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Appendix 4
Letter Sent to Mass Spectroscopists Responding to Questionnaire
DENDRAL. Program Availability on SUMEX

 

The Stanford University Medical Experimenta! computer facility (SUMEX) has been
established at Stanford with the support of the Biotechnology Resources Branch,
National Institutes of Health. Its primary mission is resource sharing, where
the resources in this case are complex computer programs applied to health-
research problems and the computing facility on which these programs can be
used via a nationwide computer network. SUMEX is actively encouraging the
development of a collaborative community of users of this facility.

The DENDRAL Project at Stanford is one of the initial collaborative projects on
SUMEX. This project is making its programs available to the outside community
within the limits of available resources. Because resources are limited, the
future may bring a more restrictive policy of access than that presently in
force. Until that time, however, the SUMEX policy is to encourage as many
qualified and interested persons as possible to access the program on a trial
basis, to determine the potential applicability of such programs to ongoing re-
search. The major programs available now are outlined below:

1!) PLANNER--Infers possible structures of unknown compounds (singly or as
mixtures) given a mass spectrum and fragmentation rules of the class of compounds
to which the unknown(s) presumably belongs. (See Smith et al., J. Amer. Chem.
Soc., 94, 5962 (1972); ibid., 95, 6078 (1973)).

2) INTSUM--Given a set of known, related structures and the mass spectrum
corresponding to each structure, INTSUM suggests possible fragmentation processes
which resulted in the observed ions, and then summarizes the results in terms of
processes which are general to the class of structures, and those which are
specific to certain members of the class. (See Smith et al., tetrahedron, 29,
3117 ($973)).

3) CONGEN--CONGEN (constrained structure generation) accepts as input known
structural features of an unknown molecule (whose elemental composition is known)
and produces all structural isomers consistent with these data. The features

and constraints are entered in an interactive session with the program and
results can be drawn at a terminal or further constraints added based on
examination of new data. CONGEN represents our initfal version of a program for
computer-assisted structure elucidation. The structure generator which underlies
CONGEN has been described (See Masinter et al., J. Amer. Chem. Soc., 96, 7/02
(1973) and ibid., 7714 (1974)).

4) MOLECULAR 10N DETERMINATION--Given a (low or high resolution) mass spectrum
in which the molecular ion may or may not be present, this program suggests a
ranked list of candidate molecular ions. (See G. Dromey, B. G. Buchanan, D. H.
Smith, J. Lederberg and C. Djerassi, J. Org. Chem., in press (March 1975)).

For additional information on these programs and access to SUMEX, write to
Professor Joshua Lederberg, SUMEX Project, Department of Genetics, Stanford
University, Stanford, California 94305, or Professor Carl Djerassi or Dr. Dennis
H. Smith, Department of Chemistry, Stanford University, Stanford, California
94305. It will be helpful to indicate the basis of your interest and intended
applications although it is understood that trial use is a prerequisite to a
considered answer to such a question.
Appendix 95>
Draft of Manuscript for American Chemical Society Symposium
on Computer Networking in Chemistry

NETWORKING AND A COLLABORATIVE RESEARCH COMMUNITY: A
CASE STUDY USING THE DENDRAL PROGRAMS.

Raymond &. Carhart*, Suzanne M. Johnson, Dennis H. Smith, Bruce G.
Buchanan, R. Geoffrey Dromey, and Joshua Lederberg.

pepartments of *Computer Science, Genetics, and Chemistry, Stantord
University, Stanford, California, 94305.

Computer Science is one of the newest, but also one of the least
"cumulative" of the sciences. Gordon (1) has recently pointed out
the uosetting disparity between the number of potentially sharable
programs in existence and the number which are easily accessible to a
given researcher. Although some mechanisms exist for the systematic
exchange of program resources, for example the World List of
Crystallographic Computer Programs (2), a great deal of programming
effort is duplicated among different research groups with common
interests. The reasons for this are understandable: these groups are
separated by geography, by incompatibilities in computer facilitie
and by a lack of a means to keep abreast of a a rapidly chanaing
field .

‘he emergence of more economical technoloagies for data
cowrtunications vrovices, in crincinle, a method for lowering toes
seodrentical and operational barriers; for creating, through computer
networking, remote sites at which functionally specialized cavabilities
are concentrated. The SUMEX-AIM (Stanford University Medical
EXperimental computer - Artificial Intelligence in Medicine) project is
an experiment in reducing this principle to practice, in the soecific
area of artificial intelligence research applied to nealth sciences.
The SUMEX-AIN computer facility (3) is a National Shared
Computing kesource being developed and operated by Stanford
University, in partnership with and with financial support from the
niotechnology Resources Branch of the the Division of kesearch
Resources, National Institutes of Health. It is national in scope in
that a major portion of its computing capacity is being made
available to authorized research groups throughout the country by
means of communications networks.

Aside from demonstrating, on managerial, administrative and
technical levels, that such a national computing resource is a viable
concept, the primary objective of SUMEX-AIM is the building of a
collaborative research community. The aim is to encourage individual
participants not only to investigate applications of artificial
intelligence in health science, but also to share their programs and
discuss their ideas with other researchers. This dlaces a
responsibility upon SUMEX-AIM to develop effective means of communication
among community members and among the programs they write. It also
places resnonsibility upon those members to design and document
programs that readily can be used and understood by others.

Another asnect of the SUMEX facility is providing service to
individuals whose interest is in using, rather than developing, the
available computer programs. Although this is not a primary
consideration, it is an essential part of the growth of these
programs. Most of the SUMEX-AIM projects have formed, or are
forming, their own user communities which provide valuable “real
world" experience. Figure 1 depicts the typical interaction of
such a project with its user community, and with other projects, ‘he
participation by users in program development is not just restricted
to suggestions, but can also include software created by
comnuter-oriented users to satisfy special needs. In some projects,
methods are being considered to further promote this kind of
participation.

The purposes of this paper are threefold: first, to indicate the
range of research projects currently active at SUMEX; second, to
describe in detail one of these projects, DENDRAL, which is of
particular interest to chemists; and third, to discuss some problems
and possible solutions related to networking and community-building.

I. Research Activities at SUMEX-AIM

The community of participants in SUMEX-AIM can be divided
geographically into local (i. e., Stanford-based) projects and renote
projects, and helow is given a brief description of the major
representatives of each. Communication with the remote projects is
accomplished through one or both of the communications networks shown
in Figure 2. In most cases, connection with SUMEX-AIM from these
remote sites involves only a local telephone call to the nearest
network “node”.

The SUMEX-AIM system is itself undergoing constant improvement
which deserves to be called research, and thus a third section is
included nere to represent system developments.
kemote projects

the kutaers project. Originating from Rutgers University are
several research efforts designed to introduce advanced methods in
computer science - particularly in artificial intelligence and
interactive data base systems - into specific areas of biomedical
research. One such effort involves the development of comouter-based
consultation systems for diseases of the eye, specifically the
establishment of a national network of collaborators for diagnosis
and recommendations for treatment of glaucoma by computer. Another
project concerns the BELIEVER program, which represents a theory of
now people arrive at an interpretation of the social actions of
others. SUMEX-AIM provides an excellent medium for collaboration in the
development and testing of this theory. The Rutgers project
includes, in addition, several fundamental studies in artificial
intelligence and system design, which provide much of the support
needed tor the development of such complex systems.

The DIALOG project. The DIAgnostic LOGic project, based at the
University of Pittsburgh, is a large scale, computerized medical
diagnostic system that makes use of the methods and structures of
artificial intelligence. Unlike most other computer diagnostic
orograms, which are oriented to differential diagnosis in a rather
limited area, the NIALOG system has been designed to deal with the
qeneral problem of diagnosis in internal medicine and currently
accesses a medical data base which encompasses approximately
fifty erent of the major diseases in internal medicine.

the MISL Project. The Medical Information Systems Laboratory at
the University of Illinois (Chicago Circle campus) has been
established to explore inferential relationships between analytic
data and the natural history of selected eye diseases, both in
treated and untreated forms. This project will utilize the SUMEX-AIM™
resource to build a data base which could then be used as a test bed
for the development of clinical decision support algorithms.

Distributed Data-Base System for Chronic Diseases. this
project, based at the University of Hawaii, seeks to use the
SUMEX~AIM facility to establish a resource sharing project for the
development of computer svstems for consultation and research, and to
make these systems available to clinical facilities from a set of
distributed data bases. The radio and satellite links which comrose
the communication network known as the ALOHANET, in conjunction with
the APPANE'T, will make these programs available to other Hawaiian
islands and to remote areas of the Pacific basin. This project coulc
well have a significantly beneficial effect on the quality of health
care delivery in these locations.

Modelling of Higher Mental Functions. A project at tne
University of California at Los angeles is using the SUMEX-AI#
facility to construct, test, and validate an improved version of the
computer simulation of paranoid processes which has heen
developed. ‘hese simulations nave clinical implications for the
understanding, treatment, and orevention of paranoid disorders. the
current interactive version (PAFPY) has been running on SUMEX-AIM and
nas provided a basis for improvement of the future version’s language
recognition capability.

Local projects

The Protein Crystallography Project. fhe Protein
Crystallography project involves scientists at two different
universities (Stanford and the University of California at San
Diego), pooling their respective talents in protein crystallogranrnyv
and computer science, and using the SUMEX-AIM facility as the central
repository for vorograms, data and other information of common
interest. The general objective of the project is to aroly problem
solving techniques, which have emerged from artificial intelligence
research, to the well known "phase problem" of x-ray crystalloqrachy,
in order to determine the three-dimensional structures of proteins.
phe work is intended to be of practical as well as theoretical value
to both computer science (particularly artificial intelligence
research) and protein crystallography.

The MYCIN project. MYCIN is an evolving computer rrodqram that
has been developed to assist physician nonspecialists with the
selection of therapy for patients with bacterial infections. fhe
project has involved both physicians, with exoertise in the clinical
pharmacology of bacterial infections, and computer scientists, with
interests in artificial intelligence and medical computin:. the
“YCIn orogram attempts to model the decision processes of the medical
exverts. It consists of three closely integrated components: the
consultation System asks auestions, makes conclusions, and gives
advice; the Explanation System answers questions from the user to
justity the program’s advice and explain its methods; and the
Rule-Acauisition System permits the user to teach the system new
decision rules, or to alter pre-existing rules that are judyed to be
inadeavate or incorrect.

The DENDRAL project. This project, being of narticular chemical
interest, is described in detail in Section II. Through the
SUNEX-AIM facility DENDRAL has gained a growing community ot
production-level users whose experience with the programs is a
valuable quide to further development. Although technically users,
some members of this community might better be described as
collaborators because they have provided SUMEX-AIM with various
special-purpose programs which are of interest to other chemicts and
which extend the usefulness of the DENDRAL programs.

SUMEX-AIM System Development
Current research activities at SUMEX-AIM are develonringa along

several lines. On a system development level there are ongoing
projects designed to make the system more user oriented. Currently,
the system can be expected to provide help to the user who is
confused about what is expected in response to a certain prompt. A
"2" typed by the user, will, in most cases, provide a list

of possible responses from which to choose. Also

available in response to typing "HELP" to the monitor is a general
help description containing voointers to files likely to be of
interest to a new user.

In an effort to facilitate communication between collaborators,

a program called CONFER has been developed to provide an orderly
method for multiple participant teletype "conference calls".
gasically, the orogram acts as a character processor for ali tne
terminals linked in the conference, accepting input from only one at
a time, and passing it out to the remaining terminals. In this wav,
the conference, in effect, has a "moderator" terminal, thus allowing
for a more orderly transfer of ideas and information.

SUMEX-AIM is also aware of the necessity of making its facilities
available for trial use by potential users and collaborators. 10
this end, a GUEST mechanism has been established for persons who wish
to have brief, trial access to certain programs they feel may be ot
value to them, and about which they would like to obtain more
knowledge. ‘this provides a convenient mechanism whereby persons, wlio
have been qiven an appropriate phone number and LOGIN
procedure, can dial up SUMEX-AIM and receive actual experience usin: a
program they may only have heard about.

Another area of system development currently being explore? at
SUMEX-AIM is that of creating a comprehensive "bulletin board"
facility where users can file "bulletins", that is, messages of
interest to the SUNEX-AI® community. The facility will also alert wovrs
to new bulletins wnich are likely to be of interest to re,
ceterzined by individual user-interest profile.

Il. UEit:nAL - Chemical Applications of Interactive Comeutin’ in
a Network Environment

ihe major research interest of the DEND&AL Project at stanford
University is application of artificial intelligence technicucs for
chemical inference, focusing in particular on molecular structure
elucidation. vortions of our research are in the area of combined
qas chromatography/high resolution mass spectrometry and include
instrumentation and data acauisition hardware and software
development. This area is beyond the scope of this report; we focus
instead on the concurrent development of programs to assist chemists
in various phases of structure elucidation beyond the point of
initial data collection. SUMEX-AIM provides the comruter supnort for
development and application of these programs.

Another aspect of our researcn is our commitment to snare
developments among a wider community. We feel that several of our
programs are advanced enough to be useful to chemists engaged in
related work in mass spectrometry and structure elucidation in
general. These programs are written primarily in the programming
jangquage INTERLISP, and thus are not easily exportable (excertions
are indicated subsequently). SUMEX-AIM provides a mechanism for
allowing others access to the programs without the requirement for
any special vrogramming or computer system expertise. The
availability of the SUMEX facility over nationwide networks allows
remote users to access the programs, in many instances via a local
telephone call.

much of the following discussion is preliminary Decause our
projrams have only recently been released for outside use. Some
announcement of their availability has been made, and other
announcements will occur in the near future, through talks,
publications in press, demonstrations and informal discussions.
Althougn most of our experience has been with local users, they nave
been good models of remote users in that their wcrevious exposure to
the actual programs and computer systems is minimal. Their
experience has been extremely useful in helping us to smooth out
clumsy interactions with programs and to locate and fix program buaqs.
such polishing is important for programs which may be utilized hy
users from widely differing backgrounds with respect to computers,
networks and time sharing systems. We are in the processes of
building a community of remote users. We actively encourage such use
for two reasons: 1) we feel the programs are capable of assisting
others in solving certain molecular structure problems, and 2) such
experience with outside users will be a tremendous assistance in
increasing the power of our programs as the programs are forced to
confront new real-world problems.

he remainder of this section outlines the programs which are
available via SUMEX, the utilization of these programs in helping to
solve structure elucidation problems and the limitations we see to
their use. we discuss current applications of the programs to our
research and the research of other users to illustrate better the
variety of potential applications and to stimulate an interchanye of
ideas. where appronriate, we point out current difficulties witn tne
use both of our programs and of SUMEX. New applications and wider
use will certainly change the nature of these problems; we strive to
solve current oroblems, but new ones will always arise to take their
place.

DENDRAL Programs

we have several programs which we employ in dealing with various
aspects of problems involving unknown structures. Some of these
programs are exportable, while the remainder are available at SUMEX.
The availability of each program is discussed below.

Our initial emphasis in studying applications of artificiel
intelligence for chemical inference was in the area of mass
spectrometry(4-6). This emphasis remains because many of our problems
require mass spectrometry as the analytical tool of choice in
providing structural information on small quantities of sample. sore
recently, we have been developing a program (CONGEN, below) directed
at more general aspects of structure elucidation. ‘This has extended
the scope of problems for which we can provide computer assistence.

we will begin, however, with discussion of the mass spectrometry
orograms. The examples used in the discussion are characteristic of
our current research problems, although we have focused on relatively
simple problems to keep the presentation brief. we trace, in what
might be chronological terms, the application of the programs to
various phases of a structure problem. In this way we hove to
illustrate the place of eacn program in the analysis. te begin bv
discussing preprocessing of mass spectral data (CLEANUP and MOLION).
Subsequent analysis of such data in terms of structure is then
covered (PLANNER). ‘The use of CONGEN is discussed for problems which
cannot be handled py the previous programs. Finally, we discuss
efforts to discover, with the use of the computer, systematics in tne
behavior of known substances in the mass spectrometer as a means of
extending the knowledge of the system for applications in new areas
(INTSUM and RULEGEN).

Applications to Molecular Structure Problems

ihe first three programs, CLEANUP, the library-search program
and MOLION are in a sense utility programs, but all three play a
critical role in processing mass spectral data. Subsequent
applications of programs (e.g., PLANNER) for more detailed spectral
analysis in terms of structure depend on the successful treatment of
the data by CLEANUP and MOLION, while the library search program
filters out common spectra which need not undergo a full analysis.
the examples used are drawn from our collaboration with persons in
the Genetics Research Center at Stanford Hospital. The exoerimental
data which are collected are the results of combined gas
chromatographic/low resolution mass spectral (GC/LRMS) analysis of
various fractions (chemically fractionated and derivatized where
necessary) of body fluids, e.g. blood, urine. A typical exneriment
consists of 58-68 individual mass spectra for each fraction, taken
sequentially over time as the various components, largely separated
from one another, elute from the gas chromatograph and pass into the
maSs spectrometer. Each mass spectrum consists of the mass analyzed
fragment ions of the component(s) in the mass spectrometer at the
‘time the spectrum was taken. Such spectra are related, indirectly,
to the molecular Structure of the component(s).

CLEANUP(7). The individual mass spectra obtained from
fractionated GC/LRMS analysis are auite often poor representations of
corresvconding ssectra taken from pure compounds. They can be
contaminated by the presence of additional peaks and/or distortions
to the intensities of existing peaks in the spectrum. Fragment ions
from either the lioguid phase of the GC column or from components
incompletely separated by the gas chromatograph are are responsible
for the contamination. We have developed a program, referred to here
as CLEANUP, which examines all mass spectra in a GC/LRMS run, selects
those spectra which contain ions other than background impurities,
and remove contributions from background and overlapping components.
A spectrum results which compares favorably with the spectrum of a
pure component. Biller and Biemann (8) have developed a similar but
less powerful program.

For example, the CLEANUP program detected components at points
marked with a vertical bar in the plot of total ion current vs. scan
number (time), Figure 3. Note that overlapping components were
detected under the envelopes of the GC peaks in the region of scans
485-488, 525-529 and 539-552. We focus our attention on the spectrum
recorded at scan 492. The raw data, prior to cleanup, are vresented
in Figure 4 (top). The spectrum resulting from CLEANUP is presented
in Figure 4 (bottom). Note that the large ions (e.g., m/e 207, 221
and 315) from background impurities are removed, and that the
intensity ratios of peaks at lower masses (e.g., 51 and 77) have been
adjusted to reflect their true intensities in the spectrum.

The CLEANUP program is capable of detection of quite low-level
components in complex mixtures as indicated by some of the areas of
the total ion current plot (Figure 3) where components were detected.
It is completely general because nothing in the program code is
sensitive to the types of compounds analyzed or the characteristics
of possible impurities associated with the compounds or from the GC
column. Its major limitation is that mass spectra must be taken
repetitively during the course of a GC/MS run. Its performance is
enhanced when such spectra are measured closely in time.

The program is offered via SUMEX as an adjunct to use of our
other programs; it is not offered as a routine service. Because the
program is written in FORTRAN, we routinely use it on our data
acquisition computer system so as not to burden SUMEX with tasks
better done elsewhere. Similarly, we would assist other frecuent
users to mount the program on their own systems,

Library Search. With a set of "clean" mass spectra available,
the next problem is identification of the various components. Over
the course of several years, libraries of mass spectral data have
been assembled(9). These libraries can be very useful in weeding out
from a group of spectra those which represent known compounds(lt)).
Clearly, one should spend time on solving the structures of unknown
compounds, not on rediscovering old ones. The CLEANUP program
provides mass spectra which are of sufficient quality to expect that
known compounds would be identified easily from such libraries.
Insert A - Dennis” sep. page. This brief example illustrates the
obvious value and limitations of library searching. The most
interesting compounds for subsequent analysis are those which are
unknown. The fractions of urine extracts are replete with
unidentified compounds because of the inadequacy of current library
compilations. As new compounds are identified they are, of course,
added to the library so that future analyses need not reinvestigate
the same material.

we currently perform library searching on our data acauisition
and reduction computer systems. we can, if necessary, offer limited
library search facilities via SUMEX. However, because commercial
facilities are available (e.g., over the GE network), routine library
search service is not available on SUMEX.

MOLION(11). At this stage we are left with a collection of mass
spectra of unknown compounds. The library search results may have
provided some clues as to the type of compound present, e.g.,
compound class. Structure elucidation now begins in earnest. The key
elements in voroblems of structure elucidation are the molecular
weight and empirical formula of a compound. Without these essential
data, the structural possibilities are usually too immense to proceed
further. Mass spectrometry is frequently used to determine molecular
weights and formulae, but there is no guarantee that the mass
spectrum of a compound displays an ion corresponding to the intact
molecule. For example, many of the derivatives of the amino acid
fractions of urine display no molecular ions. When we are given only
the mass spectrum (and for GC/MS analysis a mass spectrum may be all
that is available) we must somehow predict likely molecular ion
candidates. The program MOLION performs this task. Given a mass
spectrum, it predicts and ranks likely molecular ion candidates
independent of the presence or absence of an ion in the spectrum
corresponding to the intact molecule. The published manuscript(1ll)
provides many examples of the performance of the program.

The mass spectrum of an example, unknown X, (which we will
pursue in more detail below) is given in Figure 5. The results
obtained from MOLION are summarized in Table I. The observed ion at
m/e 263 is ranked as the most likely candidate.

Table I. Results of Molecular Ion Determination for the
Unknown Compound, X, whose Mass Spectrum is Presented
in Figure 5.

CANDIDATE RANKING INDEX
263.8 196
397.0 41

299.0 38
295.8 34
281.8 25

The MOLION program is written to operate on either low or high
resolution mass spectra. The program has certain limitations which
have been summarized in detail previously(1l).

MOLION is available on SUMEX. A FORTRAN version, initially for
low resolution mass spectra, is being written so that the program can
be run on smaller computers and exported to others. However, it will
continue to be available via SUMEX so that others can access it
easily. MOLION is contained within PLANNER as one of the available
methods for detecting candidate molecular ions.

PLANNER(12). The PLANNER program is designed to analyze the
mass spectrum Of a compound or of a mixture of related compounds,
“Because there is no ab initio way of relating a mass spectrum of a
complex organic molecule to the structure of that molecule, PLANNER
requires fragmentation rules for the class of compounds to which the
unknown belongs. This is its major limitation. For our example the
class was unknown, forcing us to resort to other means of assistance.

Applications and limitations of PLANNER have been discussed
extensively(12,13). The program is very powerful in instances where
mass spectrometry rules are strong (i.e., general, with few
exceptions). In instances where rules are weak or nonexistent,
additional work on known structures and spectra may yield useful
rules to make PLANNER applicable (see INTSUM and RULEGEN, below). One
useful feature of PLANNER is its ability to analyze the svectra of
mixtures in a systematic and thorough way. Thus, it can be applied
to spectra obtained as mixtures when GC/MS data are unavailable or
impossible to obtain. PLANNER is available in an interactive version
over SUMEX, requiring three kinds of information as input: the high
or low resolution mass spectrum, the characteristic skeletal
structure for molecules in the specific compound class, and the
fragmentation rules for the class. Additional knowledge about the
unknown can be used by the program to constrain the structural
possibilites.

PREDICTOR. The purpose of the BDENDRAL predictor is to make a
testable prediction for each candidate structure and suggest crucial
data points that would allow a chemist to distinguish among the
candidate structures. The program is a simulation of the mass
spectrometer that predicts both mass spectral peaks and metastable
peaks for each candidate. A rudimentary additional program looks for
mass spectral ions and metastable ions that are unique for each
candidate, thereby providing means of disconfirming or confirming
individual candidates,
CONGEN(14,15). Structure problems are usually not solved with
mass spectrometry alone. Even when sample size is too limited for
obtaining other spectroscopic data, knowledge of chemical isolation
and results of derivatization procedures freauently acts as powerful
constraints on structural possibilities. Larger amounts of sample
permit determination of other spectroscopic data. Taken together,
this information allows determination of structural features
(substructures) of the molecule and constraints on the plausibility
of ways in which the substructures may be assembled. The CONGEN
program is capable of providing assistance in solution of such
problems.

CONGEN performs the task of construction, or generation, of
structural isomers under constraints. The program accepts as input
known structural fragments of the molecule ("superatoms") and any
remaining atoms (C,N,O,P,...), together with constraints on how they
may be assembled. It is based on the exhaustive structure
generator(16,17) and extensions (18) which permit a stepwise assembly
of structures.

In an interactive session with the program, a user supplies
structural information determined by his own analysis of the data
(perhaps with the help of the above programs), together with whatever
other constraints are available concerning desired and undesired
structural features, ring sizes and so forth. The program builds
structures in a series of steps, during which a user can interact
further with the procedure, for example, to add new constraints.
Although very much a developing program, its ability to accept
user-inferred constraints from many data sources makes CONGEN a
general tool for structure elucidation which we are making available
in its current form.

For the unknown X, the observed fragment ions from the molecular
ion (M) at m/e 263 (Figure 5) suggest several structural features
when coupled with the knowledge of the chemical derivatization
procedures used on this fraction of the urine extract. The ion at
m/e 194 represents loss of 69 amu, probably CF3, from fragmentation
of a trifluoroacetyl derivative of an amine. This suggests the
partial structure 2, Figure 5. The ions at m/e 19 (M-74 amu) and
m/e 162 (+181 amu) suggest the characteristic fragmentation of an
n-butyl ester resulting from the second derivatization procedure,
formation of the n-butyl esters of free carboxylic acid functions.
This suggests the partial structure 1, Figure 5. Taken together, all
the above information implies (if no other elements are present) that
the empirical formula contains an odd number of nitrogen atoms, at
least three oxygen atoms, three fluorine atoms and at least seven
carbon atoms. Interestingly, there is only one plausible empirical
formula under these constraints, C11H12NO3F3.
Structural fragments ("Superatoms") 1] and 2 were supplied to
CONGEN, together with the remaining four carbon atoms and three
degrees of unsaturation (that is, rings plus multiple bonds). with
no additional constraints, 155 structures result. The inclusion of
other plausible constraints (e.g., no allenes, acetylenes,
cyclopropenes, cyclobutenes) reduces the number of structural
candidates to just the two isomeric forms of 3, Figure 5.

This problem represents a simple example of a large class of
such problems. Although a chemist could probably reach the same
conclusions quickly in this case, in the general case, piecing
together potential solutions is not a trivial task.

Although still a developing program, CONGEN is, capable of
considerable assistance in a wide variety of structure problems. Some
areas of current application are summarized in the subsequent
section. It is already proving its value in structure elucidation
problems by suggesting solutions with a guarantee that no plausible
alternatives have been overlooked.

The program has a great deal of flexibility. Many of the types
of constraints normally brought to bear on structure elucidation
problems can be expressed. However, some types of constraints cannot
be easily expressed (e.g., disjunctions of features and stereo-
constraints). Recent work by our group and Wipke’s(19) will make it
possible to add considerations of stereoisomerism relatively easily
(a good example of collaboration via SUMEX). We are depending on a
broad user community to help us guide further development of CONGEN.

Knowledge Acouisition

INTSUM(28) and RULEGEN. When the mass spectrometry rules for a
given class of compounds are not known, the INTSUM and RULEGEN
programs can help a chemist formulate those rules. Essentially,
these programs categorize the plausible fragmentations for a class of
compounds sy looking at the mass spectra of several molecules in the
class. All molecules are assumed to belong to one class whose
skeletal structure must be specified. Also, the mass spectra and the
structures of all the molecules must be given to the program.

INTSUM collects evidence for all possible fragmentations (within
user-specified constraints) and summarizes the results. For example,
a user may be interested in all fragmentations involving one or two
bonds, but not three; aromatic rings may be known to be unfragmented;
and the user may be interested only in fragmentations resulting in an
ion containing a heteroatom. Under these constraints, the program
correlates all peaks in the mass spectra with all possible
fragmentations. The summary of results shows the molecules whose
spectra display evidence for each particular fragmentation,along with
the total (and average) ion current associated with the
fragmentation.

The RULEGEN program attempts to explain the regularities found
by INTSUM in terms of the underlying structural features around the
bonds in question that seem to "direct" the fragmentations. For
example, INTSUM will notice significant fragmentation of the two
different bonds alpha to the carbonyl group in aliphatic ketones. It
is left to RULEGEN to discover that these are both instances of the
same fundamental alpha-cleavage process that can be predicted any
time a bond is alpha to a carbonyl group.

These programs are part of the so-called Meta-DENDRAL effort,
whose general goal is to understand rule formation activities. Both
INTSUM and RULEGEN are available as interactive programs on SUMEX,
the former being much more highly developed than the latter.

Although these programs can be very useful to chemists interested in
finding new mass spectrometry rules, they require having the
collection of mass spectra and molecular structure descriptions
available in one computer file. Because of this, they have been used
mostly by chemists at Stanford.

Applications and Resource Sharing

The DENDRAL programs are being developed to serve a broad
community of chemists with structure elucidation problems. Our
experience is admittedly limited. In this section we discuss some of
the applications, both local and from remote sites, where these
programs have proven useful.

CLEANUP. This program has been developed in collaboration with
the research staff of the Genetics Research Center at Stanford.
Because that staff is working on problems in which few assumptions
can be made about the samples, the CLEANUP program has been made very
general. For example, the program works with high or low resolution
spectra, and makes no assumptions about the actual GC columns used
for separating components. This program will be tried next on the
GC/HRMS data collected on the MAT=-711 in the mass spectrometry
laboratory of the Stanford chemistry department.

MOLION. The molecular ion determination program has been used
in conjunction with CLEANUP on mass spectrometry problems in the
Genetics kesearch Center. Because of the few assumptions that can be
made about the samples in the GRC, the MOLION program has been made
very general. We have incorporated this program as part of the
PLANNER, as a powerful, class-independent method for inferring the
composition of the molecular ion before structure analysis. whe
anticipate wide use of the program when the FORTRAN version is
available for export as well as stand-alone use on SUMEX.
PLANNER. The planning program has been used to infer plausible
placement of substituents around a skeletal structure for numerous
test problems in which the class of the sample was known and the
fragmentation rules for the class were known. Those tests have
resulted in a program that we believe is general. We have applied
this program to unknown mixtures of estrogenic steroids(13). We are
preparing to use PLANNER for screening mass spectra of marine sterols
to identify quickly those spectra of known compounds and to suggest
structures for spectra of new compounds.

CONGEN. CONGEN is being used locally and from remote sites in a
wide variety of applications. We have used it for construction of
ring systems under constraints(21) and for generation of structures
of chlorocarbons(22). We have investigated several monoterpenoid and
sesquiterpenoid structure problems to suggest solutions and to ensure
that all alternatives had been considered. We are currently
investigating the scope of terpenoid isomerism. Two problems relating
to unknown photochemical reaction products have been analyzed and
results used to suggest further experiments. In most cases we do not
know the precise problems under study by remote users, only that they
are using the program.

CONGEN will perhaps be the most widely used (by remote users)
program of those mentioned above as accessible through SUMEX. This is
primarily a result of the wider scope of problems which might benefit
from use of the program. However, the need for remote users to have
their mass spectral data available at SUMEX for analysis present a
significant energy barrier to use of the programs which require these
data.

INTSUM and RULEGEN. INTSUM is essentially a production program
now, and is being used as such in a variety of applications involving
correlations of molecular structures with their respective spectra.
Recent or current applications include analysis of the mass spectra
of progesterones and related steroids, androstanes, macrocyclic
antibiotics, insect juvenile hormones and phytoecdycones.

These studies serve to develop fragmentation rules which, if of
sufficient generality, can in turn be used in PLANNER in the study of
unknown compounds.

III. Problems related to networking

During this first year of operation, the SUMEX-AIM facility has
encountered a variety of problems arising from its network
availability. In most cases, there has been no clear precedent for
the handling of these situations, in fact, many problem-areas still
reflect the influences of a yet-developing policy. The hope is that
this presentation and discussion of problems and their solutions may
give foresight to others who contemplate networking or network use.
The problems to be discussed can be loosely associated into three
classes; those related to the management of the facility, those
pertaining to research activities on the system, and those involving
psychological barriers to network use.

Managerial problems

"Gatekeeping." The most general problem faced by the organizers
of the SUMEX-AIM facility is the question of "gatekeeping." In order
to insure a high quality of pertinent research, some kind of
refereeing system is needed to assess the value of proposed new
projects. The organizers of the facility would seem to be the best
source of such judgements; yet, because we are both organizers and
members of the SUMEX community, there is a danger that our decisions
would unfairly favor local priorities. In order to establish
credibility in SUMEX-AIM as a truly national resource, a management
system has been instituted that allocates a defined fraction
(initially 50%) of the SUMEX resource to external users, under the
jurisdiction of an independent national committee (the AIM advisory
group). The remaining 58%, allocated for local use, contains a
portion for flexible experiments outside of local projects, but on
our own responsibility.

Choice of computer and operating system. A second management
level problem is the choice of a computer and operating system which
optimize the usefulness of the facility for a majority of users, and
which encourage intercommunication between remote collaborators.
Because SUMEX-AIM is intended to be used primarily for applications of
artificial intelligence, and because interactive LISP (INTERLISP[ref])
is a vrimary language in this type of work, the choice of TENEX[ref] as
an operating system was dictated somewhat by necessity. TENEX
incorporates multiple address spaces, thereby allowing multiple "fork"
structure and paging, a design which is necessary to create the large-
memory virtual machine required by INTERLISP.

The PDP-1@ is a popular machine for interactive computing of
all sorts in university research environments, and thus an added benefit
of this choice was expected - the possibility of easily transferring to
SUMEX programs developed at other sites. Many of these programs were
written not under TENEX but under the 16/58 monitor supplied by the
manufacturer. Because a large and useful program library was already
available under the 10/5 monitor, one of the design criteria of TENEX
was compatibility with such programs; when a 18/58 program is run under
TENEX, a special “compatibility package" of routines is invoked to
translate 16/5 monitor calls into equivalent TENEX monitor calls.
Although the concept is sound, we have found that in practice very few
programs written for the 1@/589 monitor are able to run under TENEX
without extensive modification. Other problems with TENEX include
weaknesses in the support of peripheral devices and the lack of a
default line-editor. The latter has caused a proliferation of editing
programs, and some confusion has resulted because editor conventions
vary from program to program. These difficulties have dampened somewhat
our initial enthusiasm for the TENEX system.

Nonetheless, TENEX provides some features which are crucial to a
comfortable network environment. The standard support programs
included with this system facilitate both the sending of messages to
other users (either at the same site or at other sites on the ARPA
network) and the transfer of data and programs from site to site on
that network; also, the ability to "link" two or more terminals
allows users to communicate easily and immediately. Both the linking
and message facility have been found to be invaluable aids in
inter-group communications and in such problems as interactive
program debugging. When two terminals are linked, their output
streams are merged, thus allowing each terminal to display everything
typed at the other terminal. Since only the output stream is
affected under these circumstances, it is still possible for each
terminal to be used to provide input to separate programs, in
addition to being used in a conversational mode.

Maintaining a livable system. This third management-level
problem is multi-faceted, with major areas of concern being
resource allocation, security and file backup. Each of these issues
involves keeping the system comfortably useful for the menbers of the
SOMEX community. Although these difficulties are felt at sites which
serve only a local community, they are accentuated by network
connection,

As noted above, the computational resources of the SUMEX~AIM
facility are apportioned by the AIM advisory group and SUMEX management.
some extensions to the basic TENEX system have been made to
reflect this apportioning in the actual use of the facility.
Basically, it was recognized that users of the facility are
members of groups working on specific projects, and it is
among these projects that the facility is apportioned.

Disk space and cpu cycles are now distributed among groups
instead of among individual users. For example, a user

may exceed his individual disk allocation somewhat without
any ill effect, so long as the total allocation of his group
remains within the limits. Similarly, a Reserve Allocation
Scheduler has been added to TENEX which tries to match

the administrative cycle distribution over a ninety second
time frame. Thus a particular group cannot dominate the
machine if a lot of its members are logged in at one time.

It is typical for usage of a facility to peak
through the middle hours of the day. Indeed, one of the
advantages of having users from around the country is
the spreading of the load caused by the difference in
time zones. Even so, the facility could offer
better service if more people would shift their main
usage hours toward either end of the day. To encourage
“soft-scheduling” within groups on the system, SUMEX-AIM
publishes a weekly plot of diurnal loading .

This plot shows the total number of jobs on the system as
well as the number of LISP jobs, since these jobs seem
to make the biggest demands of system resources. The

result has been an increased awareness by users of system loading and
a noticeable increase in the number of users at all hours of

the night and early morning.

Protection for a computer system covers a range of
ideas. It means the ability to maintain secrecy - for example,
to guarantee the privacy of patient records. It also
guarantees integrity by assuring that programs and data are not
modified by an unauthorized party.

Questions of protection generally become more interesting
and complex as more sharing is involved. Consider the example
of a proprietory program which generates layouts given a user ‘s
circuit data. The program owner demands assurance that he will
be paid whenever his program is used and that copies of the
program cannot be made. The user wants guarantees that
his data sets cannot be destroyed or copied for a competitor.
yet the user must have access to the program and the program
must have access to the data. Unable to support such complicated
examples of protection, SUMEX-AIM assumes
that sharing takes place between friendly users. This is
not to imply that issues of protection and sharing have not
appeared. For example, in an effort to improve the human
engineering of programs for public use, the capability of
recording a session has been built into several of the programs.
studied by the program designers to pinpoint confusing aspects
of programs, these recordings serve to improve program
design. Since the issue of violation of privacy has been
raised, some cf these programs now request permission to
record a session before doing so. At this time, any
quarantee of privacy must be provided by the program
designer because TENEX itself does not have the
ability to render the protection .

The general design for systems offering "state of
the art" protection involves a tolerance for failure; that
is, if a potential offender succeeds in breaking through some
of the defenses, he still does not place the entire
computer system at his mercy. Encrypting of data files
provides an additional line of defense. This method is used
by at least two calendar or appointment programs on the
computer. At this time, however, there are no
general encrypting facilities available and users must
do this for themselves as needed.

Tenex provides the usual keyword protection at login time and a
measure of file protection. Owners of a file may assign a protection
number which specifies some combination of READ, WRITE, EXECUTE, or
APPEND access to a file for owners, members of a group, or other
users. This level of protection is basically enough to prevent
accidents and most mischief. System programmer s around the country
are aware of a number of TENEX bugs which permit this access to be
violated. One user of our system found a way to place himself in a
mode where he could modify any file on the system. To date, we have
no examples of such activity~ actually having a deleterious effect on
SUMEX-AIM,

To make the use of SUMEX-AIM programs easily available
on a trial basis for prospective users, a "guest" account
system has been established. Since this makes logging into
SUMEX-AIM so easy, it has invited some misuse by people
using those accounts to play the computer games. A proposed
extension to the system now being implemented is a special
"guest EXEC" which would extend the protection of
the TENEX monitor by allowing guest accounts access to only
a more restricted set of programs.

In order to assure the user maximum protection against loss of
valuable work, SUMEX operates a multi-level file backup system. In
addition to routine file backup system there are facilities to enable
the user to selectively archive his or her disk files. By issuing a
simple command to the TENEX executive the user can transmit a message
to the operator to copy specified files to magnetic tape. Each such
file is copied to two magnetic tapes within 24 hours of issuing the
archive command. File retrieval is affected by a similar process. The
user also has the alternative option of being able to lodge files in
a special backup directory. Files are held in this directory until
the next exclusive file dump (see below) at which time they are
deleted. In this way the user can remove files from his directory at
his own choosing knowing they will be archived by the exclusive dump.

On a system level, an effort is made to maintain file
backups such that the maximum possible loss, in the event of a crash
fatal to the file system, would amount to no more than one day's
work. Once each day all files that have been read or written
within the last 48 hours are dumped onto magnetic tape. Files
that exist for 48 hours are thus held on two separate tapes.

The rotation period for files dumped in this way is 6@ days.

Once each week a full file dump is made to separate

disk storage. Bach such dump is kept for two weeks at which

time it is replaced by a new file dump.

rach month there is a full system dump from disk to

magnetic tape. Files can be recovered from the system backup by sending
a message to the operator specifying the file name(s) and when

the file was last read or written (if such information is

available).

Excessive demand for production programs. One of the concepts
behind the creation of a shared resource is
elimination of the problems which arise when large, complex computer
programs are exported. Since, in theory, exportability is no longer
a problem, there is greater latitude in choice of a language in which
program development can take place. In the case of some of the
DENDRAL programs, it was thought that program development should take
place in INTERLISP, a language that lends itself well to the
artificial intelligence nature of these programs, but does not lead
to particularly efficient run-time code.
In order to ascertain the usefulness of these programs and to
determine what areas remained in need of work, chemist collaborators
were sought. As these users increased in number and began to use the
programs more frequently, it became obvious that the inherent
slowness of the predominately LISP code was affecting the whole
system as well as handicapping the efficient use of the DENDRAL
programs. Additionally, some of the chemist-users who were finding
the programs most useful and who were most enthusiastic about their
potential use, were versons who were working in industry. Although,
in one sense, this interest from industry could be interpreted as an
indication of the “real-world” usefulness of the programs, it came
aS rather a surprise to both SUMEX and DENDRAL personnel.

The fact that SUMEX-AIM is funded by NIH as a national
resource vrohibits the facility from providing a service, at
taxpayer ’s expense, to a private industry. Although
there is precedent for a site funded via government grant to charge
a fee for service, such an arrangement leads to highly complicated
bookkeeping, and is contrary to the essential purpose of SUMEX~-AIM;
to be a research-oriented rather than service-oriented facility. This
leaves the industrial users in the position of being more than
willing to pay for the use of the programs, but of having no
mechanism whereby they can be charged. Furthermore, the fact that the
programs are coded in LISP for a highly specialized environment,
almost guarantees the impossibility of export, except to an almost
identical computer system.

An intermediate solution that will help to solve the problem of
industrial users on SUMEX and will help to alleviate the system
loading resulting from heavy usage of LISP coded production programs,
is to mount CONGEN on a closely related computer which is operated on
a fee for service basis. However, in order to make this transfer
economically feasible, it has become evident that it will be
necessary to recode the LISP sections of the program into a more
efficient and easily exportable language.

Research-oriented problems

Community mindedness. Those involved in computer science research
at SUMNEX face a general problem which is absent or greatly lessened at
non-network sites; the problem of community mindedness. The
network provides a large and varied set of other researchers and users
who have an interest in their work. Although the network-TENEX
combination provides new forms of communication with these remote
parties, the traditional means of fully describing the use and structure
of a complex program, a detailed person-to-person discussion, is not
convenient. Comprehensive documentation gains importance in such a
situation, and within the DENDRAL project a great deal of time has been
needed in the development of program descriptions which are adeauate
for a diverse audience. Also, in both DENDRAL and MYCIN, effort
nas been and is being directed toward "human engineering" in program
design; to provide the user with commands which assist him in using
the programs, in understanding the logic by which the programs reach
certain decisions and in communicating questions or comments on the
programs” operation to those responsible for development. Such
"housekeeping" tasks can often be neglected, yet are guite important
in smoothing interaction with the community.

Choice of programming language. High level programming languages
which are desianed for ease of program development are frequently poor
as production=-level languages. This is because developmental
languages free the researcher from a raft of programming details, thus
allowing him to concentrate upon the central logical issues of the
problem, but the automatic handling of these details is seldom
optimal. Also, because such languages tend to be specialized for
certain computers and operating systems, the exportation of programs
can be a serious problem. One solution to these problems is the
recoding of research-level programs into more efficient language when
fast and exportable versions are needed.

Networking greatly eases the problem of exportability, but can
also aggrevate the the problem of efficiency. As mentioned in the
previous section, the DENDRAL programs, which are undergoing constant
development, found a substantial number of production-level users.
pecause of the inefficiencies of INTERLISP (a 59- to 109-fold
improvement in running time is not uncommon when an INTERLISP program
is translated into FORTRAN), this use adversely impacted the entire
system. Because the DENDRAL programs are quite large and complex,
their translation into other languages is impractically tedious. A
partial solution to this problem is provided by the TENEX operating
system, which allows some interface between programs written in
different languages. With such intercommunication, time-consuming
segments of an INTERLISP program which are not undergoing active
development can be reprogrammed in another more efficient language.
The developmental parts of the program are left in INTERLISP, where
modifications can easily be made and tested. The CONGEN program uses
three languages; INTERLISP, FORTRAN and SAIL[ref]. The SAIL segment
was added when a new feature, whose implementation was fairly
straightforward, was included in CONGEN. Since then, the SAIL portion
gradually has been taking over some of the more time-consuming tasks.
this method allows a balance in the tradeoff between ease of program
development and efficiency of the final program.

Accumulation of expert knowledge in knowledge-based programs.
Just as statistics-based programs need to worry about
accumulation of large data bases, knowledge based programs need to
worry about the accumulation of large amounts of expertise. The
performance of these programs is tied directly to the amount of
knowledge they have about the task domain -- in a phrase, knowledge
is power. Therefore, one of the goals of artificial intelligence
research is to build systems that not only perform as well as an expert
but that also can accumulate knowledge from several experts.

Simple accretion of knowledge is possible only when the "facts",
or inference rules, that are being added to the program are entirely
separate from one another. It is unreasonable to expect a body of
knowledge to be so well organized that the facts or rules do not
overlap. (If it were so well organized, it is unlikely that an
artificial intelligence program would be the best encoding of the
problem solver.) One way of dealing with the overlap is to examine
the new rules on an individual basis, as they are added to the system
in order to remove the overlap. This was the strategy for
developing the early DENDRAL programs. However, it is very
inefficient and becomes increasingly more difficult as the body of
knowledge grows.

The problem of removing conflicts, or potential conflicts, from
overlapping ru]2®s becomes more acute when more than one exnert adds
new rules to the knowledge base, Of course, the advantages of
allowing several experts to “teach" the system are enormous -- not
only is the crogram’s breadth of knowledge potentially greater than
that of a single expert, but the rules are more apt to be refined
when looked at by several experts. On the other hand, one can expect
not only a greater volume of new rules but a higher percentage of
conflicts when several experts are adding rules.
Having a computer program that can accumulate knowledge
presupposes having an organization of the program and its knowledge

base that allows accumulation. If the knowledge is built into the
program as sequences of low-level program statements -- as often
happens -- then changing the program becomes impossible. Thus current

artificial intelligence research stresses the importance of
separating problem-solving knowledge from the control structure of
the program that uses that knowledge.

Another problem , at a political rather than a programming
level, becomes apparent with one accumulation process: how does the
program distinguish an expert from a novice? In the MYCIN program we
have circumvented the problem by having the program ask the current
user for a keyword that would identify him as an expert. It is then
a bureaucratic decision as to which users are given that keyword.
There is nothing subtle in this solution, and one can imagine far
better schemes for accomplishing the same thing. The point here is
that not every user should have the privilege of changing rules that
experts have added to the system, and that some safeguards must be
implemented.

"Human nature" barriers to SUMEX use

Countering disbelief. There is sometimes a tendency among those
unfamiliar with the capabilities and limitations of computers and
computer programs to express disbelief. This is not disbelief in the
sense of worrying that the programs have errors and produce erroneous
results. Indeed, the fact that a problem is being done by a computer
seems to generate some faith that it might be right, or at least
significantly reduces questions about correctness. The disbelief is
that programs, which are designed to model, or to emulate, human
problem solving will not be capable of useful performance. This, of
course, is the classic argument against artificial intelligence - we
think in mysterious ways and have such a complex brain that a
computer program must be inferior. In some cases, authors of
artificial intelligence programs have brought such criticism upon
themselves by not stressing limitations, or by making extravagant
claims.

In the DENDRAL project, we have tried to counter this type of
disbelief in a number of ways. We have tried to stress that our
programs are designed to assist, not replace chemists. We have
always discussed limitations to give a reasonable perspective on
capabilities vs. limitations of a program. Most importantly however,
we have focused on those aspects of problems which are amenable to
systematic analysis, i.e., those problems which can be done manually,
but only with difficulty and with the consumption of a great deal of
time which a chemist could better spend on more productive pursuits.
Examples of this would include the application of PLANNER to mixtures
where all fragmentations may have to be considered as possible
fragments of every molecular ion, the systematic analysis by INTSUM