By Harvey
A. Bender
Patricia had missed her first two appointments at the Genetics
Center, but her dad assured us she'd be there this time. We scheduled
her as our last patient of the day -- just in case she'd be a
no-show again. She had been referred by her family physician,
who believed she might be manifesting early signs of Huntington's
disease (HD), a neurodegenerative disorder that is incurable and
always fatal.
HD is inherited as a dominant genetic disorder -- a single gene
passed from either parent will result in the development of this
disorder. But those who inherit this gene rarely show any visible
symptoms before reaching middle age. In fact, typically about
50 percent of those who inherit this gene will be free of any
discernible neurological impairment until their fifth or sixth
decade of life. Although representative of a group of genetic
conditions known as late-age-of-onset disorders, HD -- once initiated
-- culminates over the next 15 or 20 years in ever-increasing
debilitation, dementia and ultimately death. It certainly isn't
surprising that individuals diagnosed with HD commit suicide at
a very high rate.
Until the past decade, the diagnosis of the onset of HD was
based solely upon neurological examinations. The accuracy of such
diagnoses varied markedly when focusing upon patients in the earliest
stages of the disease. However, this situation changed dramatically
when the tools of molecular genetics, developed in concert with
the Human Genome Project, could definitively identify the HD gene.
Pat, a 38-year-old single mother, did make her scheduled appointment.
She was joined by her father, Pete, and her two daughters, Pearl,
9, and Paula, 12. The girls each had different biological fathers,
who were no longer involved with the family. We reviewed Pat's
medical and family history carefully, including the neurological
report of her family physician.
The previous Christmas Pat's mother had died at age 68 of HD,
almost 16 years after she had been first diagnosed. Observing
a family member suffering from the relentless progression of this
disease had had a profound and agonizing effect upon all members
of Pat's immediate family. Clearly Pat was quite knowledgeable
about HD and was both convinced of her diagnosis and totally resigned
to the devastating fate of developing HD. "I saw what happened
to my mother," she told me. "I know it'll happen to me just the
same."
Pat was adamant that she did not wish to undergo genetic testing.
"I just don't need to know if the test says I've got it," she
said. "I need to keep my job, and I need to have my medical insurance,
too." I assured Pat that the results of the testing would be totally
confidential -- guaranteed so by federal and state regulations.
What I didn't expect was her next comment. "But the girls need
to know -- I want the girls to know. I want Pearl and Paula to
be tested right now!"
Because of the potential impact of this knowledge on a youngster's
life, geneticists are reluctant to provide HD testing for minors
unless there is a compelling medical reason, such as specific
neurological symptoms in the child. Pat insisted, arguing that
she was hoping her sister would consider adopting Pearl and Paula
but knew her sister would do so only if they did not
possess the HD gene. "She won't take 'em if they have it," she
said, and she wanted to have the girls tested so she could plan
for their future while she was still competent to do so.
I struck a deal with Pat. "Let's test you for the HD gene with
the DNA test that's now available," I suggested. "If you're confirmed
'positive,' we'll then consider all the reasons why you should
or should not go forward with the testing of the girls." With
considerable reluctance, she agreed. A blood sample was obtained
and shipped off to the diagnostic laboratory.
Prior research had shown that the HD gene is part of a class
of genetic disorders known as "expanded repeats." In other words,
the DNA molecule of the HD mutation was found to be lengthened,
in comparison with the normal counterpart of the HD gene, by having
extra bases (steps) at one end of the DNA double helix. By ascertaining
the pattern and number of such "repeats" of the HD gene in individuals
at any age before or after birth, highly accurate confirmation
of the condition can be established (even though such individuals
may remain totally non-symptomatic for several subsequent decades).
So the lab was looking for such "repeats" in the DNA of Pat's
blood.
Six weeks later Pat returned to the clinic, and we shared the
results. The DNA test showed that the number of expanded repeats
in the region of the HD gene was well within the range of a "normal"
individual. She was not a carrier of the HD gene. And
I was off the hook about testing Pearl and Paula.
Now I look forward to receiving the annual photo from Pat and
the girls each Christmas. The girls are in high school and doing
nicely, and Pat is an avid motorcyclist.
Arguably, the three most significant biological landmarks of
the past 150 years are Darwin's articulation of the theory of
evolution (1859), the modeling of the structure of DNA (1953)
and the culmination of the Human Genome Project (HGP) with the
elucidation of the chemical sequence of the human genome (2001).
Indeed, the significance of the first draft by the HGP has been
so far-reaching that it has been referred to as the Holy Grail
of genetics. We have since been deluged by streams of magazine
and newspaper articles heralding a new era of medical advances.
It is suggested that the knowledge gleaned from the HGP will most
certainly reshape biomedicine and, in the rosiest speculation,
will mark the beginning of the end of human disease -- either
through the substitution of a normal gene for one that was defective
(gene therapy) or by the alteration of a missing or flawed gene
product critical for normal development or proper metabolism.
Not surprisingly, a whole new industry, predicated upon the
fervent belief in engineering better living through genetics
has developed -- an industry directed and thus legitimized in
great part by the very scientists whose studies in the nature
and structure of DNA made all this possible. Medical practice
is already benefiting from new and more powerful diagnostic tools
drawing on the knowledge provided by the HGP. Newborns are now
being screened for an ever-enlarging spectrum of possible genetic
disorders, ranging from relatively common conditions such as sickle
cell disease and cystic fibrosis to rare metabolic flaws. These
early diagnoses, often prior to the development of any symptoms,
are providing the opportunity for early therapeutic interventions
and, in many instances, markedly improved outcomes.
We are likely to achieve the capacity to fully recognize genetically
conditioned health risks within a decade. However, the capacity
to directly replace "aberrant" genes (gene therapy) will require
a significantly longer period of time. Francis Collins, director
of the National Human Genome Research Institute, rather optimistically
estimates that "by 2010 screening tests will enable anyone to
gauge his or her unique health risks, down to the body's tolerance
for cigarettes and cheeseburgers, and by 2050 many potential diseases
will be cured at the molecular level before they arise."
Whatever the exact time period, society is in a unique position
now, before the full implementations of these powerful technologies
are upon us, to consider some of their awesome potentials. We
are at the threshold of one of the most significant technologies
ever developed and have been accorded the opportunity to reflect
upon some of the significant social and personal implications
of the new genetic technology before its full actual implementation.
As science journalist Matt Ridley explained, "I began to think
about the human genome as a sort of autobiography -- a record,
written in 'genetish,' of all the vicissitudes and inventions
that had characterized the history of our species and its ancestors
since the very dawn of life. . . . In just a few short years we
will have moved from knowing almost nothing about our genes to
knowing everything. . . . We stand on the brink of great new answers
but, even more, of great new questions."
Some of those questions: How can and how should individuals
and society respond to these advances? Who will most benefit from
such developments? Is it likely that individuals with risks for
developing such abnormal physical or mental conditions as Lou
Gehrig's disease, breast cancer, dyslexia, schizophrenia or attention-deficit
disorder will be identified and thus constitute a genetic "underclass"?
Could genetic discrimination become a common reality? As with
any societal resource, decisions must be made. Who will and who
should determine how such technology is allocated? And, of even
greater concern, what will be the benefits, drawbacks and "costs"
to society's values and beliefs?
Understanding science is a prerequisite for dealing with these
challenging societal implications, and that understanding begins
with DNA. DNA is the genetic material. The image of the
double helix, the structure of this molecule with its paired chains
and cross "steps," is widely known through its representation
in print, popular films and video clips. What's less well known
is that each step on the twisting ladder of the double helix is
a pair of chemical bases. Only four types of such bases exist
in the DNA molecule. Amazingly, all the information required for
the full development of an individual is encoded within those
base pairs or steps. As a result of the completion of the Human
Genome Project, virtually each of the three billion steps
of our DNA molecules has been identified and logged. A full listing
is readily available to anyone on the NIH website www.ncbi.nlm.nih.gov.
That, in short, is the product of the HGP.
The gene is the fundamental unit of inheritance. It
is presently believed that there are 20,000 to 25,000 genes in
our genomes varying in size from several hundred to several thousand
steps. Thus, each of our 46 chromosomes contains a single, long
(one yard) DNA molecule. A complete chromosome set is found compacted
into each microscopic nucleus of virtually every one of the 100
trillion cells of our body. A fertilized egg contains half (23
chromosomes) of its genetic endowment from the mother's egg and
half (23 chromosomes) from the father's sperm.
The term genome refers to the genetic constitution of the egg
or sperm. Thus we possess two genomes in each of our cells. All
of the information required for the development of an individual
is provided by these two genomes. An enormous pool of integrated
information is encoded within the DNA packaged in our 46 chromosomes.
It may be useful to envision the genome as a 23-volume encyclopedia
set containing all of the composite data required for the construction
of a human being, with each individual chromosome representing
a different volume comprised of several thousand entries (genes),
each with specific structural and/or behavioral instructions.
We now believe that there are about 25,000 entries (genes) in
the human genome with the specific "wording" of these entries
crafted with a simple but clever four-letter alphabet formed by
the bases or steps of the DNA molecule. All living organisms use
the same alphabet and share a common, universal code to specify
developmental (constructional) operations. Thus, all the information
required to direct the development of an individual is contained
in the fertilized egg.
We also now possess at least some information regarding half
of our genes, and the pool of information grows on a daily basis.
The Human Genome Project was designed to allow us to identify
our genes and to provide fundamental information regarding their
function. This represents a vast contribution to so-called "pure"
or basic science. But it's important to understand that the justification
for investment of the enormous resources to support the HGP was
an implicit promise of its potential benefit to human health.
In great measure, the primary goal has been achieved. We are close
to identifying all of our genes and their functions. In turn,
that has opened the way for the screening and detection of a growing
list of genetic diseases. Today, cystic fibrosis, sickle cell
disease, Fragile-X syndrome, Duchenne muscular dystrophy, thalassemia
and Tay-Sachs disease are but a small sample of the genetic conditions
that can readily be confirmed in an individual well before birth.
Even though therapeutic interventions are not yet possible for
most of these diseases, this is a necessary first step. At this
time, information gained from the early diagnosis of an affected
fetus can provide the parents the opportunity to prepare medically
and emotionally for the management of a newborn with such a condition.
Tomorrow, it's hoped and expected that therapeutic intervention
will be available to "correct" the abnormal gene -- either by
controlling its aberrant function or by replacing it with a normal
gene.
To predict the direction of future genetic researches, it's
also important to remember now the history of the HGP project
itself. Initially, in 1990, the HGP was conceived as a private,
federal and internationally funded consortium intended to provide
freely shared results. However, significant pressure from private
industry made the program a "race" and then a dual effort, both
publicly and privately funded, to accelerate the pace of the project.
The first "draft" of the Human Genome sequence was reported jointly
in 2001, as was the more complete compendium that followed in
2003. Thus was born the new field of genomics -- the
study of information flow within cells and tissues, with primary
focus upon the organization, function and evolution of our genetic
endowment. Worldwide research activity in both public and private
arenas has been so intense and the flow of information so immense
that a whole new field of bioinformatics has emerged,
armed with sophisticated computer technologies with the primary
mission to "crunch" and decipher the huge bodies of genomic-generated
information.
Without question, both the public and, perhaps even more aggressively,
the private sector will determine the future directions of genomic
researches and, in particular, their applications for human health.
But market forces are likely to play as important a role as science
in those outcomes and the future applications. The HGP has already
spurred wonderful medical advances being implemented in the private
sector. The most obvious advance at this stage has been the enhancement
of our diagnostic capacities and abilities to identify numerous
genetic disorders, creating new diagnostic service providers.
However, special clinical, social and ethical issues have also
arisen. Some are obvious. For example, information about an individual's
genetic makeup of this nature inevitably raises concern about
privacy. To whom does "genomic" information belong? Should data
regarding your genetic health be shared with other members of
your family or with your community at large? Does this information
belong to the insurance carrier who may have paid for the testing?
What about your employer? Could information related to an elevated
risk of a future medical condition adversely affect consideration
for a possible promotion or even result in your dismissal? Will
it compromise future insurability?
Today we are moving toward the creation of a national identity
card. It doesn't take much imagination to envision a truly comprehensive
identity card that would not only have your photo and establish
your residency but also would include a CD containing your very
own DNA sequence. This would at once establish your sole identity,
be difficult if not impossible to counterfeit and, simultaneously,
would be immensely useful in a medical emergency. But giving others
such access to your own personal genetic information certainly
raises concerns well beyond privacy.
For example, what if Pat had been diagnosed with HD? Should
her young daughters be tested? If Pat's test had shown the presence
of the HD gene, would it be wise, or humane, to share those results
with the girls or their extended families, given the dire prognosis?
Because HD is also a very late-acting gene, should testing of
family members of an HD patient be undertaken when no effective
preventive measures can be offered?
Certainly, there are positive values in obtaining genetic information.
But such knowledge may likely influence personal procreative decisions.
Once we have bitten into the apple of genetic knowledge, we may
face issues of choice we never had to confront before. Are we
prepared to enter an era where genetic information not only can
but should be assayed, evaluated and incorporated in marital choices
and family planning?
Current testing for Tay-Sachs
disease -- a fatal wasting neurological genetic condition that
results in the death of an affected child by age 3 or 4 -- has
influenced such decisions by members of high-risk populations.
The abnormal gene responsible for Tay-Sachs disease is found in
all populations but in differing frequencies. The incidence in
the Ashkenazic Jewish population is tenfold that of the population
at large. Among orthodox Jewry, adolescents are required to undergo
testing to ascertain if they carry a single copy of this recessive
gene. Two copies are necessary to produce the disease; thus a
couple who are both gene carriers are at a 25 percent risk of
bearing an affected child. For some couples this is an excessive
risk, for others it may not be. Nevertheless, Orthodox Jewish
rabbis strongly discourage and may even deny the sanctioning of
marriage to a couple who are both carriers of the Tay-Sachs gene.
The results have been impressive -- over the past decade the
birth of Tay-Sachs-affected children in this population has virtually
been eliminated. Is it unethical or possibly even immoral not
to use genetic information in family planning when we know
that such information exists?
Indeed, thanks to a better climate of public awareness, we know
that a good prenatal environment is critical for the development
of the child. We urge concern for proper maternal diet and the
need to provide the fetus with a "smoke-, alcohol- and drug-free
environment." But what about prenatal or pre-prenatal genetic
concerns? Aren't we also obligated to provide society's children
the best possible genetic endowment? As the fruits of the HGP
ripen, allowing us to be ever more knowledgeable about genetic
contributions to our health and development, aren't we and our
health providers obligated to ensure the best possible hereditary
endowment, too? How so? Do we possess sanction to bear children
without concern about their future health and the welfare of future
generations? Shifting the focus, do our progeny have
the right to be born with a "sound mind and body" if possible?
What about society in general? What is society's role
in procreative issues? Since society is often called upon to support
individuals with special needs, should it play a more dominant
role in mandating widespread genetic education? But who is "society"?
Certainly all of us have a significant stake in addressing the
tough decisions the new genetics will present -- the professionals
and nonprofessionals, the young and the old, doctors and patients,
the genetically informed and uninformed, our policy makers and
policy "breakers," those with special and specific agendas. The
recent history of the Terri Schiavo case provides a vivid example
of disparate societal values and competing family, political and
public interests. In turn, this suggests that society is a multifaceted
animal and that coming to consensus or plan of action will be
a significant challenge.
The HGP has markedly accelerated the development of strategies
for the treatment of genetic disease. Gene therapy, the actual
replacement of malfunctioning genes, is in the early stages of
development. Although we currently possess limited capacity to
directly correct or replace an abnormal gene, we are ever more
able to circumvent the ravages of genetic disease at steps away
from the mutant gene, through dietary control or by providing
the missing gene or replacing an aberrant gene-controlled product.
Such intervention has proven highly effective for the treatment
of a growing number of genetic conditions including PKU (phenylketonuria),
and Factor VIII replacement in hemophilia A.
Yet these and other treatment strategies possess potential consequences.
Most notably, are we possibly polluting the human gene pool by
increasing survival rates of carriers of genetic disease by treating
and "curing" them before birth?
We will need to revisit the concept of disease itself, and what
we mean by and define as "normalcy." Most of us would agree that
many serious and life-threatening genetic diseases are "abnormal."
But what about those traits with significant genetic components
that don't directly equate with disease? Traits like physical
appearance, height, behavioral and emotional characteristics,
and cognition all have genetic components as well as environmental
ones. In the near future, we are likely to have the capacity to
choose those traits for our children, to move "nature" closer
to "nurture". Indeed, the current controversies involving performance-enhancing
drugs will seem insignificant in comparison to one focused upon
performance-enhancing genes. Who is and who should be making those
decisions? Are we, as individuals and as members of society, informed,
willing and able to determine how to properly support the "abnormal"
or "exceptional" and to decide what genetic interventions are
both desirable and appropriate?
Where does all this take us? Indeed, despite these awesome challenges,
I'm optimistic. Although our present-day predictive capability
markedly outstrips our capacity to prevent or treat genetic illness,
this gap between the potential and the reality gives us time to
ponder these questions at length and depth. We should rejoice
that human suffering can be alleviated by this knowledge. But
we also will be challenged -- and perhaps are already being challenged
-- to develop and provide new support services to fulfill the
promise offered by the Human Genome Project. That calls for a
new, shared vision of the society we want to become.
We will need a new social policy not made in a laboratory or
by executive order but by an informed, free democratic society.
As members of such a society, it is our privilege and responsibility
to prepare for a braver new world than Huxley ever imagined.
Harvey Bender is a professor of biological sciences and director
of the Human Genetics Program at Notre Dame. He has directed genetics
centers at South Bend, Indiana, hospitals since 1979 and also
serves as an adjunct professor of medical genetics at the Indiana
University School of Medicine.
(July 2005)
