Catalyzing Inquiry at the Interface of Computing and Biology

28 CATALYZING INQUIRY

Box 2.1

Some Questions for Cell Biology in the 21st Century

In the Human Genome Institute’s recently published agenda for research in the postgenome era, Francis

Collins and his coauthors repeatedly emphasized how little biologists understand about the data already in

hand. Collins et al. argue that biologists are a very long way from knowing everything there is to know about

how genes are structured and regulated, for example, and they are virtually without a clue as to what’s going

on in the other 95 percent of the genome that does not code for genes. This is why the agenda’s very first grand

challenge was to systematically endow those data with meaning—that is, to “comprehensively identify the

structural and functional components encoded in the human genome.”^1

The challenge, in a nutshell, is to understand the cellular information processing system—all of it—from the

genome on up. Weng et al. suggest that the essential defining feature of a cell, which makes the system as a

whole extremely difficult to analyze, is the following:^2

[The cell] is not a machine (however complex) drawn to a well-defined design, but a machine that can and does

constantly rebuild itself within a range of variable parameters. For a systematic approach, what is needed is a

relatively clear definition of the boundary of this variability. In principle, these boundaries are determined by an as-

yet-unknown combination of intrinsic capability and external inputs. The balance between intrinsic capability and

the response to external signals is likely to be a central issue in understanding gene expression.... A large body of

emerging data indicates that early development occurs through signaling interactions that are genetically pro-

grammed, whereas at the later stages, the development of complex traits is dependent on external inputs as well. A

quantitative description of this entire process would be a culmination and synthesis of much of biology.

Some of the questions raised by this perspective include the following:

• What is the proteome of any given cell? How do these individual protein molecules organize themselves
  into functional subnetworks—and how do these subnetworks then organize themselves into higher- and
  higher-level networks?^3 What are the functional design principles of these systems? And how, precisely, do
  the products of the genome react back on the genome to control their own creation?


• To what extent are active elements (such as RNA) present in the noncoding portions of the genome? What
  is the inventory of epigenetic mechanisms (e.g., RNA silencing, DNA methylation, histone hypoacetylation,
  chromatin modifications, imprinting) that cells use to control gene expression? These mechanisms play impor-
  tant roles in controlling an organism’s development and, in some lower organisms, are defense responses
  against viruses and transposable elements. However, epigenetic phenomena have also been implicated in
  several human diseases, particularly cancer development due to the repression of tumor suppressor genes.
  What activates these mechanisms?


• How do these dynamically self-organizing networks vary over the course of the cell cycle (even though
  most cells in an organism are not proliferating and have exited from the cell cycle)? How do they change as
  the cell responds to its surroundings? How do they encode and process information? Also, what accounts for
  life’s robustness—the ability of these networks to adapt, maintain themselves, and recover from a wide variety
  of environmental insults?

(^1) F.S. Collins, E.D. Green, A.E. Guttmacher, and M.S. Guyer, “A Vision for the Future of Genomic Research,” Nature 422(6934):835-847,

2003. To help achieve this grand challenge, the institute has launched the ENCODE project, a public research consortium dedicated to
      building an annotated encyclopedia of all known functional DNA elements. See http://www.genome.gov/10005107.

(^2) G. Weng, U.S. Bhalla, and R. Iyengar, “Complexity in Biological Signaling Systems,” Science 284(5411):92-96, 1999.
(^3) The hierarchy of levels obviously doesn’t stop at the cell membrane. Although deciphering the various cellular regulatory networks is a
huge challenge in itself, systems biology ultimately has to deal as well with how cells organize themselves into tissues, organs, and the whole
organism. One group that is trying to lay the groundwork for such an effort is the Physiome Project at the University of Auckland in New
Zealand. See http://www.webopedia.com/TERM/W/Web_services.html.