A day of systems and synthetic biology for non-experts : Reflections on day 1 of the EMBL/EMBO joint conference on Science and Society

DOI 10.1002/bies.080225 Science and society

A day of systems and synthetic biologyfor non-expertsa

Reflections on day 1 of the EMBL/EMBO joint conference on Science and Societyy

Andrew Moore*

BioEssays Editorial Office, Wiley-Blackwell, Weinheim, Germany

From understanding ageing to the creation of artificialmembrane-bounded ‘organisms’, systems biology andsynthetic biology are seen as the latest revolutions in thelife sciences. They certainly represent a major change ofgear, but paradigm shifts? This is open to debate, to saythe least. For scientists they open up exciting ways ofstudying living systems, of formulating the ‘laws of life’,and the relationship between the origin of life, evolutionand artificial biological systems. However, the ethicaland societal considerations are probably indistinguish-able from those of human genetics and genetically mod-ified organisms. There are some tangible developmentsjust around the corner for society, and as ever, our abilityto understand the consequences of, and manage, ourown progress lags far behind our technological abilities.Furthermore our educational systems are doing a badjob of preparing the next generation of scientists andnon-scientists.

Keywords: education; science and society; synthetic biol-

ogy; systems biology

Synthetic biology: not just ‘biobricks’ andthe great biological Lego box

One need hardly ask what synthetic biology means to the

general public in the light of Craig Venter’s creation of the first

‘artificial’ bacterium. But another branch of this research field

unites technological application with a fundamental, even

philosophical, question of basic research: that of how—at the

dawn of life on Earth—organic molecules self-assembled into

ordered information-carrying entities capable of copying

themselves, or being copied; and how the minimum genetic

material for an artificial organism might be defined. These

yThe 9th EMBL/EMBO joint conference on Science and Society ‘Systems and

synthetic biology—scientific and social implications’ took place on 7–8

November 2009 at the European Molecular Biology Laboratory, Heidelberg,

Germany

*Correspondence to: Andrew Moore, BioEssays Editorial Office, Wiley-

Blackwell, Boschstrasse 12, 69469 Weinheim, Germany.

E-mail: [email protected]

BioEssays 31:119–124, � 2009 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim

areas of enquiry were addressed by three speakers at the

conference.

With the subtitle ‘How life began, and the implications of

doing it again’, Doron Lancet (Weizmann Institute, Rehovot,

Israel) presented his favoured hypothesis: that the first self-

replicating entities were ordered aggregates of amphiphilic

lipids. These allegedly grew, and upon reaching a certain size

they split because of shearing forces in the medium. This

made new nuclei for accretion in a kind of replicative process

(Fig. 1). In contrast to the four-letter RNA world hypothesis,

lipids in all their chemical diversity (which probably existed on

early Earth) would have much more information carrying

capacity. Not restricting themselves to combinatorial science

of lipids, Lancet and his group have developed a computer-

driven matrix for assaying the affinity between different

combinations of diverse organic molecule. This sheds light on

the likelihood of certain permutations forming, persisting and

replicating. On a computer, networks of molecules are formed

and then break in favour of other networks on the basis of

kinetic and thermodynamic properties. ‘In the year 2035 or

2055, chemistry in silico may provide a highly accurate re-

enactment of protein folding, the evolution of life and many

other phenomena’ concluded Lancet.

Lipids, or rather lipidmembranes, were also a key topic of a

talk given by David Deamer (University of California at Santa

Cruz, USA). A membrane not only partitions organic

components from the exterior environment (and concentrates

them), but it can concentrate organic molecules in two

dimensions, limiting their diffusion and increasing their

effective concentration and probability of interaction. How-

ever, the first organic molecules probably formed in space. On

the surface of minute interstellar dust particles, ice, ammonia

and CO2 can polymerise into a whole series of organic

compounds. These particles, and also comets andmeteorites

containing organic compounds, fell into a cooling Earth, and

likely acted as the seeds for the chemistry of life, Deamer

believes. Some monocarboxylic acids found in meteorites

have been shown to have self-assembly properties, forming

membrane-like compartments, which were very likely present

on early Earth. In Deamer’s lab decanoic acid has assembled

into membrane structures capable of trapping and concen-

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Figure 1. Doron Lancet’s ‘LipidWorld’. Amphiphilic lipids, hypothesised to be present in substantial diversity on early Earth, associate and form

mixed micelle-like formations with differing kinetics, and with resultant structures of differing thermodynamic stability. Certain combinations are

thermodynamically favourable, persist long enough for growth, and ultimately split as a result of physical forces, hence forming ‘daughter’ nuclei

for renewed growth (adapted from a Powerpoint slide, by Doron Lancet). See also http://ool.weizmann.ac.il/slides.html.

Science and society A. Moore

trating nucleic acids (Fig. 2). Already scientists can assemble

the membrane and basic cytoplasmic components of a cell,

and these work together for appreciable spans of time.

However, as the Santa Cruz researcher noted, the ribosomes

do not reproduce themselves, and because of the lack of

feedback mechanisms, the system gets out of balance very

quickly. ‘The origin of life can be considered a giant

Figure 2. Lipid vesicles that spontaneously assemble from decan-

oate/decanol in the lab. Similar membrane structures have been

shown to form from organic substances extracted from carbonaceous

meteorites. These membrane bound compartments are capable of

concentrating nucleic acids and dye molecules. According to Deamer,

they may well have been the structures upon which the first primitive

biochemical reactions took place: the first proto-cells (reproduced

from a Powerpoint slide, courtesy of David Deamer).

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experiment in combinatorial chemistry. . .. There is going to

be a second origin of life in a lab someplace. It is going to be a

version of life using the information we have in order to put

together and reconstitute a system ofmolecules that can grow

and replicate using stuff from their environment’ Deamer said.

Antoine Danchin (Institut Pasteur, Paris, France) presented

his thesis on the implications of information creation and

maintenance in living systems. He noted that cellular systems

involved in these activities consume a significant amount of

energy, and are therefore under substantial selection

pressure during evolution. Some mathematicians now

entertain the concept that in addition to matter, energy, space

and time, also information counts as a fundamental natural

measure. The production of offspring is essentially an

information-producing function, since the young are always

newer (less thermodynamically degraded) than their parents.

Living organisms can be considered ‘information traps’ that

tend to accumulate more information as a consequence of

evolution. The driver for capturing information is natural

selection, and the energy source is probably polyphosphates,

as demonstrated in vivo by the observation that polypho-

sphates can sometimes replace ATP.

Since this form of information creation is a ubiquitous

feature of life, it must have a common origin. This is

evidenced, according to Danchin, by the existence of two

main groupings of genes (Figure 3): the paleome (ancient

genes involved in survival and perpetuating life); and the

cenome (newer genes involved in living in context and

adapting to changing environments). The clustering of

evolutionarily persistent genes (paleome) has been demon-


Figure 3. ‘A tale of two genomes’: schematic representation of

bacterial genomes showing the division into ancient genes respon-

sible for essential functions of life—the so-called ‘paleome’ (greek:

palaioz ‘palaios’¼ancient) and the ‘cenome’ (greek: koinoz ‘koi-

nos’¼ common), which contains genes for living in context, exploiting

niches and adapting to changing environments. The latter is the realm

of metagenomics, the study of genetic material recovered from the

environment (e.g. genomic mining of marine water columns). The

genes necessary to construct a minimal organism reside in the

paleome (about 250 of the 500 odd genes in the Paleome) (redrawn

from a Powerpoint slide, courtesy of Antoine Danchin).

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strated in bacteria by genomic analysis. The paleome

encodes the gene expression machinery (the ‘operating

system’ of the cell), energy-dependent degradation, sulphur

metabolism (anabolism, salvage and catabolism), and

‘chemical frustration’ (metabolic ‘patches’, similar to software

patches). It is expected to hold the genes essential for making

a synthetic bacterium (about 250 genes out of the roughly 500

in the Paleome). To the audience, Danchin’s profound

discourse might well have seemed like the formulation of

the ‘laws of life’. Perhaps it really was. . .

Systems biology: modelling the emergentbehaviour of complex systems

A nightmare to synthetic biologists, the unpredictable

‘emergent’ behaviour of a complex biological system is by

contrast the veritable object of curiosity and study for a

systems biologist. A basic definition of systems biology might

sound something like this: a discipline that focuses on

understanding and modelling a system as a whole, rather

than merely examining the behaviour of its parts individually

(be those parts of a cell, parts of an organism or components

of an ecosystem); an approach that makes it possible to

predict and closely model features of the system that emerge

from the complex interaction of the parts, and which are not

predictable by simply combining the properties of these parts.

Clearly systems biology is a very powerful approach to

understanding complex biological phenomena in their entirety.

The aspect of integration of information is not new, but the


concept of biological phenomena ‘emerging’ from the

complex (unpredictable) behaviour of networks (rather than

single entities) is novel for much of the biological community.

But, if Marvin Cassman (formerly California Institute for

Quantitative Biosciences ‘QB3’, USA) is to be believed, the

term ‘systems biology’ also often means a nice new way of

attracting funding—even if one is not really working on

systems approaches at all. Figures from the International

Assessment of Research and Development in Systems

Biology show that globally the number of systems biology

programmes hadmore than doubled between 2004 and 2006.

‘Most programmes are not really studying dynamic networks

and integrative biology’ commented Cassman, adding ‘many

of these can be better defined as some variant of an ‘‘omics’’’.

The ‘paradigm’ shift accompanying systems biology is

underpinned by a broadening of focus from ‘molecular’

aspects of systems (reductionist) to the identification, study

and integration of functional ‘modules’ in a cell. The

unmanageable complexity of a large system is made tractable

by reconstructing it from definable ‘modules’. Adding to the

definition of a functional module by Von Dassow in Nature

(2000), Cassman gave the following preferred definition: ‘A

module is a set of genes and their products which, as an

emergent consequence of their interactions, performs some

task nearly autonomously, and whose inputs and outputs can

be predictively modelled and confirmed by experiment’. In the

course of this research, it transpires that—as pointed out by

Cassman—natural systems are not ‘fine-tuned’ (as many

biologists sill erroneously think), but robust with respect to

external conditions, often containing much redundancy.

Systems biology should be capable of accounting for

emergent properties not obvious by separate analysis of the

parts. In this sense, it certainly represents a shift from

reductive genomics. There is clearly a need for systems

biology, as Cassman pointed out: ‘most biologists still behave

as if a single gene is responsible for something. Systems

biologists say that a network causes something by emergent

behaviour’. A good analogy given by Lars Steinmetz

(European Molecular Biology Laboratory, Heidelberg, Ger-

many) is the spots on a printed picture: seen close-up, they

are simply dots of different colours contrasting or comple-

menting each other; from a distance, they are integrated into

an image with meaning—an emergent pattern.

The emerging social benefits of systemsbiology

What does systems biology mean to the general public? The

simple answer is ‘not much yet’, and it would be unfair to

expect a definition. But the products of systems biology will

probably have significant impacts on human health, to name

but one area.

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Insights into increasing longevity with improved quality of

life, or individually tailored drug therapies, are examples of the

potential value of systems biology for the wealthy developed

nations. With an average life-span increase in the West of 2–

2.5 years per decade, the ageing of society is certainly not to

be underestimated as a problem. Having extended our life

spans thus far, we risk producing a large number of ‘final’

years that are compromised with protracted suffering and high

medical costs. ‘The ageing process is particularly suited to a

systems biology approach, because its mechanisms are

multiple, complex, highly interactive and stochastic’ according

to Thomas Kirkwood (Institute of Ageing and Health,

University of Newcastle, UK). Much cellular age-related

damage is manifested at the level of DNA, RNA and proteins

(Fig. 4), but the upstream mechanisms are very complicated.

Through systems biology, massive quantities of data from

functional genomics projects are being combined with

hypothesis-driven experiments. A good target for systems

biology is, for example, DAF-16, a key player in the insulin-

signalling pathway. DAF-16 in turn regulates 100s of genes

involved in ageing (e.g. stress resistance, antimicrobial

resistance, ubiquitin-mediated protein turnover). And the

mystery of why telomeres translocate into mitochondria when

they are damaged might be explained by analysing another

ageing-related network: that regulating damage between

telomeres, mitochondria and chromosomes.

Figure 4. DNA, RNA and proteins are major targets of ageing-related ce

mutations, transcription and translation errors ultimately cause defects th

Reactive oxygen species (ROS) (produced by respiration in mitochond

Antioxidants and chaperones act respectively to curb DNA damage and

complex genetic networks that influence these processes in concert w

Powerpoint slide, courtesy of Thomas Kirkwood).

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Leroy Hood (Institute for Systems Biology, Seattle, USA)

works on understanding the cellular networks that are

influenced in disease and which give rise to changes in

levels of proteins secreted into the blood. Using the prion

replication network as an example, he claimed that the

dynamic activity of metabolic modules can explain all aspects

of the pathophysiology of the disease. Considering the blood

as a window to disease might be an old concept (essentially,

doctors have been doing this ever since blood sampling

began). However, assaying the blood for secreted proteins

with 800 antibodies (not a distant prospect by any means) will

enable blood-based proteomics, the elucidation of which

requires nothing short of a systems approach; i.e. feeding the

data into a model that has predictive power at the level of the

individual patient. We are on the brink of P4 medicine:

predictive, preventive, personalized, and participatory. But the

last Pmight well be the hardest to achieve, because it involves

educating the public (particularly older people) so that they

can indeed become involved.

This is not some kind of science fiction, but a near

prospect. Neither will it be a digital virtual reality: prodigious

though the powers of systems biology might be, we may well

never have a perfect model of the cell on which to do virtual

experiments—and most certainly not in time to address

serious diseases in our lifetime. Insights from systems biology

will have to be coupled with the derivation of real stem cells

llular damage. Copying errors and telomere shortening, spontaneous

at compromise normal cell function and the ability of cells to divide.

ria) also attack proteins, lipids and other macromolecules directly.

protein aggregation. Systems biology is capable of elucidating the

ith environmental factors and stochastic events (reproduced from a


A. Moore Science and society

from patients so that real experiments can be performed with

them. Technology is racing ahead of our social management

of it once again: anyone who can afford it can obtain his or her

entire single nucleotide polymorphism (SNP) profile via a 399-

Dollar kit these days. As Thomas Lemberger (Molecular

Systems Biology journal, EMBO, Germany) reported of a

small survey he had conducted, the most frequent answer

given as to why one would want to get one’s genome

sequenced and analysed was ‘just for fun’. In the long run, this

is anything but a joke. But perhaps a playful or entertaining

approach is the way to engage the public. Assaying the

experiences and testing the values of members of society is

about as close as researchers can get to true experiments

with society. Leroy Hood is working on games involving

healthcare scenarios, and would ‘love to create a TV

programme like CIS, but instead with extremely interesting

medical problems’. Dr. House’s days could be numbered. . .

The link between systems biology andsynthetic biology

Does synthetic biology somehow emerge as an unavoidable

consequence of systems biology, or is it perhaps a part of

systems biology: its ultimate aim and realisation in techno-

logical applications? This is certainly what some observers of

science believe, but the connection between the two fields is

probably at a rather more profound, synergistic, level. Victor

de Lorenzo (Centro Nacional de Biotechnologı́a, Madrid,

Spain) summarises this: ‘synthesis is not only an engineering

endeavour: you can use synthetic biology to test basic

research hypotheses. If your synthetic system works as

expected, your hypothesis is right’. Systems biology and

synthetic biology might be regarded as different sides of the

same coin, according to de Lorenzo.

Synthetic biology does not appear to be essentially

dependent on systems biology—indeed, though it did not

yet have the fashionable name, it can easily be argued that

synthetic biology started long before molecular systems

biology. Although synthetic biologists want to modify, engineer

or redesign a system for their ends, they would not

understand—or need to understand—the system fully before

being able to modify components of it, according to Luis

Serrano (Centre for Genomic Regulation, Barcelona, Spain).

Their metier ultimately has to do with subsets of the whole,

and howchanging these parts has an effect on the outcome of

a reduced system whose starting assumptions might be very

different from a natural system. Even individual molecular

machines are fair game for synthetic biology: Jason Chin

(Medical Research Council, Laboratory of Molecular biology,

Cambridge, UK) presented a synthetically adapted ribosomal

translation system capable of reading a completely novel

genetic code (even quadruplet instead of triplet codons), and


of integrating unnatural amino acids into a growing polypep-

tide chain.

Synthetic biology seeks to identify parts of a system that

can be used. In this sense, the behaviour of these parts

seems to be more important than the integration of their

properties to understand the whole organism in which they

naturally reside. In support of this notion is the fact that (as

Cassman noted) we are not yet able to model a complex

signal transduction pathway, let alone a cell. And yet synthetic

biology is still marching ahead. Also, systems biology seeks to

produce models, yet as all scientists know, models are

inaccurate, even ‘wrong’. Synthetic biology seeks to produce

concrete measurable outcomes, tailored to an aim. The aim is

decided in advance, and the system tweaked until it reaches

that aim. That the underlying model from the natural system is

in some way ‘wrong’ seems less important, because the aim

of synthetic biology is not necessarily to mimic natural

‘correctness’ anyway.

Synthetic biology certainly has the air of a sophisticated

evolution of biotechnology into very targeted strategies: a

concept that currently relies on the identification, re-use or

adaptation of existing systems or parts of systems—

‘biobricks’ as some people call them. But as Victor de

Lorenzo, remarked ‘I am not sure that synthetic biology is a full

discovery’.

Societal concerns, education and politics

As far as they are articulated, the societal concerns about

systems and synthetic biology certainly concentrate around

the latter rather than the former. But are the ethical and

societal concerns surrounding synthetic biology anything

new? Probably not, as de Lorenzo also emphasised: ‘This has

all been thoroughly thrashed out in the GMO debate for years;

there is nothing new to say in my opinion’. And yet an

interesting additional phenomenon might well have occurred:

having identified a parallel between synthetic biology and

electronic systems or engineering concepts, many scientists

describe synthetic biology in those terms. They claim that if

the workings of the individual modules are well enough

understood, they can be defined as ‘blocks’ that could be built

together in various ways to produce larger systems with

predictable (desirable) behaviours, products or outcomes.

However, if the systems in question exist inside an

organism capable of replication and reproduction, the

hardware (proteins and other biological molecules) is not

really ‘hard’: it is produced from software (genetic code) that

can mutate from one generation to the next. Hence, the well-

defined synthetic ‘building blocks’ of a novel self-replicating

organism would (in the absence of a control or in-built fitness

disadvantage) be as malleable as natural living systems, and

theoretically capable of mutation and evolution. In Danchin’s

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view, however, artificial ‘cell factories’ will age, lose informa-

tion, eventually become defunct and need to be ‘rebuilt’

(genetic replication accumulates errors; only reproduction

can renew the system, he impressed on us): what better

safety control mechanism? But the extent to which the public

believes that novel synthetic organisms would simply perish,

or be eaten, outside the lab is not in the hands of scientists

and their technical arguments; however true these might be.

As with the public resistance to the principle of genetic

modification, it is largely about perception and values.

However we view the social meaning and impact of

systems biology and synthetic biology, the needs of their

practitioners in future generations of scientists are clear—and

they are not currently being met. As Marvin Cassman

remarked, ‘we need much better training of biologists in

mathematical tools, otherwise biology will be left to engi-

neers’. ‘Biology is seen by people as a way of doing science

without doing mathematics’. And mathematics in turn is used

to ‘sort people out’ and exclude them from the more

mathematics-dependent areas of biology. This is a wrong-

headed strategy. ‘We need smart ways of getting round the

complexity of the systems with the most simple models of

them’ asserted Thomas Lemberger. These ‘smart ways’

involve novel insights and mathematical modelling, and that

area in turn must not exclude the very people who understand

the biology best: the biologists.

One could include this in a larger approach to the provision

of suitable education for everyone in society: enabling

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appropriate societal input into technology development,

regulation and exploitation and derivation of personal benefit.

But as Helga Nowotny (European Research Council, and

Vienna Science and Technology Fund, Austria) concluded

sanguinely ‘(in Europe) we have been overwhelmed with

organisational aspects of the Bologna Process, and taken our

view off the content of educational programmes. . . the

importance of the mixing of art and science’. ‘Politicians

must not be overestimated as to how much they can absorb,

understand and act on; instead we need intermediate

institutions that represent the prospects, needs and concerns

of science and technology and society. Do not put too much

hope on enlightened politicians. They exist, but they are rare.’

In conclusion, whether systems biology and synthetic

biology truly represent paradigm shifts is less important than

the impression that each is a rapidly developing endeavour on

the verge of producing tangible products for society. Society at

large does not really care about paradigms and their shifts.

The benefits for health will, inevitably, touch society in wealthy

nations first. In relation to synthetic biology, the public that

says ‘do we really need this?’ will probably start to consume

the technology without batting an eyelid when the first

personally useful and desirable products emerge on the

market—as continues to be predicted of genetically modified

food. And the question of the origin of life?Well, thatmight well

remain a mystery forever, but in the meantime it continues to

inspire both science and technology, and some of the most

creative thinkers in these disciplines.


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A day of systems and synthetic biology for non-experts : Reflections on day 1 of the EMBL/EMBO joint conference on Science and Society