152 CATALYZING INQUIRY
(^67) For purposes of the discussion in this subsection (Section 5.4.3.1), regulation refers to cis-regulation.
(^68) C.H. Yuh, H. Bolouri, and E.H. Davidson, “Genomic Cis-regulatory Logic: Experimental and Computational Analysis of a
Sea Urchin Gene,” Science 128(5):617-629, 1998. Some of this discussion is also adapted from commentary on this article: G.A.
Wray, “Promoter Logic,” Science 279(5358):1871-1872, 1998.
(^69) In this context, a multifunctional organization of the regulatory system means that the protein associated with the endo16
gene is differentially expressed in various cells in the sea urchin.
5.4.3 Genetic Regulation,
The problem of genetic regulation—how and under what circumstances and the extent to which
genes are expressed as proteins—is a central problem of modern biology. The issue originates in an
apparent paradox—every cell in a complex organism contains the same DNA sequences, and yet there
are many cell types in such organisms (blood cells, skin cells, and so on). In particular, the proteins that
comprise any given cell type are different from those of other cell types, even though the genomic
information is the same in both. Nor is genomic information the whole story in development—cells also
respond to their environment, and external signals coming into a cell from neighboring cells influence
which proteins the cell makes.
Genetic regulation is an extraordinarily complex problem. Molecular biologists distinguish be-
tween cis-regulation and trans-regulation. Cis-regulatory elements for a given gene are segments of the
genome that are located in the vicinity of the structural portion of a gene and regulate the expression of
the gene. Trans-regulatory elements for a given gene refer to proteins not structurally associated with a
gene that nevertheless regulate its expression. The sections below provide examples of several con-
structs that help shed some light on both kinds of regulation.
5.4.3.1 Cis-regulation of Transcription Activity as Process Control Computing,
It has been known for some time that the genome contains both genes and cis-regulatory ele-
ments.^67 The presence or absence of particular combinations of these regulatory elements determines
the extent to which specific genes are expressed (i.e., transcribed into specific proteins). In pioneering
work undertaken by Davidson et al.,^68 it was shown that cis-regulation could—in the case of a specific
gene—be viewed as a logical process analogous to a computer program that connected various inputs to
a single output determining the precise level of transcription for that gene.
In particular, Davidson and his colleagues developed a high-level computer simulation of the cis-
regulatory system governing the expression of the endo16 gene in the sea urchin (endo16 is a gut-specific
gene of the sea urchin embryo). In this context, the term “high-level” means a highly abstracted repre-
sentation, consisting at its core of 18 lines of code. This simulation enabled them to make predictions
about the effect of specific manipulations of the various regulatory factors on endo16 transcription levels
that could be tested against experiment.
Some of the inputs to the simulation were binary values. The value 1 indicated that a binding site
was both present and productively occupied by the appropriate cis-regulatory factor. A 0 indicated that
the site was mutationally destroyed or inactive because its factor was not present or was inactive. The
other inputs to the simulation were continuous and varied with time, and represented outputs (protein
concentrations) in other parts of the system. The output of this process in some cases was a continuous
time-varying variable that regulated the extent to which the specific gene in question was transcribed.
Davidson et al. were able to confirm the predictions made by their computational model, conclud-
ing that all of the regulatory functions in question (and the resulting system properties) were encoded in
the DNA sequence, and that the regulatory system described is capable of processing complex informa-
tional inputs and hence indicates the presence of a multifunctional organization of the endo16 cis-
regulatory system.^69