Qiy tit.10 is "what is a gene ?" but `what I really want to

talk about@ some recent work on the fine-stMreLe of the gene; w&
which may lead us to understand more about the ftaa~stxmnrkxxa

molecular basis of genetics and perhaps something about 1 that

genes act.

  Let me first sketch for you the classical picture of the

gene. You can find this in any elementary textbook of genetics.

It starts by describing some simple breeding experiments - usually
the historic experiments of Bliendel on peas - an8 shws how

they can be explained by a straightforward theoretical scheme.

Then the complications due to "recombination" - as it is called -

are introduced, and finally  the reader learn@ how all these

ideas can be understood In terms of the chromosomes, the small

thread-like bodies within the nuclei of cells. The chromosomes

carry the hereditary determinants, and the genes, the units of

heredity, are strung out along the chromosome, in a linear

order, like beads on a string.

The gene, then, is the unit of heredity. It is the building

brick of the material passed on to a child from its parents,
          d*d i+ i-9 km fk"

half from each of them,Lwhich mainly determine& the sort of
                                l&id
child it Is. It is not known how many differenl+gene$ there are,
but each human being probably has more than 1OflOO oP+hna&6~~ aCJ#

That is the standard picture  - but I want to explain to

you that the gene  - the Kene in the very old-fashioned sense
           rib

of the lndivinle unit of heredity - has been split, and split

decisively. To do this I shall discuss a simpler system so that
you can grasp the essential pol>s more easily .


The system I shall describe is that of a virus that attacks

bacteria.  You may feel that this is rather remok from human

genetics, but it Is one of the astonishing discoveries of modern

biology how similar the basic biochemical and genetic processes

are In all living material. This virus is quite a small object

by normal standards -  It is too small to be seen even with a

very polzerful light microscope  - but as viruses go it Is quite

large.  Its moleeular weight  - If we may us8 such a term - is
about two hundred million (the molecular weight of water is 18)

and it is twenty or thirty times bigger than a small virus such

as the poliomyelltus virus.  It iS made up of only two typ8S of

chemical -  protein and deoxyribonucleic acid ( DNA for short),

Most if not a&l of th8 protein uomponent corresponds to the body
          r*bw

of the virus+& the genetic part appears to consist mainly if

       I'
     .
not entirely of DNA.

   Let me say first, without giving the evidence, that the

genetic material appears to be all in one gflan~a long piece - in

a higher organism we would say that there was one chtomosome -

and that there is only one copy of It in the virus. To use the

genetic jargon It is haploid, whereas human beings, for example,

are diploid;  that is, we have two copies of each chromosome, one

from each parent. It Is the fact that th8 virus is haploid which

simplifies the explanation. The exact number of genes in this

virus is not known, but a conservative estimate would be twenty,
                                                                           .
arranged in a linear order along the chromosome,

  When the virus cqmes into contact with a Suitable bacterial
cell it attaches itself bv Its tail (it has,a polygonal head          I

and a long thin rigid cylindrical tail). All the DNA then en&ers


the bacterial cell and most of the protein stays outside.

Twenty minutes later the cell bursts open and a hundred or SO

new complete virus particles are released.   Thus in this short

time the system has made many copies of the infecting ViruS,

Moreover the copies are exact copies. Various strains of the

virus exist and the viruses that come out of the cell are exactly

like the particular virus particle which went in. In Other words

the virus breeds true,

   Very occasionally, however, the replicating mechanism

makes a mistake, and a slightly different virus emerges. If

we now infect a seaon@ time with thia changed virus its descendents

are all like itself:t'?at is, of th8 aleered form. In a higher

organism such a change would be called a mutation, and there

seems no reason why we should not use the word here, The virus,
<-                                             )MLc~crml-

then, can experience a mutation, and the m will breed

true.

  Y'oa what will happen If one infects with txo different

mutants of the virus simultaneously ?  It can be shown that

both penetrate into the cell, both multiply Inside the cell,

and copies of both emerge when the cell Is burst open. But the

interesting fact is that, in addition, new virus strains appear

whose genes come partly from one parent virus and partly from

the other,  The picture evoked to explain this is that during

the copying process Inside the cell a new copy may occasionally

start to be formed on one parent and then, at some random point,

skip4 over and finishes the process of copying on the other

parent. This process is called "recombinatkon"  - again because

of its similarity to a similar process in higher organisms.


4
/

   It is this recombination which allows geneticists to map

the genes on the chromosome. If txo genes are very alose together

the chance of the skipping-over   process taking place between them

is rather small, If, on the other hand, they are far apart St

will happen more often. By finding how frequently recombination

occurs for an.y two genes one can get some idea of their distance

apart, and it is by tM.s method that geneticists have shown

that genes are arranged in a linear array along the length of

the chromosome.

   Let us for~eet recombination for a moment, and think about

what happens if we have a vir-LB one of whose genes is defective.

If this virus is uS8d by itself it may be unable to reproduue.

Bowever &f another Strain of virus, with that particular gene

intact, is used simultaneously, it may be able to do that part

of the work for two, and both viruses may be able to reproduce*

In fact if the second virus has a defect %.n a different gene,

of which the first has a good copy* they may be able to help

each ko other.  A pretty picture ?
  Fortunate19 It has some technioal use. For suppose both

these two viruses, Instead of having their defects in different
                                                                           --
genes, had a mistake in the same gene. Then neither of them would

have a nood copy, and reproduction might not be pos..Able. Thus
this test ( of seeing whether two defective viruses can assist
each other or not) shows whether the defects are in the same

,geae or not. This is one of the dsfinitions of the gene, In fact

- the unit of physiological action, and it is the meaning

I shall be using when I use the word gene,


It is not the only definiti.On, hOW8Ver. \I8 could define the

gene as the "unit of mutation". That is, the smallest part of

a chromosome which can change, or mutate, independent of the

other parts. C;r again, we could define the gene -  and indeed

many &eneticists do -  as th8 unit of reaombination -  thtg

smallest part. that can be moved about by the recombination

process:  the smallest step In the skipping-over process if

you like.

So there we have three defintions of the qene, The unit+t ~9'

action, the unit of mutation and the unit of r8COmbinatiOn,

and for many years it was felt that, in spite of some exceptions,

these three defFn%tions refered to the same thing -

as it was called.

It is now becomin,? clear that this picture was A oversimplified.

Let me give YOU the new picture strais'lt away, to help you

follow the argument, In the new picture the unit of action iS

a large thing, roughly ~~~ampatr;ak%tg corresponding to what used to

be thought of as the gene, but the other two units now appear

to b8 very much smaller. 'de can put this another way. Let us for
  Wi-Aktik

the IBQ+W?& use the word gene for the unit of action,  Then we

can summarise the new discoveries by saying that not only

can geneticists map the order of genes on a chromosome, but they

can map the order of the different changes within  a gene. In

other words, the gene  - the unit of action - has-been split

by the genetic mapping technique.

Now I would not want you to think that this is a totally

new idea, because evidence along these lines has been available

for years. illhat has transformed the Situation is the weight of


the new evidence. This has mainly come from two sources. Drs.

Pontecorvo and Roper, working in Glasgow on the mould Aspergillus,

and fr. Benser working at Purdue University, in the States, on

the virus system I have described, Br. Benaer's system has a

technical advantage over that of the Glasgow workers because it

can be pushed more quickly to finer limits, but the work on

the mould makes us think that the new data on the virus is not

a freak, but likely to be of general oucurence. Moreover cases are
known in flFs, in corn and In other organisms.

Let me briefly aummarise what Dr. Benz;er finds. For

technical reasons he has studied one particular gene, known


  as  r II . i3ls first finding is that r II is not one gene, but

two, next to one another@ and with close19 related functions*

Me has picked up mutants of this pair of genes on about a

thousand different occasions. Sometimes he finds that a newly-

ariging mutant appears by his tests to be identical with one

he has found before, but often it Is quite different from

any previous one.  In all he has so far found about 250 different

mutants in his two genes combined. In other words each of his
genes has been marked (or split, if you like) In over 100

different places.

   His next finding is that he can arrange all these different

mutants in a linear  order, as if they were a lot of different

marks on a piece of string. There are no real exceptions to this.

There are a few apparent exceptions, but these appear to be due

to "deletions'* as they are called  - meaning the actual loss of

a small piece of the string. In every such CC& he never finds
                                               (I


a reverse mutation yl' 3/ the lost piece of the string never
reappears a,ainl,~~~~eli--~~~~
                            ~-~-e.---      ----.- ..-
    As far as he can tell, allotting for the limitations of his

*echnlque, there is no space bet!veen his two genes. As soon as

one ends, according to his mapping, the other begins, without

any appreciable gap.

Another interesting finding is t%?at thsre are mutants which

he can tell are different, but which he cannot sepsrate on the

map;  they appear to occur at t?le same point. Ycu might wonder

how he knows they are different.  The charscter which distinguishes

them is their reverse mutation: rate -  the rate at Which they

mi;tate back to the original version. Foi- example one particular

mutation s%ta is very common. Se has picked it up about 130
                          iJci% 130
times out 0 f his set of 1,GGO .  About half of %&es-e have one

back-mutation rate, whereas the rem@der(with one exception)

have another one.  In fact he appears to be finding that the

unft of mutation is vlot quite We same as the unit of recombination

thou.qh both appear much smaller than the unit of physiological

action.

It is not unreasohable to ask how small his smallest unit

is. How near Is he to the molecular limit - the molecular

"graininess" if you like  - of the genetic material 7  It is

possible to make a very rough estimate of this if certain s

simplifyin,? assumptions are made. The gentle mater'ial consists

mainly of DNA. Let us assume +hat it is wholel;y DNA. Now DNA,

as you know, is a polymer, made up of small molecules called

nucleotides joined end to end.  The total number of nucleotides


in t,he ,,whole virus is about f&DO, O'JO  thotigh there #are reasons
          I\

for beleiving that only part of this corresponds to the

genetic map. Knowwing roughly the total length of the gen)ic

                                                              q ,- La
WPU zc -1 *LA rLA-fin edscale

Bemeer has calculated the number of nuoleotldes which

correspond to his smallest map-distance. The answer, which IS

only approximate,  comes to around half a dozen  - and It might

be fewer. In other words by genetic means he Is dividing the

gene down to, or almost down to,  the molecular level. You can

understand why those of us who are interested in the molecular

basis of genetics find his l.vork tremendously interesting.

Finally we may ask - what next ? It Is a very reasonable

SPgculatiOn that each gene controls, directlg or indirectly, the

production of a particular protein molecule, More precisely,

that it controls the order of the amino acids In one polypeptlde
         lMk;d rL L&4 i /w-bq l44& it CFluw
chain of a proteln moleculek Uhat we suspect la that the linear
order Inside a gene corresponds to the linear order of amino
                                                                           "

acids along the polypeptlde chain of the relevent protein,w?zi&a
                                       cv&-OULb 59
t-T? +LL-p+uehy
                               , ',  Xf we could find the protein CLcsry-
a Dr. Benaer's gene we might be able-to discover, with modern

techniques, the change in the order of the am&no acids produced

by any particular mutant.  If we could do this we could soon see

if the two orders   - the linear mapping of the gene and

the linear arrangement of the amino acids - were related.

o

Dr. Benzer is coming to work with us at Cambridge next year, and

this Is exactly what we shall try to do.