Part I--Genetic Fortune-Telling
The Great Unraveling

Mike Field
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Staff Writer

     The recent discovery in a Hopkins lab of a gene that seems
to inhibit antisocial behavior and extreme sexual aggressiveness
in mice (see page 1) is not the first instance where scientists
have claimed to isolate behavioral activity encoded in DNA.
Previous studies have identified genes thought to contribute to
obesity and homosexual behavior.

     Nor is this latest discovery likely to be the last, say
experts. The possibility of a hereditary component in alcoholism,
depression, memory retention and even musical ability has been
hypothesized. As the 23 human chromosomes (see diagram) are
painstakingly unraveled and mapped, gene by gene, it becomes
increasingly likely that specific genetic mutations will be
linked to any number of behavioral variations for good or ill. Do
serial murderers share a common genetic aberration? Are painters
or poets inspired by a strange twist in their DNA? No one can say
for sure.

     What they can say, with a fair degree of certainty, is that
the human genetic code has a profound--and, for now, only
slightly understood--influence not only in how we look, but also
how we act, think and view the world. The fault (or the virtue)
is not, as the poet said, in the stars. It's in ourselves, coded
in the spiraling structure of our deoxyribose nucleic acid, the
ladderlike complex molecule that contains the complete and
detailed recipe of who we are.

     Or, perhaps not.

     For while there are a small number of human diseases
associated with the absence or mutation of one particular gene--
the so-called Mendelian diseases that can be traced in families
using Mendel's laws of genetic inheritance--the bulk of disease,
including most cancers, is the result of the actions of one or
more genes in combination with any number of environmental
factors. Behavioral patterns, say researchers, are probably
similar, with a genetic component that predisposes an individual
to certain responses to given stimuli within a specific
environmental context.

     "When you talk about alcoholism, obesity, homosexuality or
the like, you are talking about highly complex and variable
patterns of behavior," said pediatrics professor Neil Holtzman, a
School of Medicine geneticist with joint appointments in
Epidemiology and Health Policy and Management at the School of
Public Health. "I remain doubtful that we are ever going to find
a single gene directly responsible for most of those who have
these conditions."

     Holtzman is working on the second front of genetic research.
He chairs the Task Force on Genetic Testing of the NIH-DOE
Working Group on Ethical, Legal and Social Implications of Human
Genome Research. The task force is charged with establishing
criteria for safe and effective genetic testing and making
recommendations for assuring the criteria are met.

     Since genes affect--at least potentially--lifestyle as well
as life expectancy, the prospect of a simple blood test that
could be used, say, to identify a predilection to violence has
caused considerable concern, not only in the labs and classrooms
of academia, but also across the nation's editorial pages and
even through the halls of Congress. Who would administer such a
test, and to what purpose? 

     Do individuals--even, hypothetically, potential serial
killers--enjoy an indisputable right to genetic privacy? Should
someone genetically predisposed to breast cancer or Alzheimer's
or depression be given the same job opportunities as someone
genetically predisposed to live to an advanced age in perfect
health? Should their health insurance cost more?



Understanding DNA
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Getting Down 
to the Basics

     Although genetics may be confusing to many, most of us
display an implicit concept of heredity when we say, "She's got
her mother's eyes and her father's nose." Understanding how genes
work is really just an elaboration of this fundamental
perception.

     Genes are the basic unit of human heredity. Best thought of
as recipe files, each gene contains directions on how to create
one specific protein, the building blocks from which the human
body is composed. The human genome--that is, the sum total of all
genetic material defining the characteristics of human beings--is
thought to contain at least 100,000 genes, most of which have not
yet been identified.

     Take almost any cell in your body--a bit of skin, or a drop
of blood or a piece of hair--and within that cell's nucleus you
will find every single gene needed to define who you are. These
genes are contained in chromosomes. There are 23 pairs of
chromosomes in each cell nucleus; they contain every gene needed
to create and maintain life. Chromosomes vary in appearance,
content and function and can be separated and identified with a
high-power microscope. When scientists talk about "chromosome 9,"
they are referring to the same chromosome, with genes that serve
the same purposes, in every human being.

     Each chromosome is composed of a tightly coiled strand of
DNA combined with protein. DNA, or deoxyribose nucleic acid,
looks remarkably like a long ladder, with two side rails and
rungs between them, that has been twisted just like a piece of
licorice. The DNA pictured above is in the process of replicating
itself into two identical strands, the basic process in cell
division.

     The side rails of DNA are composed of sugar and phosphate
molecules in a regular pattern; they are connected by "rungs"--
called base pairs--consisting of either adenine and thymine (A-T)
or cytosine and guanine (C-G), which are nitrogen-containing base
molecules.

     If you imagine DNA as an incredibly long ladder, every so
often--say from rung 100 all the way to rung 1,000--a section has
a specific function: these are genes. A gene is a length of DNA
containing a specific sequence of base pairs (or rungs); genes
vary tremendously in length, and often contain thousands of base
pairs (the entire human genome is estimated to contain 3 billion
base pairs). Genes along the strand of DNA are often separated by
sections whose functions aren't currently understood.

     The task of the Human Genome Project is to sequence--that
is, to determine the order of the base pairs--each chromosome and
thus every gene in the human body. 

     Why? By mapping the normal sequence of each gene, mutations
can be identified and, it is hoped, associated with specific
diseases, physical characteristics or even behavioral patterns.
Interestingly, the Human Genome Project is not directed to
discovering the purpose or function of each gene, but only its
location and base pair sequence; it will be up to other
scientists in future research to determine the function of the
100,000 or so genes in the human body.
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     Like a genie in a bottle, the $3 billion project to identify
and locate every human gene--known as the Human Genome Project--
offers the prospect of untold knowledge with far-reaching,
perhaps unimaginable, consequences. Yet like the genie, there is
a sense of lurking danger associated with unraveling nature's
fundamental design code, the feeling that while knowledge may be
power, it is a power we may not know how to wield in a way that
will better most people's lives. 

     So strong has been the sense of discomfort that the Human
Genome Project has, from the start, carried money within its
budget to provide for research into the moral and ethical issues
associated with the research outcomes. Initially funded at 3
percent of the NIH's annual Human Genome Project budget, the
commitment to ethical investigation was subsequently raised to 5
percent, partly because members of Congress became uneasy with
some of the results research was suggesting.

     Part of that sense of unease lies within the cumulative
nature of scientific discovery. In order to prevent or treat
genetic diseases it is first necessary to identify the gene, in
much the same way that the existence of microbes and bacteria had
to be demonstrated before antibiotics could be developed. 

     "There is a natural trajectory," said Holtzman, "where you
develop the ability to test before you develop the ability to
treat. This is the area where issues of genetic discrimination
and other problems arise."

     Unfortunately, identifying the genetic basis for such late
onset diseases as Alzheimer's or ALS--diseases that, currently,
have no effective treatment--means that potentially thousands of
Americans could be told they were going to come down with an
untreatable ailment years or even decades before the disease
begins to manifest itself. However, even this scenario fails to
encompass the full complexity of the issues at stake.

     "If genetic testing becomes widespread there will be a
certain number of false negative tests, where people are assured
they are not at risk but will manifest the problem nonetheless,"
Holtzman said.  "This is simply because it is unlikely we will
ever be able to detect every possible genetic variant or possible
problem. Only a handful of those affected with any of these
problems will have a major gene that increases susceptibility,
and for which a test can be devised."

     Yet the false negatives are, in all probability, the lesser
problem when compared with the implications of how a false
positive test can affect an individual's choices for the future. 

     "One major problem that many people, including physicians,
do not understand is that mutations do not necessarily lead to
disease," Holtzman said. "Even if a mutation is detected, the
person may simply never develop the illness [or the behavior
patterns] associated with the gene. This leaves us with a very
difficult question of what are we to do with these positive test
results? They may be very helpful as a confirmation of a
diagnosis, but many questions remain about their values in
predicting risks in healthy people."

     How, then, should genetic testing be implemented, and how
should we respond?


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Next:
     As the number of genetic tests grows, so do the
possibilities for discrimination, misdiagnosis and
misinformation. Genetic counselors on the front lines in Part II
of "Genetic Fortune-Telling."
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