1. Pat Langley Silicon Valley Campus Carnegie Mellon University Department of Computer Science University of Auckland A Web-Based Environment for Explanatory Biological Modeling Thanks to Glen Hunt, John Furber, Chris MacLellan, and Seungchan Kim for their contributions to this research, which was funded in part by Daimler Benz.

2. Challenges in Scientific Modeling 1.The social nature of science requires use of interpretable formalisms that researchers can understand. 2.Science operates in a cumulative manner that extends and revises models by filling in technical details. 3.Science is concerned with explaining observations in terms of familiar concepts and mechanisms. The creation of complex scientific models raises three separate but interrelated challenges: Software environments for scientific modeling should address each of these issues. We are developing such a framework for biology, with a special focus on biogerontology.

3. The Complexity of Biology  Mutation of the mitochondrial DNA  Accumulation of lipofuscin in the lysosomes  Protein crosslinking in the extra-cellular matrix  Shortening of telomeres in the nucleus Biology differs from fields like physics in that detailed models play a more important role that general laws. One example is biogerontology, where there is agreement that aging involves many interacting processes, including: The daunting complexity of these and related processes suggests the need for computational assistance.

4. Furber’s Network Diagram of Aging [top portion]

5. Challenge 1: Representing Models of Aging   Localized in describing changes in a variety of places   Entity-oriented in specifying interactions among substances   Causal in that interactions involve asymmetrical influences   Qualitative in specifying only the directions of effects We want a notation for models of aging that is interpretable by scientists yet precise enough for a digital computer. Many traditional formalisms from computational biology will not suffice because our knowledge of aging is: These characteristics place constraints on our representation. We also need a notation that makes close contact with biologists’ ideas about aging.

6. A Formalism for Models of Aging   Places in the cell (e.g., lysosome, cytoplasm)   Quantities that are measured in a place   For transient entities or variables (e.g., ROS, Fe, rates)   For stable entities (e.g., oxidized proteins, lipofuscin)   Hypothesized causal influences between quantities   Increase/decrease of one quantity with another   Dependent terms may be amounts or rates of change We have developed a formalism for aging models that involves: Each hypothesis describes a qualitative causal link between two quantitative variables.

7. A Modeling Environment

8. Stating a Lysosomal Model Places cell lysosome in the cell cytoplasm in the cell Entities oxidized protein in the lysosome is stable lytic enzyme in the lysosome is transient damaged membrane in the lysosome is stable junk protein in the lysosome is stable lipofuscin in the lysosome is stable ROS in the lysosome is transient degradation rate in the lysosome is transient Fe in the lysosome is transient H2O2 in the lysosome is transient H2O2 in the cytoplasm is transient junk protein in the cytoplasm is stable lipofuscin in the cytoplasm is stable

9. Stating a Lysosomal Model Hypotheses Fe in the lysosome increases with junk protein in the lysosome H2O2 in the lysosome increases with H2O2 in the cytoplasm ROS in the lysosome increases with Fe in the lysosome ROS in the lysosome increases with lipofuscin in the lysosome damaged membrane in the lysosome increases with ROS in the lysosome degradation rate in the lysosome decreases with lipofuscin in the lysosome junk protein in the lysosome decreases with degradation rate in the lysosome junk protein in the lysosome increases with junk protein in the cytoplasm lipofuscin in the lysosome increases with oxidized protein in the lysosome lipofuscin in the cytoplasm increases with damaged membrane in the lysosome lytic enzyme in the lysosome decreases with lipofuscin in the lysosome oxidized protein in the lysosome increases with ROS in the lysosome

10. Visualizing a Lysosomal Model

11. Stating a Mitochondrial Model Places cell, mitochondria in the cell, nucleus in the cell Entities ROS rate, ROS, ATP, Lon Protease, mutated mtDNA, damaged mitochondria, antioxidants in the mitochondria, Lon rate, Lon Protease mRNA in the nucleus Hypotheses ROS in the mitochondria increases with ROS rate in the mitochondria mutated mtDNA in the mitochondria increases with ROS in the mitochondria Lon Protease mRNA in the nucleus decreases with Lon rate in the nucleus Lon Protease in the mitochondria increases with Lon Protease mRNA in the nucleus mutated mtDNA in the mitochondria decreases with Lon Protease... damaged mitochondria in the mitochondria increases with mutated mtDNA... damaged mitochondria in the mitochondria decreases with Lon Protease... ROS in the mitochondria decreases with antioxidants in the mitochondria ROS in the mitochondria increases with damaged mitochondria in the mitochondria ATP in the mitochondria decreases with damaged mitochondria in the mitochondria

12. Visualizing a Mitochondrial Model

13. Encoding Empirical Facts   A quantity increases (decreases) with another quantity   E.g., lipofuscin in the lysosome increases with time   E.g., lytic enzyme decreases with ROS in the lysosome   A quantity does not change with another quantity   E.g., H2O2 does not vary with ROS in the lysosome We must also represent empirical findings about aging; for this we use a notation similar to that for hypotheses: Each statement specifies, in constrained English, a pairwise relation between two quantities. Note: These describe phenomena that the model should aim to predict; they are not part of the model themselves.

14. Visualizing Empirical Facts

15. Challenge 2: Extending Models of Aging   Adding a place, entity, hypothesis, or empirical fact   Adding a note (including URLs) to a hypothesis or fact   Removing a place, entity, hypothesis, or fact   Changing the graphical layout of places and entities   Saving revisions to a file that can be loaded later Biologists should be able to extend and revise models of aging easily and efficiently. Our environment lets users alter the current model interactively in five basic ways: The modular character of models makes them straightforward to update and revise.

16. Adding a New Entity

17. Adding a New Causal Hypothesis

18. Challenge 3: Reasoning About Aging   What biological effects does the model predict?   What observations/experiments does the model match?   How does the model explain a given phenomenon?   How would changes to the model alter its predictions? We also want our models of aging to relate causal hypotheses to observable phenomena. We would like the system to answer scientific questions like: Model complexity can make these difficult to do manually, but we can provide computational support for such reasoning.

19. Simplifying Assumptions   All quantities are positive, including those describing rates   The system being modeled exists in a single qualitative state   If nothing influences a quantity, then it has a constant value   Stable quantities accumulate effects on them over time   Transient quantities do not accumulate effects over time Our approach to prediction makes five modeling assumptions: These assumptions seem appropriate for aging and age-related disease, but not for all biological problems.

20. Generating Experimental Predictions   Chains backward from dependent term D to find all paths that connect it with independent term I.   If no paths exist, then it predicts no empirical relationship.   If a path has an even number of decreases links, it predicts D increases with I, else that D decreases with I.   Provides a definite relationship if all path predictions agree.   Notes an ambiguous relationship if path predictions disagree. Given a qualitative query about the relation between two model quantities, the environment: This form of qualitative reasoning predicts changes in response to experimental manipulation.

21. Generating Experimental Predictions + – A B C D – D increases with A – + A B C D + D decreases with A + A B C D + D does not vary with A + – A B C D – + + A D E F + F increases with A + – A B C D – – + A D E F + ambiguous relation

22. F increases with A Avoiding Ambiguity with Dominance Relations + – A B C D – D increases with A – + A B C D + D decreases with A + A B C D + D does not vary with A + – A B C D – + + A D E F + F increases with A + – A B C D – – + A D E F + A-B-C-F dominates A-D-E-F

23. Generating Temporal Predictions   Chains backward from dependent term D to find the start of all paths that lead to D.   If no paths exist, then it predicts no change over time.   Assumes that any transient quantities not preceded in a path by a stable quantity are constant.   Assumes the first stable quantity in a path increases/decreases depending on its predecessor’s influence. Given a qualitative query about the relation between a model quantity and time, the environment: Otherwise, it follows the same strategy as used for experimental settings to determine how D changes over time.

24. – – – + Generating Temporal Predictions + A B C D – D decreases with time – + A B C D + D increases with time B C D + D decreases with time + – A B C D – + + A D E F + F increases with time + – A B C D – + A D E F + A [unstable]

25. Visualizing Model Predictions

26. Visualizing an Explanatory Pathway

27. Visualizing an Alternative Explanation

28. Status of the Modeling Environment   Load, examine, and visualize a qualitative model of aging   Extend, revise, and save the modified model   Compare the model’s predictions to empirical facts   Examine the explanations that support each prediction Our modeling environment is still under development, but the system already lets users: We have not yet implemented pathway dominance, but we have the basic machinery to support models of aging. We have generated initial versions of both the mitochondrial and lysosomal portions of Furber’s diagram.

29. Web Access to Models of Aging   The front end, which runs in JavaScript on user’s machine:   Handles both textual and graphical displays   Accepts user queries and changes to models   The back end, which runs in Lisp on a Web server:   Stores model content and layout information   Generates predictions and associated explanations The modeling environment and its initial models are available on the World Wide Web: The ability to access, utilize, and modify models on the Web opens the way to community-based model development. See http://cll.stanford.edu/qme-demo/

30. Generality of the Approach   Diverse results require abstract, qualitative models that still provide explanations;   Scientists have at least informal hypotheses about causes of known phenomena; and   Experimental and temporal influences on quantities are primarily monotonic in character. Our framework for biological modeling should prove useful in any domain for which: Candidates for other applications include age-related diseases like Alzheimer’s, Parkinson’s, and many forms of cancer.

31. Directions for Future Research  Provide additional content about mechanisms of aging  Augment system to group causal influences into processes  Support methods for hiding content in large, complex models  Extend notation to include contextual and arithmetic conditions  Evaluate the software’s usability for biogerontologists  Support community-based development of aging models Our effort is still in its early stages, and we need further work to: Such an extended system could aid researchers by letting them codify knowledge and evaluate alternative hypotheses.

32.   Formalizations of biological knowledge (e.g., EcoCyc, 2003)   Qualitative reasoning and simulation (e.g., Forbus, 1984)   Scientific simulation environments (e.g., STELLA )   Web-based tools for biological visualization (e.g., KEGG) Intellectual Influences Our approach to computational biological aides incorporates ideas from many traditions: However, it combines these ideas in novel ways to assist in the construction of system-level models of aging.

33.   BioBike (Shrager, 2007)   JustAid (Mahidadia & Compton, 2001)   HyBrow (Racunas, Shah, Albert, & Fedoroff, 2004)   P ROMETHEUS (Bridewell et al., 2006) Precursor Systems Our work on interactive biological modeling has also been strongly influenced by a few earlier systems: Each of these combines formal representations and reasoning with facilities for high-level user control.

34. Key Contributions In summary, we are developing an interactive environment for biological modeling that supports: We are still developing the system, but a more advanced version should offer many benefits to biologists.   Abstract yet interpretable models of aging that state causal relationships among biological quantities;   Interactive extension of models to improve their coverage that requires little training and effort; and   Reasoning over these models in ways that answer generate predictions and explain them.

35. Demonstration of Modeling Environment

36. End of Presentation