(Reprrnred frm Nature, Vol. 207. No. 4992, pp. 9-13,
           3uly 3, 1965)

SIGNS OF LIFE

CRITERION-SYSTEM OF EXOBIOLOGY
  By PROF. JOSHUA LEDERBERG

Department of Genetics, Stanford University School of Medicine,
            Palo Alto, California

T HE imminence of interplanetary. traffic calls for
  systematic  criticism of the theoretical basis and
operational methods of `exobiology', t,he init,ial search
for and continual investigation of the life it might en-
counter.  Very little science is totally irrelevant to it,
and the policy-maker must face a riot of potential
approaches to space flight experiments. By every stand-
ard, this is an epochal enterprisa: a unique event in the
history of the solar system and of the human species,
and the focus of an enormous dedication of cost and
offort.  It, requires a new perspective in experimental
policy.  The broader interfaces of eso-(Earth's own)
biology, by cont,rast, permit it,s fruitful growth within
the context of methodologies and instruments that can
lag behind broadly established needs and imaginative
possibilities. A system for orderly appraisal of the problem
would rationalize the partition of labour, our only means of
managing a complex problem.

Mars is our prior t,arget.  Our premissed information is
only: (1) terrestrial observation: osobiochemistry ; (2)
the implications of Mars being a `terrestrial planet'; (3) a
very small body of definite observational results.  The
choice of our first experiments must take account of a
wide range of theoretical possibilities not yet narrowed
by the experimental process. Over this broad reach,
logical necessity rarely coincides with logical sufficiency.
The most compelling inferences might stem from the least
likely event.  Our speculation will be narrowed and
policy simplified by t,angible information about any
aspect of Mars, especially if it encompasses the varia-
bility of the planet's fcat,ures in space and time.

Evolutionary Stages and the Definition of `Life'
Fundamental to all biological theory, eso- or exo-, is
the evolutionary principle. As is now commonplace, we
recognize the following stages in the Earth's history:
(A) Chemogeny (orgo& chemislr?/). The production of
complex organic compounds by a variety of non-replica-
t,ive mechanisms-the primitive cosmic aggregation,
photochemistry of isolated atmospheres, thermal and
spontaneous reactions of inorganically catalysad, previ-
ously formed reagents.


(B) Biogeny (biology).  The replication of a specifically
ordered polymer, DNA being the terrestrial example,
which specifies the sequence of its own replicas, and of
the working materials, like RNA and proteins, from which
cells and organisms are fashioned. Random experiments
of error in replication, and natural selection of their
developmental consequences, result in the panoply of
terrestrial life.

(C) Cognogeray (history). The evolution of the mechan-
isms of perception, computation, and symbolic expression
and interpersonal communication, whereby t,radition can
accumulate, culture unfold.

Mars must be supposed to have had an initial history
similar to Earth.  To ask whether Mars has life is to ask
how far has its chemogeny gone; how like and how unlike
the Earth's; has its evolution passed through the biogenic
(ordered macromolecular) stage ?  Then through the
cognogenic ?

In evaluating a complex set of possibilities it is helpful
to &d classifying parameters which can be scanned
systematically, if sometimes only implicitly, to generate
a probabilitv space.  In this case, the evolutionary

principle furnish& the parameter : chemical complexity:
The initial planetogeny and the consequent differences
in physical and chemical environment determine the
possibie points of departure of the evolutionary processes.
On these grounds, Jupiter must have special interest for
comparative cosmochemistry; but it is still much less
accessible to close investigation, and we have even less
of a basis to predicate a homologous chemogeny there
than we do for Mars.  In so far as Mars does retain some

environmental analogies to Earth we might at least
predicate, for one branch of our analvsis, that any Martian
iife is based on chemical linkkges, predominantly
-C-C-, -C-O-, -C-N- and -O-P-, which
are barely stable in aqueous medium.  We leave to
hypothesis the extent to which the constructions from
thoso and other radicals emulate terrestrial biochemistry
at each level of complexity.

The cosmic abundance of these elements is relatively
high, and there is every reason to believe that Mars is at
least as richly endowed as Earth in them.  If the initial
budget of carbon has not, like that of the Earth's crust,
been completely requisitioned by life, then what form
will we find it in ?

Chemogeny generates a vast mixture of products
through the level of random macromolecules.  Mars
must have nurtured such chemistry, whether or not it
had progressed to biogeny.  A negative assay for organic
materials would preclude biology, but could we believe
such a result ? It would properly be blamed on defici-
encios in the particular sample.  The positive assay, if it
told something of t,he concentration and composition of


organic molecules, would add t,o our uuderst'anding of
Mars's development'. and would contribute to our judg-
ment of the life-detection problem.  But it would not
answer it.  On the other hand, onto life has appeared on a
planet, it would dominate its organic chemistry-most
carbon compounds would bo witnesses of biogenic (or
cognogenic) specificity.  The cataloguing of organic
molecules is a description of the consequences of evolution
and must make up a large part of our effort.

The Chemical Scan

To promise an actual complete scau of hypotheses of
molecular complexity would be pretentious and witless,
notwithstandirig that a computer can now bc programmed
to visualize all the possibilities. However, the fantasy
of such a scan is a constructive exercise in evalua-
tion of evidence for life.  For each chemical species the
imagination of the specialist might be challenged to ask:
(a) is there any information concerning t,he existence of
this it,em relevarit to scientific inferollce in exobiology;
(b) what are my prior expectations on the distribution
of this species, with and without life; (c) what other data
could contribute; (d) how would the observation be inter-
preted from a t,errestrial foray; (e) what special methods
are available or could be devised to detect the species ?

We might nurture a hope of turning up a special
treasure, a rare example of a molecule which would reveal
something about the evolution of the planet and help
narrow our choices among the confusing array of pqssible
targets. In practice this advantage does not materialize
so easily, for the hope is false.  Not that no chemical

M

B       C
LF

Fig. 1. Contingency ~pxe. `l'lie rmivcrse of possible observations I
includes the overlapping domains II and C, the predictions of biogeny
and chemogeny, respectiwly. Tlw remainder is N, contradictions of
these models, and possible cons~~~~nc~s of cognogeny.  Should this also
                I,l~ bourdYl `)


species is potentially informative; paradoxically, every
one is.
Consider hydrogen.  In term.5 of tho simple Venn
diagram (Fig. l), most expected observations would fall
in the region (B4"), that is, would be consist,ent with
biogeny but not imply it.  However, the sensible absence
of hydrogen from Mars' surface would fall in region
(--H.G), that is, virtually preclude life. But if we could
produce no plausible physical model for the disappearance
of hydrogen, we would have to reconsider the region
(I.-C), t,hat is, to ask whct,her the anomaly implies a bio-
gonic or cognogenic sequestration of the element. On the
other hand, certain microscopic distributions of H are
hard t,o reconcile wit,h any chemogenic model, and
point to tho region (U.--C), t)hat is, an inference in favour
of biogeny. This verges on morphology, but can still bn
formulated as molecular statistics.
On another tack, suppose a specimen consisted of pure
protium, 1H, to the exclusion of deut'crium, 2H.  Tll0
price of pure prot,ium on thn t,errcstrial market hints at,
the obstacles to a chomogenic model.  Apart from cogno-
genie activity, if a biogenic q;stem were exqisitcly
sensitive to deutsrium-tosicit,y it might evolve a dis-
crimination against it,.
The arguments have been laboured, but are rluite
typical of those that. discovery of any other species would
arouse.

      Entropy or Unlikelihood ?
Given the evolutionary continuity of lifo and our
understanding of the organism as a chemical machine.
there can be no absolutely distinctive signature of lift.
Some conjunctions-like a planetary depot of protium-
would be so unaccountable to our present model of chemi-
cal behaviour that we would feel obligated to postulate
the operation of a goal-directed system (biogeny or
cognogeny) rather than accept tho improbability of such
a conjunction by chance. This choice plainly depends
on our freedom of choice of models.  For example, OUI
present knowledge of chemogeny permits a wide latit'udc
of hypotheses as to the range of molecular species that
atmospheric photochemistry might generate.   Further
developments in our knowledge of chemogeny or of the
available chemical and physical resources of Mars might
confer useful constraints on the data that might now be
`explained away' as chemogeny, and thus cannot yet make
a crucial contribution t,o our search.
From terrestrial ospcrienco we judge that the occur-
rence of any of a number of compounds in high purity is
a sign of life.  Such deposits at a macroscopic level tend
to signify cognogeny-a smelter, a chemical laboratory,
a communications cablo, rather t~ha.n biogmy-organic


structure usually being built of microscopically dcfincd
components. Kegentropy is a noccssar~, but not sufficient',
sign of life.  However, it can help filter out the most
promising situations.  Then only the details of exparicnco
or confident USC of available theory can decide whothcl
tho eddy has a chemical-kinetic explan&ion or a bio- 01
cogno-genie one.  Lacking our oxperienco, a Martian
visitor might credit diamantane carbon to some mysteri-
ous biogenic function, inhibit'ed by I' chromosomes; if hc:
were cleverer, to the General Electric Co. He would noed
vory special knowledge of the Earth to predict t,het
diamonds would be found in the ground (and even more
to understand lvhy mon dig them up, only so t,hat womc'n
will wear them).
Kinetic instability in the context of local chemical anal
physical conditions is another clue: For example, cove1
of photosensitive pigments (witness terrestrial chloro-
phyll) recluires special att.ention to the magnitude of
plausible synthetic processes, atmospheric-chemical versus
biogenic, by which their st'eatly-state concentrat,ion could
be maintained.  dnalogous reasoning would apply to
compounds which are thermolabile in relation to thr
ambient tcmpcrature,  or chemically unstable species
\vhich should reach equilibrium with coexistent, oxidant.
Do we see a forest fire . `p Then wo must, think of tho
efficient system of photosynthesis which will restore the
steady-state vegetation.  Top-heavy structures, which
high-altitude reconnaissance could perceive even without
resolving single trees, houses, or bipeds, likewise tell
of kinematic instability, and in turn, some process to re-
raise what must some time fall.  But geophysics competes
with biophysics, and we have to discriminate life from
vulcanism and orogeny.
In sum, unlikelihood in terms of the chemogenic model
gives weight to any finding as a datum for exobiology.
It, should be possible to quantitate chcmogenic likelihood,
essential if a datum is to be given a measured value in
any decision-making programmc. Tho resolut,ion of the
Ineasurement need not be very high. to make it still very
useful in comparing disparate approaches.
In more general terms, biota have a high `density of'
internal information: the root of our conceptual distmc-
tion bctwocn matter and life is the rich story tha.t lifo
can tell about itself, a plot, tho details of which wo ca.n
scarcely deduce from our simple knowledge of the initial
conditions. But there must bo a plot, that is, tho informe-
tion must have some interesting pattern, or we would not.
distinguish a cell from the dislocations in a snowflake.
        Optical Activity
?ileny molecular species can contribute in an important
\vay to our appreciation of life.  A ~Aori, WC have a very

                    .?


limited basis to predict which species will be most cogent.
We should, of course, give high, but not exclusive,
priorit,v t,o terrest,rial prototypes like amino-acids and
nucleotidcs. Fortunately, there is a generic classificat,ion
of compounds which is relatively independent of detail
of struct,ure, yet should pervade a biogenic chemistry.
This is optical act'ivity.

The argument for logical necessity of net optical activity
has nothing to do with optical rotation. It depends on the
crucial role of t,he informational macromolecule in a
definition of life. JVhen tetravalent carbon is incorpor-
ated into macromolecular structure, each carbon stands a
reasonable risk of being an asymmetric centro, of having a
distinctive substituent on each of its four valences.  Such
an atom is subject to stereo-(optical) isomerism, and its
Ori0nt&iOn, D- or L-, must be specified if the macro-
molecule is to be fully ordered, more concretely, if it is
t,o have a ndl-defined t,hree-dimensional shape.  Con-
versely, biogenic macromolecules, having ordered asym-
metric centres, have the necessary information to dis-
criminate among the isomers of monomeric substrates.
i)n Earth, where biogeny has dominated the st,atistics of
organic molecules. n-c find that the ratio of D- to L-glucose
residues is at least 1O'j : 1.

Logical sufficiency can also be argued. Chemical en-
antiomorphs should be generated in equa,l proportions
except under the influencn of a catalytic system which is
already asymmetrically organized. The global organiza-
tion of a planet int'o one catal~t~ic system of particular
orientation is a catastrophe of :L magnitude unique to
biogeny.  Spont,aneous &solution miiht occur locally.
Hence this criterion has its great<& weight when annlied
to a species which Rows thro<gh the p!a&ary circufa?,ion.
A paragon would be labile molecules condensrd from the
atmosphere : optically a&iv-c smog.

Within the biogcmc systrrn, both enantiomorphs of a
metabolite might be gcncxri\tcd, but' this would be in pre-
cisely equal amounts wit,h no greater likelihood than anv
two " species designated at random.  Chemogeny anh
sterically ordored biogeny thus give sharply contrasted
expectations on these statistics, and biogomc chemist,ry
can hardly avoid becoming sterically ordcrrd.

These lines of inference do not account for such paro-
chialisms as the undeviating series of z-isomers of amino-
acids in esobial proteins. For example, D-idanilx would
be at least as interesting AS L-valinc in expanding t,he
homologues of glycine. Rut,for that mat,tw, why is cc-amino
butyric acid passed over ? We rn?y know better \rhen the
rules of polypoptido conformntlon are bettor known;
more likely, from the details of evolution of amino-acid
anabolism and problemsof discriminationamong analogues.
It is precise& at this level that, the local biological theory
fails, and thereby points to tho crucial issws of a cosmic
biology.

(i


In view of the theoretical generality and historical
tradition of the Pasteurian principle, it is paradoxical
that the direct measurement of optical activity is weak by
comparison to other instrumental approaches. However,
the basic criterion is not optical rotation but molecular
statistics.  Enantiomorpbs can be assayed wit,h optically
active reagents to give resolvable diastereo-isomers, and
oxploit the most sensitive methods known to chemist'ry.

Macromolecu!es

Informational macromolecules dofine the boundary of
chemogeny and biogeny, of chemistry and life.  Their
description on anot,her planet is the fundamental challenge
of exobiology. Replication of macromolecules (genes) and
t,he inevitability of random error (mut,ation) open the
door to natural selection and t.he evolut,ion of more and
more complex forms of life.  A random polynucleotido is
not life; routes to its photochemico-synthesis from simple
gases and inorganic phosphate are in sight. Can w-e
deduce the replication of a polynucleotide by any means
short of the most recent achievements of direct observa-
tion and &S vi@0 enzymology ? Historically, we could
deduce the informationality of macromolecules just from
compositional data. When the same sequence occurs in
many molecules--as in a sample of crystalline haemo-
globm-we have to invoke an informational process to
programme and implement the synthesis of the protein.
In fact, only recently and rarely could we gain complete
specifications of an actual sequence.  This is usually
inferred from fragment,ary analyses of a fraction found
to be monodisperse on a few measures and then assumed
to be sequentially homogeneous.

The sequence need not be the gene itself. Macro-
molecular sequencing is also manifest in gene products,
RNA and proteins.  It is import(ant that the sequence
imply ordering from a template which selects from an
abundance of kinetically equivalent choices, not merely a
pattern inherent in the chemistry of the monomer, as in
crystallization.

Molecular esobiology faces the same met.hodological
problems.  This challenge gives us the groundwork for
exobiology and assures that any instrumental advanced
will have redoubled utility. But it is a chastening note
that biochemistry has barely reached the point of affirma-
tion that antibody y-globulin has an informational
sequence or is specified by a polynucleotide. That this
abundant and medically important molecule can still
be so controversial must evoke some humility in ow
postulations and experimentma efforts concerning macro-
molecules on another planet.


How We Detect Informational Macromolecules

(A) Co~npositionnl annb&s. (a) Does the sample
contain macromolecules ? (b) What is their composition ?
(c) =Iny evidence of informational ordering ?

Gobiology is firmly founded on the isolation of mncro-
molecular species and their purification before attempts
at analysis.  Some of the most successful methods arc
empirical recipes of extraction and precipitation.

More rational techniques include diffusional propcrtirs
of large molecules, free diffusion, sedimentation, dialysis,
molecular sieves, and electrophoresis, in principle also
vapour phase diffusion (to remove monomers)-molecular
distillation, gas chromatography and mass spectromet,ry.
Solution chromatographic methods may also rely on t.he
coincidence of functional groups on one molecule, for
example, a polyelectrolyte.

Similar principles underlie non-separative methods of
detection which have not been extensively developed to
date. Rotational relaxation times can be me`asured by
How or electric birefringence, or the analogous polariza-
t,ion of fluorescence.  Polvfunct,ionalitv is tested bv inter-

molecular interact,ions o"f adsorbed &yes (for example,
optical shifts in acridina orange on DNA4) or the mono-
meric units with one another in special oases (hypo-
chromicity of DNA4, diagnosable on heat-denaturation).
More direct chemical tests for polyfunctionality also
suggest themselves.

The previous methods, in so far as they lack perfect
generdity, may give only a clue as to the composition of
the macromolecule, as well as its molecular size. At the
other extreme, we would seek the complete primary
structure to emulate the recent tours deforce of chemical
technique. Reasonable inferences might be drawn from
less complete evidence of structural individuality, hard
to evaluate in advance: homogeneity in molecular weight
or end-group analysis, crystallinity, or sharp fractionation
by any other procedure. A sharp X-ray dia,gram of a
heteropolymer sample could imply it#s individuality long
before it had yielded t.o full analysis.

Other partial measures of great utility include the
scission of the polymer by specific reagents, especially
enzymes, to give a pattern of characteristic fragmems
(the polypeptide `fingerprint').

The underlying generalization is `molecular speci&ion'.
Chemogenic synthesis of macromolecules should generate
a continuum of nearly cquiprobable forms.  Biogeny
chooses a few of these and generates a sharply discon-
tinuous polydiscrcte spectrum, that is, it speciates.
Speciation can be discerned by many measures, for
example? the distribution of molecular weight.  Thus a
sample under analysis by a sophisticated instrument
might reveal a sac of haem-polypeptidc, containing about

8


Auto-replication

lneipient polymer (ssmc
species) and polgmcr-
building monomer
Incipient polymer (different
species) and polymcr-
building monomer
Yormrd pol~~ler, similar
specks

Substrate-ratalytic effect
Cofactors-to forrrillolo-

DNA : DNA + dconynucleo-
side tripbosphatcs

1)NA : RN.4 + nucleosido
triphosphatcs

                 organisms
lIornwr~s, toxins, nntricnts  Swum albumin: l~ormones.

toxins
Permeuses: nutrients and
metsbolites for transport
in and out of cells

a billion (a thousand million) atoms of iron.  Virtually all
t'he iron-polypeptide consists of a single species, that is,
almost all the molecules have 2,9X carbon atoms, no
more, no less.  After removal of iron and porphyrin,
equal numbers of sub-units containing just C,,, and C,,,
are assayed. It would be difficult to escape an allusion
to life after a single encounter with the red blood cell
that has just been described.

(B) Functional am-dysis. The adaptive values, the usee
that biogeny has discovered for some species of ma,cro-
molecules, reveal short cuts to their singularity.  These
functions are all reducible to a structural specification:
the stereospecificity of the polymer in reacting wit,h other
molecules.

In this list, the enzymatic fimctions are particularly
promising in the light of their specificity and amplifying
capability.  Many enzymes have turnover numbers of
LO' substrate molecules/set `enzyme molecule.  If suitable
precursors (nut,rients) can be defined, integrated cnzyme-
sequences or metabolic systems, like respiration or photo-
synthesis, extend the versatility of this approach.

The simpler the level, the more likely itl`e me to find K
metabolic analoguc on Mars, for example, for the assimila-
tion of elementary nutrient,s, C, N, 0, S or P, into organic
molecules.  The next more complex molecules, H20,
CO,, and 0, and NH,, are the most pervasive metabolites
of terrestrial life, and the choice among them for searching
for evidence of their conversion into other compounds
will depend mainly on instrumental considerations. In
general, the more complex the metabolite being tested,
the less our prior expectation that it was part of an
extraterrestrial biogonic system. However, the complete
system offers the largest amplification--a single bacterium
could grow'and multiply into tonnage masses in a few days,
but might make tho most exacting demands of the en-
vironment.

9


Morphology

Biogeny rapidly elaborates higher forms of organiza-
tion :  cells,  tissues,  organisms,  populations, which
might be recognizable according to their own forms
and to their rectifications of the environment.  However,
what systematic rules distinguish biological forms in
general ? Some forms are recognizable, for example, a
friend's face, and recognition then contains many bits
of useful information.  Compound vesicles, apparent
cells, are most inescapable in morphogenesis ; their absence
would at least set an upper limit to the stage of biogeny.
Their presence would be extremely provocative, but
properly would raise many scepticisms of chemogenic
artefact.  Nevertheless, esobiology has so many roots in
morphology that we could scarcely ignore the insights
that our historic practice of it would offer.  Any recogniz-
able forms would provoke tangible and hence useful
working hypotheses of the Martian system.

Some aspects of morphology can be systematized.
=Is an example which might illustrate speciation, ultra-
structural spacings in the range of 20-500 A could be
detected by powerful optical (electron microscope, X-ray
diffraction) as well as separative techniques.  Approaches
so cogent to esobial ultrastructure must play an important
part in exobiology. Unfortunately, we have little empiri-
cal basis to prejudge the morphological detail that might
be exhibited by an infra-biogenio planet, since so much
of the chemical diversity of Earth has been preempted
by life.

As is well known, five-fold symmetries are anathematic
in crystallography.  Hence,  regular pentagonal and
dodecahedral forms might occur as elementary unit,s, for
oxamplc, perhaps a ferrocene, but no simple law of crystal
growth could account for their occurrence in diverse
sizes.  A glen of periwinkles has a deductively simple
signature of life.

Signals

So far I have tacitly assumed that whether or not Mars
has achieved biogeny, it has not passed to cognogeny.
Reaction to the once notorious Schianarellian canali mav

                            I               Y
account for a position which has no rigorous basis.
True, we have had no scientifically admissible sign of
intelligent activity on or communication from that
planet. However, we can only fancy whether an exot,ic
culture would have either the means or the motive t,o
effect recognizable communication.  We Can generalize
that the works of cognogeny would constitute the most
startling unlikelihoods, exceptions to biogony and chemo-
geny alike.

It is no trivial exercise to speculate how we could most

                10


        compactly summarize our scientific culture. For esamplo,
        a description of DNA and our amino-acids could portray
       the convergence of physical and chemical ideas in biology,
       and some of the least predictfable aspects of esobiogeny.  If
        we could but do it. a detail of the inter-neuronal synapse
        and the cytoarchitecture of t,he cerebral cortex would go
          even farther.  How ,much of our cognogeny would then
          be deducible from these facts and our awareness of them ?
         Purposeful emissions cost, enough more than mere
        listening that we do not undertake them ourselves, but.
          we have made casua,l efforts to hear them.  Further, u-c?
       might hope to eavesdrop on the internal communications
        of another planet, perhaps more likely lar beyond t,he solar
       system. Among other difficulties, efiicient informat,ion is,
       by definition, indistinguishable from noise t,o the unbriefed
        eavesdropper.
        While a rigorous answer to any notions of Martian
        intelligence is difficult, a realistic policy is not.  cog-
       nogeny would reveal itself in divers ways, and, at least
        for Mars, wc have no better recourse than to keep eyes,
       ears and noses alert, for any signs of it as we make pro-
        gressively closer approaches to the planet.

                      Instrumentation

         The rational classificat'ion of existing instruments, or
       those proposed for analytical purposes, is a t,ask as difficult,
        as it is urgent.  The real aim, a classificat,ion of possible
        instruments, requires a total knowledge of physics, and
       some system for classifying this information that will
        help us to understand the r4stionships among rxist'ing
        instruments and suggest new ones.  A proposed scan
       parameter is the energy-level of the transition by which
        the molecule is racognizcd. Further parameters include
        whether photons are introduced or emitt'ed, whether chem-
       ical reagents are employed, including auto-reactions,
       whether the displacement or state of t,ha analysand or of
       the probe is diagnostic, and, for radiation probes, the role
       of power, polarization, phase, wave-length, or flux vector
        of the probe.  The first step in a detailed rationalizatSion
       is to determine whether any more dimensions are needed
       for our matrix of possible configurations.
         Radiation probes arc usually limited, either in selec-
        tivity-say, absorptiometry, or sensitivity-say, nuclear
        magnetic resonance-but they have special value in
        conjunction with chemical reagents.  Absorption (power
        loss) measurements have dominat,ed instrumental analysis.
-        Convent'ional optical metShods rarely stabilize or measure
       input power better than 1 : 1,000, with corresponding
        limitations to detectivit,y. For example, optical molar
       absorptivity rarely exceeds 10" so that IO-* molar solutions
         (6 x 10'2 molecules in a 1 -cm-3 cell) would give the
        Lowest useful signal under t.he most, favourable condit,ions.

                             II


By contrast,,  fluoromctric measurement (which ran
exploit shifts in wave-length, flux vect,or, polarization
and pha.sc) can easily measure lo* molecules and can be
ostondcd at least to lOi.  The delicacy of excitation
methods (which could also include chemical, nucleonic
and thermal excitation) stems from the measurement
of the data signal merely against a detector noise back-
ground as compared with the much larger power fluctua-
tions of practical probes.

Optical activity is also usually measured via loss of
power (attenuation of polarized light by a crossed
analyser) :  t'he molar rotations are relatively small,
present detectivit,y being about 1Ol5 molecules. If some
method of transforming optical rotation to an excited
signal were developed, it tvould cnormous!y enhance the
power of this technique.

The most sensitive approaches to analysis are two-st,agc
mechanisms: the selective displacement of the ana.lysand,
then a sensitive detection.  In principle, such methods
might detect a single molecule, as in mass spect'rometry:
selective m/e displacement followed by t,he sensitive
detection of an ion that can be accelerated to arbitrary
cnorgy.  The potential information content of a mass
spectrum is especially high since the theoretically mcasur-
able mass of a single molecule is defined to a resolution
far better than lOP, independent of the variety of energetic
states, which broaden other physical features. Existing
inst,ruments still lag behind theoretical limits of mass
resolution, yet have already demonstrated their power in
organic analysis.  Further, the mass datum at high
resolution for an intact molecular ion is deductively
reducible to a molecular composition, unlike the inferential
data given by most other spectroscopic techniques, and
the statistics of the fragments also give detailed insight
into t,hc complete structure of the molecule.  From these
considerations the combinat,ion of a mass spectrometer
with a simple, rugged, separative device, like the gas
chromatograph, promises to be the most powerful com-
ponent of analytical systems for biochemistry.  However,
a science of metrology, the orderly study of methods of
measurement, remains to be developed.  I can have little
confidence that the last word has been said on this issue.

Some Private Thoughts on Exobiological Strategy
The mult'itude of possible means and detailed ends in

exobiology leaves little hope that a brilliant flash will
illuminate the whole picture as a happy substitut'e for the
diverse paths of esobiology. Nor should there be any
discouragement of the variety of talents and insights that
would be needed in any event for t'he full development of
the subject.  The overriding problem in planning is, of
course, how little we actually know about surface detail


and atmospheric composition of Mars.  We are also
bedevilled by the uncertain hazards, but immense stakes,
to either planet of an intemperxte rupture of the inter-
planetary barrier.  Earth-based telescopes can, to be
sure, add significantly t,o our present appreciation of
Mars, and hence of the hazards of landing.  But the next
significant step would be a Mars-orbiting observatory,
keeping the planet under a constant synoptic scrutiny
from a safe distance, close enough to measure significant
surface detail, and large enough to maintain the most
sophisticated instrumentation, telemetry to Earth, and
perhaps even some Earth-based regulation of its surveil-
lance schedule and precautions against accidental intact
landing.

Such an approach to Mars would also open the way to
political agreements to unify terrestrial strategy and can
allow constructive co-operations like the International
Geophysical Year of recent history, for example, to
facilitate the relaying of synoptic data.   While it is
essential to mount vigorous instrument development
efforts to assure that a landing can ever be implemented,
the detailed specifications of experiments should take full
advantage of the most up-to-date plenetological informa-
tion. That is to say, the 6nal decision to implement a
landing on Mars should be suspended until we can have
digested the data from a Mars orbiter. This criterion lends
further weight to the strategy of designing a general-
purpose laboratory for planetary investigation, in which
many investigators can participate, and which has the
flexibility to be readily roprogrammod in the light of new
data.  -4t present, for a biologist to participate actively
in spece research rcquircs a commit,ment to engineering
efforts which few are willing to undertake.

The deliberate staging of the exploration of Mars,
perhaps with international agreement to proceed first
with reconnaissance while preparations are made for
comprehensive landed missions, would allow for the
widest participation of intcrcstod scientists, both in the
design of experiments in exobiology and in the prudent
determination of global policy for the solar system.

~rmtd i Great Britain by Fisher. Knight & Co.. Ltd.. St. Albans