Grantee: California Institute of Technology, Pasadena, CA, USA
Researcher: Lea Goentoro, Ph.D.
Grant Title: Evolving diversity with few parts
https://doi.org/10.37717/220020365
Program Area: Studying Complex Systems
Grant Type: Scholar Award
Amount: $450,000
Year Awarded: 2013
Duration: 6 years
In this exciting time, when we have come to understand biology in details unimaginable to scientists mere two generations ago, the question only becomes more urgent: How do we make sense of biological complexity? The Molecular Biology revolution and the triumphant sequencing of the human genome leave us with one paradox: the deep conservation of the molecular processes that constitute biology. As we look into more and more organisms, we find similar molecules, similar pathways, similar chemistry. Biology has evolved immense diversity with the same few parts.
The research program in my lab aims to build a quantitative framework for understanding how the same few parts can generate diverse organisms. We integrate mathematical and experimental approaches to analyze the architecture of the conserved molecular pathways, their deployment into diverse contexts, and the way the molecular processes are connected to one another and embedded into the larger network.
Where we have looked, we see evidence that these deeply conserved processes may have evolved special properties that facilitate diverse uses and adaptation to new uses. We see evidence of design features that allow these conserved molecular pathways to function robustly in the presence of cellular noise. We see evidence of design features that allow these molecular pathways to be easily plugged into diverse contexts. We see evidence that these molecular processes may be connected in a way that facilitates rapid adaptation to environmental change. Moreover, we see evidence of design features that explain how these molecular pathways may be so conserved when natural selection acts on a distant level. As in music, the Internet, or electrical system,1 having conserved parts (e.g., chords, TCP/ IP, plugs and sockets) may facilitate evolvability in biology.
The paradox of conserved parts and diverse organisms
The complexity of biological systems has bewildered many imaginative minds in history. The doctrine of Vitalism reigned up to the nineteenth century, and prescribed the presence of vital force in biological organisms2 – an idea that still resonates today in the way we use the word "soul". Even Alfred Russel Wallace – who independently conceived the theory of evolution, insisted that, as a consequence of his hyperadaptionatist view,3 human intelligence could not be accounted for by the theory of evolution.4 The current optimism that all aspects of biological complexity is not beyond the sphere of science comes from biological revolutions in the twentieth century, and the rapid progress that followed. From the re-discovery of Mendel's work by de Vries in 1900, to the elucidation of DNA structure by Watson and Crick in 1953, to the complete sequencing of the human genome in 2004: within one hundred years, biology has turned from a descriptive science into a predictive experimental science.
The great waves of revolution leave us with one paradox–one that I believe to be the grand challenge for the present students of biological complexity. The abundant anatomical and behavioral diversity we see in animals around us is underlain by deep molecular conservation (Figure 1). Biological systems are built using the same few parts. There are two parts of the argument here: conservation and economy. Molecular processes are deeply conserved: all cells rely on DNA as the genetic material; cellular components are conserved (e.g., nucleus, organelles); body plan and the controlling genes are conserved; and, most strikingly, all animal cells utilize conserved molecular pathways. Not only biology builds diversity with the same parts, it does so with staggering economy. The fact that we are only 20% different (by comparing proteins) from the single-cell amoeba illustrates the mystery.5,6 The human genome encodes about 20,000 genes, about 1.5 times more than the tiny fruit flies.7,8 From starfish on the oceanbed to bumblebees in our backyard to humans on the streets of New York, we are built using the same few parts. If the parts are the same, how do we build humans? How do we build bumblebees? How do we build starfish?
Figure 1. Diverse organisms, conserved parts. The immense diversity in anatomy, function, and behavior arises from repeated use of few, conserved molecular parts.
What is so special about the conserved parts?
The paradox between conserved parts and diverse outcomes may be explained by combinatorial uses of the parts (Figure 2A). For example, in the fruit fly Drosophila segmentation, different combinations of transcription factors give rise to different cell fates.9 In some mutants, this results in flies carrying a perfect, second pair of wings (Figure 2A).9,10 The paradox between conserved parts and diverse outcomes may also be explained by higher specialization of the parts (Figure 2B). For example, inputs to signaling pathways vary from species to species. In the Wnt signaling pathway that is found in all animal cells: the pathway has 7 inputs in fruit flies, 12 inputs in sea anomeone, and 19 inputs in mice and humans.11-13 Finally, the paradox between conserved parts and diverse outcomes may also be explained by using each part in a quantitatively different manner (Figure 2C). For example, the beak morphology of Galapagos finches has been correlated with the expression domain of the conserved signaling protein Bmp.14
In each argument, what is common is the ease by which biology can implement a relatively simple change and produce a complex, and useful, new function. Combinatorial use implies the ease by which conserved processes can be plugged into different contexts. Input diversification implies the ease by which conserved processes can evolve response to new stimuli. The Darwin’s finches example implies the ease by which a simple change in protein expression can trigger a coordinated response from the general head morphogenesis, skeletal system, circulatory system, and nervous system – each itself constituted of conserved molecular processes – to produce a functional beak. In each example, a network of conserved processes responds to a simple change and produces useful phenotypes. Each example suggests that the conserved parts themselves have special properties that facilitate diverse and new uses.
This is the centerpiece of the research program in my lab: What kind of properties do the conserved parts have that facilitate versatile uses? The idea that the conserved parts themselves may facilitate verstile uses, and consequently evolvability, was first proposed by Kirschner and Gerhart in their Theory of Facilitated Variation.15 We want to expand and build the quantitative foundation for this argument. In my lab, we integrate mathematical and experimental approaches to explore the architecture of conserved processes in biology. Our approach is indeed bottom-up: we look for properties that allow these conserved parts to be used in a robust manner (Direction 1), plugged into diverse contexts (Direction 2), and facilitate evolvability (Direction 3). As I will illustrate here, analyzing the complexity at the level of molecular pathways gives us leverage to address complexity at the level of tissues and subsequently at the level of embryos.
Figure 1. (A) Conserved parts can be used in different combination to generate different outcomes. For example, altering combination of transcription factors can produce mutant flies with a second pair of wings.9,10 (B) Conserved parts may evolve new inputs and outputs. For example, the genome of the fruit fly Drosophila melanogaster contains 7 Wnt genes.11 That means the fly genome encodes 7 proteins that have very similar sequences and act as ligands in the Wnt pathway. The sea anemones have 12 Wnt genes.12 Mouse and humans have 19 Wnt genes.13 (C) Conserved parts may be quantitatively tuned to produce different outcomes. For example, in the finches, the embryo of the large-beaked Geospiza magnirostris shows a broad expression of the signaling molecule Bmp. By constrast, the embryo of the narrow-beaked Geospiza fortris shows a narrow domain of Bmp.14 Drawing of the finches is taken from ref. 15.
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