U.S. Department of Health

& Human Services 

National Institutes of Health 

National Institute on Alcohol Abuse 

and Alcoholism 

Number 75 April 2008 

SYSTEMS BIOLOGY: 

The Solution to Understanding 

Alcohol-Induced Disorders? 

In 2001, scientists finally cracked the code that reveals the 

complete genetic blueprint of the human body (the human 

genome) (1,2). With this genetic blueprint in hand, they 

hoped to be able to better understand and treat illnesses that 

affect millions of people worldwide, such as lung diseases, diabetes, cancer, obesity, Alzheimer’s disease, and alcoholism (3). 

The new map of the human genome has provided researchers 

with enormous amounts of information about how the body 

works on a molecular level, which already has led to great 

progress in understanding how the body functions in health 

and illness. However, many questions, particularly about 

complex diseases such as alcoholism, remain unanswered. 

The human genome catalogs the distinct genetic parts of 

the human body, but it does not reveal the intricate ways 

in which these parts and others (such as transcriptome, proteome, metabolome, etc. [see below for definitions of these 

terms]) function together. To understand such complex phenomena as alcohol addiction, it is not enough to understand 

how individual molecules—for example, those involved in 

communication networks in the brain—interact, or even 

how they are affected by alcohol. Instead, scientists also must 

understand how a system of these molecules—for example, 

the brain as a whole—functions. How do other influences 

such as alcohol exposure produce their complex effects on 

and far-reaching consequences for the body? Systems biology 

is a new field that makes use of advanced technology to 

explore how the parts of the human body work together, in 

health and disease, as a synchronized whole. 

Systems biology is especially relevant to alcoholism, a multifaceted disease that involves many interrelated and interacting mechanisms. Systems biology approaches provide tools 

that can help researchers better understand how alcohol 

affects various body tissues and how the resulting changes 

lead to the development of addiction to alcohol and organ 

damage. This new information also has the potential to help 

researchers develop better and more targeted medications 

for alcohol-induced disorders (3). This Alcohol Alert describes 

how systems biology might be applied to alcohol research. 

It examines this innovative approach and suggests ways in 

which it can lead to practical, targeted treatment interventions for alcoholism. 

What Is Systems 

Biology? 

How is a systems biology approach 

different from approaches scientists 

have used in the past? Traditionally, 

researchers have focused on individual 

molecules and their interactions. 

Systems biology’s difference—and 

its advantage—is that it integrates 

this research to examine larger 

“ Systems biology is a new field that 

makes use of advanced technology to 

explore how the parts of the human body 

work together, in health and disease, as a 

synchronized whole.” 
systems as a whole. Dr. Hans Peter Fischer 

(2008) compares the human body to a passenger jet plane (see figure at right) (3). Both consist 

of many individual parts—whereas the body 

is made up of billions of individual molecules 

and cells, a plane may include thousands of 

screws, cables, wheels, and other diverse elements. Dr. Fischer notes that, although it is 

not possible to understand the workings of a 

jet plane without a catalog of these parts, simply identifying them will not describe how a 

jet plane works. Only by exploring how they 

interact—how the mechanical parts are connected by wires with electronic components 

and how flipping one switch affects the movement of different parts—is it possible to 

understand complex processes such as takeoff, 

navigation, communication, or landing, or 

problems with these processes. Similarly, 

although it is necessary to identify the genes, 

proteins, and cells that make up the human 

body, knowing how each part functions will 

not explain how body systems work or the 

diseases that affect them. Rather, it is necessary to understand how these parts work 

together to create complex effects that are 

larger than the sum of their parts. 

“–Omics” Technologies: 

The Driving Force 

Behind Systems Biology 

The systems biology approach has been made possible by 

two developments: the complete sequencing of the human 

genome and recent technological advances known collectively 

as “–omics” technologies. These technologies—which most 

prominently include genomics, proteomics, and metabolomics, 

described below—enable researchers to study hundreds of 

samples or molecules in a cell simultaneously. 

Genomics approaches are concerned with the activity and 

function of the complete genetic content (i.e., the genome) 

of a cell, organ, or organism. One example is the National 

Institutes of Health (NIH)-sponsored Collaborative Study on 

the Genetics of Alcoholism (COGA), in which researchers 

are collecting data from hundreds of families with or without alcoholism (4). COGA will compare hundreds of genes 

in people with and without alcoholism; the resulting information eventually may allow investigators to identify gene 

variants that put people at risk for developing alcoholism. 

Similar studies in laboratory animals that differ in how 

sensitive they are to alcohol’s effects already have identified 

some DNA regions that may influence the animals’ response 

to alcohol (4). 

However, it is important to know not only which gene 

variants are found in a person but also how active these 

genes are. Although all cells contain the same set of genetic 

information, not all genes are active in all cells at the same 

time. For example, some genes are active only in brain cells, 

and others only in liver cells. Scientists now can routinely 

analyze the expression of tens of thousands of genes simultaneously. Such studies already have found that in the 

brains of alcoholics, the expression of certain genes in various brain regions differs from those in nonalcoholics (4). 

Proteomic studies examine the 

structure and functions of all the 

proteins1 found in a cell, organ, or 

organism. In alcohol research, such 

1

Y1

Y3

Y2

Y4

10

R2

R3

R4

R5

C1

C2 C3

2 11

3 12

4 13

5 14

6 15

7 16

+2.5V

+2.5V +2.5V

8 17

9 18

“Scientists now can routinely analyze 

the expression of tens of thousands of 

genes simultaneously.” 

Mapping Complex Systems 

A B 

Like a modern jet plane (A, top), the human body 

consists of many parts. A technical blueprint for a 

microchip (A, bottom) catalogues some of the parts in 

a jet plane, and helps engineers to understand complex 

processes known as emergent properties—for example, 

takeoff and landing. Similarly, a map of a human liver 

cell (B, bottom), catalogues the complex network of 

biochemical reactions within liver cells (B, top), and 

helps alcohol researchers understand such emergent 

properties as detoxification within the liver. 

1 Proteins are large molecules produced from genetic 

information stored in DNA.

2
 
studies can potentially help investigators to understand how 

chronic alcohol abuse affects the body. For example, in 

alcoholics, changes in brain function contribute to physical 

dependence, craving for alcohol, and reduced sensitivity to 

alcohol’s effects (i.e., tolerance). These changes likely occur 

because certain proteins in the brain are produced at higher 

or lower levels than normal, allowing the brain to adapt to 

the constant presence of alcohol in the body. If researchers 

can identify the proteins that are involved in these processes, 

it may help them to develop new treatment strategies for 

alcoholic patients (5). 

Metabolomics is the study of small molecules (i.e., metabolites) that are produced when larger molecules, such as proteins and fats, are broken down or transformed into other 

molecules in the body. The levels of these metabolites 

change in response to certain signals, both 

from within the body and from influences 

outside the body. For example, excessive 

alcohol use can lead to a disruption in fat 

metabolism, contributing to the development 

of early stages of liver disease (i.e., fatty liver) 

(6). Metabolomic approaches that determine 

how exactly alcohol interferes with fat metabolism may help researchers develop safe medications to treat these disruptions and the 

resulting liver disease (6). 

Together, the –omics technologies have allowed 

researchers in the alcohol field and other areas 

to gather enormous amounts of information 

about the workings of the cell on the molecular 

level. However, –omics technologies also create 

considerable challenges. Can scientists determine how these diverse and complex systems 

of genes, proteins, and other “parts” fit together? 

The answer to this question lies in another 

integral component of systems biology: the 

development of mathematical models and 

computer simulations. 

Mathematical Models 

and Computer 

Simulations 

To interpret the enormous amounts of data 

generated by –omics technologies, systems 

biologists can incorporate these data into 

mathematical equations that model how parts 

of the cell interact. Using these equations, 

researchers are attempting to predict how a 

biological system functions under various conditions, or how it would respond, for example, 

to a potential new drug. The equations are so 

complex, however, and the amount of data so 

extensive, that it generally is not possible to 

solve them “manually”; instead, researchers use computer 

simulations, or models, to solve them (3). Computer models are especially useful because they can incorporate data 

from many types of experiments, including experiments 

done in test tubes, cell cultures (i.e., groups of cells grown 

outside of the body), and animal studies (7). 

There are several advantages to using computer models. 

Computer models (or “dry experiments”) often are less 

expensive and time-consuming than biological experiments 

(or “wet experiments”). Mathematical models from dry 

experiments can suggest new avenues of research that experimental biologists can then test in new wet experiments. 

Conversely, theoretical biologists can incorporate the additional data from the new wet experiments to further refine 

the models (see figure below) (3). 

Systems Biology Approaches 

Biological phenomenon 

Experimental data 

(Experimental determination 

of structures, functions, 

and interactions) 

Mathematical model 

Hypothesis 

New data New data 

Wet 

experiment 

(laboratory 

experiment) 

Dry 

experiment 

(computer 

simulation) 

Systems biology allows researchers to combine approaches 

in exploring biological phenomena. Data are integrated 

into mathematical models that help to generate new 

ideas (or hypotheses) about how the body works.These 

hypotheses are tested using both “wet experiments” 

that take place in the laboratory and “dry experiments,” 

or computer simulations.These experiments generate 

new data that can help researchers form new hypotheses 

and refine their mathematical models. 

3
 
Advantages of a Systems 

Biology Approach 

Systems biology allows scientists to integrate data from different experiments, revealing complex properties that may 

not be apparent from any single experiment and to integrate and interpret enormous amounts of information 

about how the human body functions. Systems biology 

allows researchers to examine body functions on many 

levels of complexity, from how the body “reads” DNA 

information to produce various proteins to changes that 

occur in behavior. 

Alcohol and Systems Biology 

Drs. Q. Max Guo and Sam Zakhari (2008) observe that 

“alcoholism is indeed a systems biology disorder” (8). 

Alcohol exerts complex effects on many levels: individual 

molecules, cells, and organs, and even a person’s behavior. 

Many of these effects, such as organ damage and alcohol 

dependence, are the result of a variety of interdependent 

factors (3). Examining alcohol’s effects on only one level 

(e.g., the molecular level) reveals only a piece of the puzzle. 

For example, simply examining alcohol’s relationship to a 

single gene or even a group of genes provides only a fragmented view of a complex picture. On the other hand, 

systems biology gives scientists a means to obtain a more 

comprehensive picture of how alcohol affects body systems 

and behavior. 

Applications of Systems 

Biology in Alcohol Research 

Modeling alcohol’s effects during fetal development—Alcohol consumption by a pregnant woman poses 

a hazard to the health and development of her unborn 

child. Depending on the timing and amount of alcohol 

consumption during pregnancy, the effects on the children 

range from subtle deficits in brain function (e.g., slight 

learning disabilities) to a condition called fetal alcohol syndrome, which features characteristic facial abnormalities, 

growth retardation, and brain damage (9). Researchers 

already have learned a great deal about how maternal alcohol consumption leads to these birth defects. Much of this 

research has focused on alcohol’s effects on the developing 

brain, such as the formation of new brain cells and the 

Systems Biology Lexicon 

DNA (deoxyribonucleic acid): The molecule that 

carries the genetic code in all organisms except some 

viruses. 

Emergent properties: The characteristics of a 

complex system that arise when various components 

interact. 

Genome: The entirety of all genes of an organism. 

Genomics: The study of the structure and function 

of an organism’s complete genetic content, or genome. 

Metabolite: The intermediary products generated 

when the body breaks down a particular molecule. 

Metabolome: The entirety of all metabolites present 

in a given cell, tissue, or organism. 

Metabolomics: The study of small molecules (i.e., 

metabolites) that are produced when larger molecules, 

such as proteins and fats, are broken down or transformed into other molecules in the body. 

Protein: The large molecules produced from genetic 

information stored in DNA. 

Proteome: The entirety of all proteins of a cell, 

tissue, or organism. 

Proteomics: The large-scale study of the structure 

and functions of proteins. 

Transcriptome: The entirety of all mRNA molecules 

(i.e., messenger RNA, the key intermediary between 

DNA and proteins) present in a cell, tissue, or organism. 

Transcriptomics: The large-scale study of the expression of mRNAs in a given cell, organ, or organism. 

wiring that occurs among these new cells. However, many 

questions remain—for example, how do different levels of 

alcohol consumption at different times during pregnancy 

affect the developing brain? Systems biology approaches 

may help to fill this knowledge gap (7). 

Because researchers cannot directly study alcohol’s effects 

on human fetal development they rely on laboratory animals. Yet the brain structure and development differ 

between mice, rats, monkeys, and humans. To address these 

differences, researchers have developed 

computer models that integrate different types of data on how alcohol 

affects normal rodent or monkey brain 

development. Researchers then can 

compare these models to what is 

known about fetal brain development 

in humans, enabling them to translate 

research findings from other species 

into information that is useful for pre­

“Systems biology gives scientists a 

means to obtain a more comprehensive 

picture of how alcohol affects body 

systems and behavior.” 

4
 
 

dicting alcohol’s effects on humans (7). In particular, such 

models might help researchers determine the effects of even 

low levels of maternal alcohol consumption on the developing fetus (7). 

Understanding alcoholic lung disease—Alcohol abuse 

has long been known to increase a person’s risk of developing pneumonia. However, recent studies found that it also 

increases a person’s risk of a severe form of acute lung injury 

called acute respiratory distress syndrome. Scientists estimate 

that in the United States, tens of thousands of deaths occur 

each year from alcohol-related lung injury (10). Systems 

biology approaches may help researchers to determine how 

alcohol produces such devastating lung damage. These 

approaches may be instrumental in identifying the genes 

and proteins that are altered in the lungs of alcohol-exposed 

animals as compared with animals that have not been 

exposed to alcohol (10). Eventually, systems biology approaches 

may help identify new strategies for treating people with 

alcoholic lung disease (10). 

Exploring alcohol-related brain disease—The brain is 

particularly vulnerable to excessive alcohol use. Alcoholics 

often exhibit problems with memory, learning, planning, 

and other advanced brain functions. In severe cases, they 

may even develop dementia. To date, systems biology 

approaches have not been used specifically to study alcoholrelated brain disease. However, systems biology studies 

already have helped expose the mechanisms contributing 

to other brain disorders, such as Alzheimer’s disease. 

Researchers have identified some genes involved. Systems 

biology also has helped identify molecules that can be used 

to more accurately diagnose people with Alzheimer’s, even 

in its early stages (11). 

Enhancing drug discovery and development—The traditional 

process for developing, testing, and obtaining approval for 

a new drug is time-consuming and expensive—the process 

can take more than a decade and cost as much as $900 million (12). Researchers expect that systems biology will help 

to streamline this process, making drug development more 

efficient. In particular, computer simulations of diseases 

will allow researchers to use dry experiments to assess the 

potential safety and effectiveness of new drug candidates. 

Recently, a number of pharmaceutical companies have 

begun systems biology programs to support drug discovery 

and development (13). 

At the same time, publicly and privately funded initiatives 

and consortia have brought together researchers from 

diverse disciplines—such as biology, genetics, biochemistry, 

physics, mathematics, computer sciences, statistics, and 

engineering—to contribute to a systems biology approach 

to treating disease (3). For example, NIH’s new Roadmap 

for Medical Research includes an initiative on Bioinformatics 

and Computational Biology, which seeks to create a national 

software engineering system to allow biomedical researchers 

to collect and evaluate large amounts of data. This initiative 

brings together scientists from across the country, enabling 

them to share and analyze data using a common software 

system (14). 

Conclusion 

With the decoding of the human genome, researchers 

gained access to extensive information about the molecules 

in the body, how they function in the healthy organism, 

and how they may contribute to certain diseases. However, 

despite this wealth of information, many questions remain 

about the ways in which these molecules interact to control 

more complex phenomena, including the development of 

many common disorders. Systems biology offers scientists 

a promising tool with which to deal with such complexities 

and may revolutionize the prognosis, diagnosis, and treatment 

of alcohol use disorders and other multifaceted disorders. 

These new approaches provide researchers with new opportunities to work together, share data, and use computer 

technology and mathematical modeling to steer research 

in exciting new directions. 

References 

(1) Landers, E.S.; Linton, L.M.; Birren, B.; et al. Initial sequencing and 

analysis of the human genome. Nature 409:860–921, 2001. PMID: 

11237011 (2) Venter, J.C.; Adams, M.D.; Myers, E.W.; et al. The 

sequence of the human genome. Science 291(5507):1304–1351, 

2001. PMID: 11181995 (3) Fischer, H.P. Mathematical modeling of 

complex biological systems: From parts lists to understanding systems 

behavior. Alcohol Research & Health 31(1):49–59, 2008. (4) Sloan, 

C.D.; Sayarath, V.; and Moore, J.H. Systems genetics of alcoholism. 

Alcohol Research & Health 31(1):14–25, 2008. (5) Hiller-Sturmhöfel, 

S.; Sobin, J.; and Dayne Mayfield, R. Proteomic approaches for studying alcoholism and alcohol-induced organ damage. Alcohol Research 

& Health 31(1):36–48, 2008. (6) Harrigan, G.G.; Maguire, G.; and 

Boros, L. Metabolomics in alcohol research and drug development. 

Alcohol Research & Health 31(1):26–35, 2008. (7) Gohlke, J.M.; 

Hiller-Sturmhöfel, S.; and Faustman, E.M. A systems-based computational model of alcohol’s toxic effects on brain development. Alcohol 

Research & Health 31(1):76–83, 2008. (8) Guo, Q.M.; and Zakhari, 

S.D. Commentary: Systems biology and its relevance to alcohol 

research. Alcohol Research & Health 31(1): 5–11, 2008. (9) Stratton, 

K.; Howe, C.; and Battaglia, F., eds. Fetal Alcohol Syndrome: 

Diagnosis, Epidemiology, Prevention, and Treatment. Washington, 

D.C.: National Academy Press, 1996. (10) Kershaw, C.D.; and Guidot, 

D.M. Alcoholic lung disease. Alcohol Research & Health 31(1):66–75, 

2008. (11) Pasinetti, G.M.; and Hiller-Sturmhöfel, S. Systems biology 

in the study of neurological disorders: Focus on Alzheimer’s disease. 

Alcohol Research & Health 31(1):60–65, 2008. (12) Service, R.F. 

Surviving the blockbuster syndrome. Science 303(5665):1796–1799, 

2004. PMID: 15031490 (13) Mack, G.S. Can complexity be commercialized? Nature Biotechnology 22(10):1223–1239, 2004. PMID: 

15470456 (14) Kantor, L.W. NIH roadmap for medical research. 

Alcohol Research & Health 31(1):12–13, 2008. 

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▲

R e s o u r c e s 

Source material for this Alcohol Alert originally appeared in the issue of Alcohol Research & Health 

that examines the topic of systems biology. 

Alcohol Research & Health, Volume 31, Number 1, 2008. This issue describes 

the discipline of systems biology and explores how its approaches can benefit 

alcohol research. Articles highlight the genetics of alcoholism, the study of 

metabolomics and proteomics, and the use of mathematical modeling in 

systems biology. Other articles show how scientists are putting systems 

biology approaches into practice in the study of alcohol-related disease. 

Full-text articles from each issue of Alcohol Research & Health are available 

on the NIAAA Web site at http://www.niaaa.nih.gov. 

Subscriptions to Alcohol Research & Health are available from the 

Superintendent of Documents for $25.Write to New Orders, Superintendent 

of Documents, P.O. Box 371954, Pittsburgh, PA 15250–7954; or fax 

202/512–2250. 

Full text of this publication is available on NIAAA’s World Wide Web site at www.niaaa.nih.gov. 

All material contained in the Alcohol Alert is in the public domain and may be used or reproduced 

without permission from NIAAA. Citation of the source is appreciated.
 

Copies of the Alcohol Alert are available free of charge from the National Institute on Alcohol Abuse and Alcoholism
 

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