . [ 26 ]  Avery went with him to Trudea Sanatorium for a cure. [ 26 ]  Afterwards, Avery went back to take vacations at the sanatorium. [ 26 ]  He became interested in tuberculosis and began doing research in the Trudea Laboratory, where he looked at the clinical and experimental aspects of tuberculosis. [ 26 ]  Here he carried out 100 consecutive blood cultures of tuberculosis patients in the active phase of the disease. [ 26 ]  He never found evidence of secondary infection. [ 26 ]  His careful clinical investigation caught the eye of  Dr. Rufus Cole  at Rockefeller Institute. [ 26 ]


At Hoagland, Avery performed a chemical and toxicological study of a product derived from tubercle bacilli. [ 27 ]  With White as a colleague, he extracted the product with alkaline ethanol. [ 27 ]  The research was published in 1912. [ 27 ]  This further showed his systematic effort to observe and analyze bacterial activity using their chemical structure. [ 27 ]  In 1911, Avery instructed staff of H. K. Mulford Company in bacteriological techniques, and they taught him the industrial methods for production of antitoxins and vaccines. [ 27 ]


Throughout his time at Hoagland, Avery published nine papers, one of which was a chapter on "Opsonins and Vaccine Therapy". [ 27 ]  He collaborated with Dr. N. B. Potter for this chapter, which was put in Hare's Modern Treatment - a popular medical magazine at the time. [ 27 ]  Avery also taught a course to student nurses at Hoagland. [ 27 ]  During the course, he conveyed the dangers of pathogens spread through sneezing. [ 27 ]  During his teaching, he was given the nicknames "The Professor" and "Fess". [ 27 ]  While working at Hoagland, Avery was mailed two written offers from Rockefeller Institute, and he denied them both. [ 28 ]  Avery did not accept the offer until Rufus Cole from Rockefeller came to offer the position to him in person. [ 28 ]


Oswald Avery entered Rockefeller Institute as Assistant in 1913, and in 1915, he became an Associate. [ 28 ]  In 1919, Avery was promoted to an associate member. [ 28 ]  He was granted full membership in 1923 . [ 28 ]  At the institute, Cole, Avery and  Alphonse Dochez  developed the first effective immune serum against a strain of  pneumococcus , a bacterium causing  pneumonia . The serum was produced from the blood of infected horses. [ 29 ]


Research showed that various pneumonia cultures isolated from different patients had different immunological properties. [ 30 ]  This made it difficult to develop a serum effective against all of the different strains. [ 30 ]  Four main groups of pneumococcus had been discovered - type I, type II, type III, and type IV. [ 31 ]  Avery investigated distribution of different pneumococcus types in healthy individuals versus individuals with symptoms of pneumonia. [ 32 ]  Avery found different subgroups of type II pneumococcus. [ 31 ]  These groups were similar to the type strain in certain aspects. [ 31 ]  However, the subgroups of type II had similarities amongst each other that they did not share with the other main groups of pneumococcus. [ 31 ]  Avery wrote about the results of his findings in a 1915 paper called "Varieties of Pneumococcus and Their Relation to Lobar Pneumonia". [ 32 ]  In the paper, he argued that people who appeared to be healthy could be carriers of pneumonia [ 32 ]  Avery also suggested it was important to identify the type of strain, based on agglutination of the pneumococci, when determining the appropriate serum for the patient. [ 32 ]  Avery suggested pneumococci strains that produced more severe symptoms had higher virulence than strains that cause less severe symptoms. [ 32 ]  A serum effective against type II pneumonia was developed. [ 33 ]  Avery tested the serum in horses. [ 32 ] [ 33 ]  He processed the serum and measured its antipneumococcal activity. [ 32 ] [ 33 ]  Avery concentrated the serum so that a minimal amount of foreign protein was needed in it. [ 32 ]  Avery wrote the monograph, Acute Lobar Pneumonia: Prevention and Serum Treatment, that was published by The Institute explaining this improvement. [ 33 ]


Avery also helped Dochez in his research on specific soluble substances found in the blood and urine of pneumonia patients. [ 34 ]  The presence of specific soluble substances in a urine sample allowed him to rapidly test the type of pneumonia without having to wait for a culture to grow. [ 35 ]  Avery and Heidelberger realized that the capsules of different strains of pneumonia had different polysaccharide structures and concluded that polysaccharides play a role in immunological specificity. [ 36 ]  Their work with specific soluble substances showed that it is important to consider the factor in the chemical composition of organisms to design anti-serums. [ 32 ]  Avery published papers on specific soluble substance findings between 1923 and 1929, along with an additional paper he published with Goebel in 1933. [ 37 ]  He worked with Goebel until 1934, and then Gobel continued their work upon his cessation. [ 37 ]  Later, Avery concluded that a protein determines the specificity of Diplococcus pneumoniae after he observed that the active protein was the same for all pneumococcal strains but different than that of other bacteria. [ 38 ]


Avery became an emeritus member of The Institute when he retired in 1943. [ 28 ]  However, he continued to work in the lab until 1948. [ 28 ]


At the height of the  1918 influenza epidemic , the dominant hypothesis was that the causative agent in the disease was a  bacterium  — specifically,  Haemophilus influenzae  (then called 'Pfeiffer's bacillus' or  Bacillus influenzae ),
a microbe first isolated by German bacteriologist  Richard Pfeiffer , which he had identified in nasal samples of patients infected by  seasonal influenza  decades earlier and which was also found in many but not all samples taken from patients in the 1918 epidemic. [ 39 ]   The failure to isolate  B. influenzae  in some patients was generally attributed to the difficulty of culturing the bacterium. [ 39 ]


Peter Olitsky  and  Frederick Gates  at the Rockefeller Institute found that nasal secretions from infected patients could still cause disease in the lungs of rabbits after having been filtered through a bacterium-excluding  Berkefeld filter , but other researchers were unable to reproduce their results. Avery initially doubted Olitsky's and Gates's data, and set out to prove the  B. influenzae  hypothesis. For that purpose, he developed improved culture media for  B. influenzae , which were widely adopted and reduced the possibility of  false negatives . [ 39 ]  However,  B. influenzae  could still not be found in all influenza patients. The true cause of influenza, a virus, would not be discovered until the 1930s. [ 40 ]


After the influenza epidemic, Avery returned to his work on pneumococcus. He identified R and S strains of the bacterium; the latter caused disease and had a  polysaccharide  capsule, while the former lacked the capsule and was harmless.  Griffith's experiment  of 1928 showed that the ability to produce a capsule could be transferred from S to R strain bacteria, even if the S strain bacteria were killed first.


For many years, genetic information was thought to be contained in  cell   protein . Continuing the research done by  Frederick Griffith , Avery worked with  Colin MacLeod  and  Maclyn McCarty  on the mystery of  inheritance . He had received  emeritus  status from the Rockefeller Institute in 1943, but continued working for five years, though by that time he was in his late sixties. In 1944 at the Rockefeller Institute's Hospital for medical research, Oswald Avery, along with Colin MacLeod and Maclyn McCarty, isolated S-strain bacteria and killed them with heat. [ 41 ] [ 42 ]  They used available techniques to remove various macromolecules - proteins,  RNA , and DNA - from the bacteria. [ 41 ] [ 42 ]  Then, the killed S-strain bacteria, with various substances removed, were placed with live R-strain bacteria. [ 41 ] [ 42 ]  Avery hypothesized that if the live R-strain bacteria did not transform into S-strain bacteria, then the missing substance contained genetic information and was the "transforming principle". [ 41 ] [ 42 ]  Proteins were removed with protease enzymes and upon transfer of  S-strain bacteria into R-strain, the R-strain transformed into S-strain. [ 41 ] [ 42 ]  Therefore, proteins were not the "transforming principle". [ 41 ] [ 42 ]  Next, the S-strain bacteria were treated with ribonucleases to degrade their RNA, and the remainder of the S-strain was placed with the live R-strain bacteria. [ 41 ] [ 42 ]  The R-strain still transformed into S-strain, suggesting that RNA was not the transforming substance. [ 41 ] [ 42 ]  Finally, the S-strain bacteria were treated with a  deoxyribonuclease  enzymes, which removed the  DNA , and the S-strain bacteria were placed with the live R-strain bacteria. [ 41 ] [ 42 ]  After this treatment, the R-strain bacteria did not transform into S-strain bacteria. [ 41 ] [ 42 ]  The lack of transformation suggested that DNA was the substance that transformed R-strain into S-strain bacteria and indicated that it was the carrier of genetic information in cells. [ 43 ] [ 44 ] [ 42 ] [ 41 ]


Avery's conclusion, that "The evidence presented supports the belief that a  nucleic acid  of the  desoxyribose  type is the fundamental unit of the transforming principle of  Pneumococcus  Type III" greatly influenced  Erwin Chargaff , who upon reading those words dedicated his work to identify a "chemistry of heredity" which he later elucidated in  Chargaff's rules . Chargaff would later comment that "As this transformation represents a permanently  inheritable  alteration of a cell, the chemical nature of the substance responsible for this alteration had been elucidated for the first time. Seldom has more been said in so few words." [ 45 ]


Alfred Hershey  and  Martha Chase  furthered Avery's research in 1952 with the  Hershey–Chase experiment . These experiments paved the way for  Watson  and  Crick 's discovery of the  helical  structure of DNA, and thus the birth of modern  genetics  and molecular biology. Of this event, Avery wrote in a letter to his youngest brother Roy, a bacteriologist at the Vanderbilt School of Medicine: "It's lots of fun to blow bubbles but it's wiser to prick them yourself before someone else tries to." [ 46 ]


Nobel laureate  Joshua Lederberg  stated that Avery and his laboratory provided "the historical platform of modern DNA research" and "betokened the molecular revolution in  genetics  and biomedical science generally".


While working at Rockefeller Institute, Avery contracted  Grave's disease , which caused him to experienced mood swings of depression and irritability. [ 47 ]  After undergoing a thyroidectomy, Avery once again became more lively and began sailing, where he fell in love with the sport. [ 47 ]  Shortly after, he retired in  Nashville, Tennessee , where he lived close to his brother and his brother's family, where he was regarded not as a scientist, but as a pleasant family man and a kind country gentleman. [ 48 ]   While in the southern United States, Avery took a particular interest in the local flora and would act as a gardener would, learning about and appreciating the flowers and trees. [ 48 ]


Avery's enthusiasm toward researching nucleic acids continued into his retirement, and he would continue his work with  Dr. Hugh Morgan , chairman of the department of medicine at  Vanderbilt Medical School . [ 48 ]  Dr. Morgan was given a research grant from the Department of Defense to study immunity to streptococcal infection, and he convinced Avery to help him in his research. [ 48 ]  Avery worked on this research with Dr. Bertram E. Sprofkin. [ 48 ]  The two wrote a joint report on "Studies on the bacteriolytic property of  Streptomyces albus  and its action on hemolytic streptococci". [ 48 ]


During his later years, Avery became terminally ill with extensive  hepatoma , or liver cancer. [ 48 ]  He died at age 77 on February 20, 1955, and was buried in  Mount Olivet cemetery  in Nashville. [ 48 ]


The collected papers of Avery are stored at the Tennessee State Library and Archives and at the Rockefeller Archive. Many of his papers, poems, and hand written lab-notes are available at the National Library of Medicine in the Oswald T. Avery Collection, the first of their  Profiles in Science  series. [ 49 ]


Leslie Barnett  (born 12 October 1920 as  Margaret Leslie Collard  – died 10 February 2002) [ 1 ]  was a British biologist who worked with  Francis Crick ,  Sydney Brenner , and Richard J. Watts-Tobin to genetically demonstrate the  triplet nature of the code  of  protein translation  through the  Crick, Brenner, Barnett, Watts-Tobin et al. experiment of 1961 , which discovered  frameshift mutations ; this insight provided early elucidation of the nature of the genetic code.


In her professional life, Barnett was a microbiologist who joined the  Laboratory of Molecular Biology  in Cambridge, where she worked as an assistant mainly with Crick and later Brenner, with whom she remained for many years until he left and she retired.  During this long period, Barnett was involved in a number of the important 20th-century advances made in molecular biology and genetics. [ 2 ]


At the beginning of the Second World War, she had started training in the Institute of Agriculture in Essex; but in 1939 took a job in  Felixstowe  as a milk testing apprentice at a local dairy, and later with  United Dairies  in London. After evacuation to Banbury and several further jobs she returned to London where she met and married James in 1945.  He insisted that she took up the offer of a place at  Reading University  and she remembered these as some of the happiest days of her life, studying for her BSc in dairying. Leslie continued to be fond of James despite their divorce when the children were quite young. She had two daughters, Penny and Marion.


Barnett came to work as a technician in the MRC Unit [ 3 ]  shortly before the move from the  Cavendish Laboratory  to "The Hut" in  Cambridge , which would later go on to become the  MRC Laboratory of Molecular Biology (LMB) . Her role was to help with the computing for the crystallographers. On the arrival of Sydney Brenner, however, help was needed to set up the  phage  research and then to prepare for the arrival of  Seymour Benzer  and other American visitors that autumn. Leslie worked with  Vernon Ingram  in determining the GLU to VAL amino acid change in the beta chain of Hb responsible for the  sickle cell  phenotype; this was the first molecular disease characterized. Barnett showed her versatility when she transferred to Brenner's programme and made a major contribution to the laboratory work, becoming a co-author of their two major papers on the results. In 1966 she was appointed Senior Tutor at the new graduate college,  Clare Hall, Cambridge . She proved very popular in this work.


On Brenner's retirement in 1986, Barnett left the LMB to work for him in the new MRC Molecular Genetics Unit in  Addenbrooke's Hospital . She trained the late  Francis Crick  in experimental work on phage and assisted him.


Barnett also helped set up Sydney Brenner's laboratory in Singapore, many years later.


Barnett was amongst the early Fellows elected to join Clare Hall, the newly founded graduate college. In 1972, she became a tutor for graduate students; in 1975, she took over the leading role of Senior Tutor, which she held until her retirement in 1985. She was remembered by hundreds of students of various nationalities, ages and subjects for her "steadfast care, wisdom in solving their problems, and motherly love." [ 2 ]


Barnett played a leading role in college affairs, particularly in the organising of social events and parties and will be remembered with great affection by her colleagues and other friends associated with the college.  As a token of her contribution to the college the Governing Body has named a student residence the Leslie Barnett House, and a bronze head by the late Lois Tilbrook represents another tribute to her on the site.   On retirement she was elected to an Emeritus Fellowship and attended regularly until her last illness. [ 2 ]


Eric Miller, who was a visiting scientist at the Molecular Biology Laboratory in 1986–87, wrote: "Leslie Barnett should be recognised for her immense scientific contributions to the field of gene structure and function.  Professionally, to which I am sure Francis Crick and Sydney Brenner will attest, many of the seminal discoveries in molecular biology would not have occurred without the careful hand, watchful eye and steadfast focus that Leslie brought to the bench and experiments." Francis Crick said: "Alex Rich and I engaged Leslie in 1955 to do some x-ray calculations for us, since in those days electronic computers were still very primitive.  After we discovered that Leslie had biological qualifications she did various types of experimental work.  Among other things she worked with us on the phase-shift mutants of phage T4.  She was invaluable, as she was always such a careful and meticulous experimentalist." [ 2 ]


In 1978 at Clare Hall a second neighbouring house in Cambridge, now called Leslie Barnett House, was obtained for graduate student accommodation; it was named after the popular Senior Tutor.


Jean Duthie Beggs  (née Lancaster, born 16 April 1950) is a Scottish geneticist. She is the  Royal Society  Darwin Trust Professor in the  Wellcome Trust  Centre for Cell Biology at the  University of Edinburgh . [ 1 ] [ 2 ] [ 3 ]


Beggs was born Jean Duthie Lancaster on 16 April 1950 to Jean Crawford (née Duthie) and William Renfrew Lancaster. [ 1 ]  She attended  Glasgow High School for Girls . She graduated from the  University of Glasgow  with a BSc (Hons) in  Biochemistry  in 1971, [ 4 ]  and received her PhD from the University in 1974. From 1974-1977 she held a postdoctoral position in the Department of Molecular Biology at the  University of Edinburgh  working with Professors  Kenneth  and  Noreen Murray . [ 1 ] [ 4 ]  Having received a  Beit Memorial Fellowship for Medical Research , Beggs moved to the  Plant Breeding Institute  in  Cambridge , working there for two years. In 1979, she began work as a lecturer in the Department of Biochemistry at  Imperial College London . In 1985, Beggs returned to the University of Edinburgh's Molecular Biology department at Edinburgh, where she was appointed Professor of Molecular Biology in 1999. [ 1 ] [ 4 ] [ 5 ]


Her research interests are in RNA splicing. [ 6 ]


In 1972 she married Dr Ian Beggs. They have two sons. [ 1 ]


She has been a  Fellow of the Royal Society of Edinburgh  since 1995 [ 1 ] [ 7 ]  and was elected a  Fellow of the Royal Society  in 1998. [ 8 ]


In 2003, she was awarded the Royal Society's  Gabor Medal  "for her contributions to the isolation and manipulation of recombinant DNA molecules in a eukaryotic organism, adding a new dimension to molecular and cellular biology". [ 9 ]


She received a  CBE  in the  2006 Queen's Birthday Honours  for her services to science. [ 10 ]


She was the  Royal Society of Edinburgh  Vice President for Life Sciences from 2009 to 2012.


In 2016 she was awarded an honorary DSc by the  University of St Andrews . [ 11 ]


In 2018  RNA Society  Lifetime Achievement Award. [ 12 ]


This article about a British scientist is a  stub . You can help Wikipedia by  expanding it .


Seymour Benzer  (October 15, 1921 – November 30, 2007) was an American  physicist ,  molecular biologist  and  behavioral geneticist . His career began during the molecular biology revolution of the 1950s, and he eventually rose to prominence in the fields of molecular and behavioral genetics. He led a productive genetics research lab both at Purdue University and as the James G. Boswell Professor of Neuroscience, emeritus, at the  California Institute of Technology . [ 1 ] [ 2 ] [ 3 ]


Benzer was born in the  South Bronx  to Meir Benzer and Eva Naidorf, both  Jews from Poland . [ 4 ] [ 5 ]  He had two older sisters, and his parents favored him as the only boy. [ 6 ]  One of Benzer's earliest scientific experiences was dissecting frogs he had caught as a boy. In an interview at Caltech, Benzer also remembered receiving a microscope for his 13th birthday, “and that opened up the whole world.” [ 7 ]  The book  Arrowsmith  by  Sinclair Lewis  heavily influenced the young Benzer, and he even imitated the handwriting of Max Gottlieb, a scientist character in the novel. Benzer graduated from  New Utrecht High School  at 15 years old. [ 8 ]


In 1938 he enrolled at  Brooklyn College  where he majored in physics. [ 3 ]  Benzer then moved on to  Purdue University  to earn his Ph.D. in solid state physics. While there he was recruited for a secret military project to develop improved radar. He performed research that led to the development of stable  germanium  rectifiers and discovered a germanium crystal able to be used at high voltages, among the scientific work that led to the first  transistor . [ 2 ] [ 3 ] [ 9 ]


At  Brooklyn College , as a sixteen-year-old freshman, Benzer met Dorothy Vlosky (nicknamed Dotty), a twenty-one-year-old nurse. He later married her in  New York City  in 1942. [ 8 ]  They had two daughters, Barbie (Barbara) and Martha Jane.


Benzer died of a stroke at the  Huntington Hospital  in  Pasadena, California . [ 9 ]


Upon receiving his Ph.D. in 1947, he was immediately hired as an assistant professor in physics at Purdue. However, Benzer was inspired by  Erwin Schrödinger's  book  What Is Life? , in which the physicist pondered the physical nature of the gene and a “code” of life. This catalyzed Benzer's shift in interest to biology, and he moved into the area of  bacteriophage  genetics., [ 10 ]  spending two years as a postdoctoral fellow in  Max Delbrück 's laboratory at California Institute of Technology, and then returning to Purdue. At Purdue University, Benzer developed the  T4  rII  system , a new genetic technique involving  recombination  in T4 bacteriophage  rII  mutants. [ 11 ]  After observing that a particular  rII  mutant, a mutation that caused the bacteriophage to eliminate bacteria more rapidly than usual, was not exhibiting the expected phenotype, it occurred to Benzer that this strain might have come from a cross between two different  rII  mutants (each having part of the  rII  gene intact) wherein a  recombination  event resulted in a normal  rII  sequence.  Benzer realized that by generating many  r  mutants and recording the  recombination frequency  between different  r  strains, one could create a detailed map of the gene, much as  Alfred Sturtevant  had done for  chromosomes . [ 8 ]  Taking advantage of the enormous number of recombinants that could be analyzed in the  rII  mutant system, Benzer was eventually able to map over 2400  rII  mutations. The data he collected provided the first evidence that the gene is not an indivisible entity, as previously believed, and that genes were linear. [ 12 ] [ 11 ]    Benzer also proved that  mutations  were distributed in many different parts of a single gene, and the resolving power of his system allowed him to discern mutants that differ at the level of a single  nucleotide .  Based on his  rII  data, Benzer also proposed distinct classes of mutations including  deletions ,  point mutations ,  missense mutations , and  nonsense mutations . [ 13 ]


Benzer's work influenced many other scientists of his time (see  Phage group ). In his molecular biology period, Benzer dissected the fine structure of a single gene, laying down the ground work for decades of mutation analysis and genetic engineering, and setting up a paradigm using the  rII  phage that would later be used by  Francis Crick  and  Sydney Brenner  to establish the  triplet code  of  DNA . In addition, Benzer's mapping technique was taken up by  Richard Feynman . [ 8 ]


In 1967, Benzer left the field of phage genetics and returned to the California Institute of Technology to work in  behavioral genetics .


Benzer was one of the first scientists to rise to prominence in the field of  behavioral genetics . As the field began to emerge in the 1960s and 70s, Benzer found himself in scientific opposition to another of the field's leading researchers,  Jerry Hirsch . While Hirsch believed that behaviors were complex phenomena irreducible to the level of single genes, Benzer advocated that animal behaviors were not too complex to be directed by a single gene. This translated to methodological differences in the two researchers' experiments with  Drosophila  that profoundly influenced the field of behavioral genetics. Hirsch artificially selected for behaviors of interest over many generations, while Benzer primarily used  forward genetic  mutagenesis screens to isolate mutants for a particular behavior. [ 14 ]  Benzer and Hirsch's competing philosophies served to provide necessary scientific tension in order to accelerate and enhance developments in behavioral genetics, helping it gain traction as a legitimate area of study in the scientific community.


Benzer used forward genetics to investigate the genetic basis of various behaviors such as  phototaxis ,  circadian rhythms , and learning by inducing mutations in a Drosophila population and then screening individuals for altered phenotypes of interest. [ 10 ]  To better identify mutants, Benzer developed novel apparatuses such as the countercurrent device, which was designed to separate flies according to the magnitude and direction of their phototactic response. [ 15 ]  Benzer identified mutants for a wide variety of characteristics: vision ( nonphototactic ,  negative phototactic , and  eyes absent [ 16 ] ), locomotion ( sluggish ,  uncoordinated ), stress sensitivity ( freaked-out ), sexual function ( savoir-faire ,  fruitless ), nerve and muscle function ( photoreceptor degeneration ,  drop-dead ), and learning and memory ( rutabaga ,  dunce [ 17 ] ). [ 18 ]


Benzer and student  Ron Konopka  discovered the first circadian rhythm mutants. Three distinct mutant types—arrhythmic, shortened period, and lengthened period—were identified. These mutations all involved the same functional gene on the X chromosome and influenced the eclosion rhythm of the population as well as rhythms in individual flies' locomotor activity. [ 19 ]  To monitor  Drosophila  locomotor activity, Benzer and postdoctoral researcher, Yoshiki Hotta, designed a system using infrared light and solar cells. [ 19 ]  All three mutations were mapped to the X chromosome, zero centimorgans away from each other, indicating that the mutant phenotypes corresponded to alleles of the same gene, which Konopka named  period . [ 19 ]  This was the first of several seminal studies of single genes affecting behavior, studies that have been replicated in other animal models and are now the basis for the growing field of molecular biology of behavior. In 1992 Benzer, working with Michael Rosbash, furthered this work by showing that the PER protein, which  period  codes for, is predominantly located in the nucleus. [ 20 ]  The work with Period mutants was catalytic in the study of circadian rhythms and served to propel the field forward.


On 2 October 2017, Dr. Rosbash, along with Drs. Michael W. Young and Jeffrey C. Hall, were awarded the Nobel Prize in Physiology or Medicine in recognition of their cloning of circadian rhythm genes, and the elucidation of the biochemical mechanisms by which the circadian rhythm protein products regulated behavior.


Benzer was at the forefront of the study of neurodegeneration in fruit flies, modeling human diseases and attempting to suppress them. He also contributed to the field of aging biology, looking for mutants with altered longevity and trying to dissect the mechanisms by which an organism can escape the inevitable functional downfall and its associated diseases. [ 21 ]  In 1998, Benzer and his colleagues Yi-Jyun Lin and Laurent Seroude published findings of a long-life mutant in  Drosophila , then named Methuselah. The mutant gene coded for a previously unknown member of the  GPCR  family. By testing against temperature stress, it is thought that these mutants have an increased ability to respond to stress and thus to live longer. [ 22 ]  One of Benzer's final research projects was on dietary restriction and longevity research. A paper was published, in ' 'Cell' ', on the longevity effect of 4E-BP, a translational repressor, following dietary restriction. Although the research was done before his death, the paper was published afterwards and dedicated to his memory. [ 23 ]


In 1978, Dotty was in the hospital with breast cancer, and Seymour's friend, colleague, and mentor  Max Delbrück  was diagnosed with cancer. Consequently, Seymour Benzer took interest in cancer biology and attended several conferences on breast cancer. [ 8 ]
Benzer later remarried with Carol Miller, a  neuropathologist . Together, in the early 1980s, they used  antibody staining  techniques to find nearly identical  genes  between flies and humans. [ 8 ]


He was a member of the  French Academy of Sciences , the U.S. National Academy of Sciences, the  American Philosophical Society  and the  Royal Society .


Benzer is the subject of the 1999 book  Time, Love, Memory : A Great Biologist and His Quest for the Origins of Behavior  by  Pulitzer laureate   Jonathan Weiner , [ 8 ]  and  Reconceiving the Gene: Seymour Benzer's Adventures in Phage Genetics  by Lawrence Holmes. [ 6 ]


The  Boveri–Sutton chromosome theory  (also known as the  chromosome theory of inheritance  or the  Sutton–Boveri theory ) is a fundamental unifying theory of  genetics  which identifies  chromosomes  as the carriers of  genetic material . [ 1 ] [ 2 ] [ 3 ]  It correctly explains the mechanism underlying the laws of  Mendelian inheritance  by identifying chromosomes with the paired  factors  (particles) required by Mendel's laws. It also states that chromosomes are linear structures with  genes  located at specific sites called  loci  along them. [ 2 ]


It states simply that chromosomes, which are seen in all dividing cells and pass from one generation to the next, are the basis for all genetic inheritance.
Over a period of time random mutation
creates changes in the DNA sequence of a gene. Genes are located on chromosomes.


"1. The chromosome group of the presynaptic germ-cells is made up of two equivalent chromosome-series, and that strong ground exists for the conclusion that one of these is paternal and the other maternal.
2. The process of synapsis (pseudo-reduction) consists in the union in pairs of the homologous members (i. e., those that correspond in size) of the two series.
3. The first post-synaptic or maturation mitosis is equational and hence results in no chromosomic differentiation.
4. The second post-synaptic division is a reducing division, resulting in the separation of the chromosomes which have conjugated in synapsis, and their relegation to different germ-cells.
5. The chromosomes retain a morphological individuality throughout the various cell-divisions.
"


The chromosome theory of inheritance is credited to papers by  Walter Sutton  in 1902 [ 5 ]  and 1903, [ 6 ]  as well as to independent work by  Theodor Boveri  during roughly the same period. [ 7 ]  Boveri was studying  sea urchins , in which he found that all the chromosomes had to be present for proper  embryonic development  to take place. [ 8 ]  Sutton's work with  grasshoppers  showed that chromosomes occur in matched pairs of maternal and paternal chromosomes which separate during meiosis and "may constitute the physical basis of the Mendelian law of heredity". [ 9 ]


This groundbreaking work led  E.B. Wilson  in his classic text to name the chromosome theory of inheritance the "Sutton-Boveri Theory". [ 10 ]  Wilson was close to both men since the young Sutton was his student and the prominent Boveri was his friend (in fact, Wilson dedicated the aforementioned book to Boveri). Although the naming precedence is now often reversed to "Boveri-Sutton", there are some who argue that Boveri did not actually articulate the theory until 1904. [ 11 ]