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Limits of the Genetic Revolution
Angela Scheuerle, MD, PA
Arch Pediatr Adolesc Med. 2001;155:1204-1209.
ABSTRACT
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The genetic revolution will touch all disciplines of medicine, much
like the antibiotic discoveries in the last century did. However, genetic
medicine is not an immediate "magic bullet" for all noninfectious conditions.
Despite the sometimes melodramatic announcements by the lay media, there are
hurdles to overcome before genetic treatments become as ubiquitous as antibiotics.
These barriers fall into 3 categories: molecular, economic, and behavioral.
First, the molecular difficulties include the biochemical complexity of genes
and genetic disease, variation in pathogenesis among races, and gene-environment
interaction. Second, economic disincentive to develop orphan drugs, and the
expense of such medications, may hinder production of treatments for truly
rare genetic diseases. Third, patients are unlikely to be any more compliant
with new medications or recommendations than they are with the current ones.
The "magic bullet" of folic acid is not used by the majority of women who
are aware of its usefulness in preventing birth defects. While the genetic
revolution has much potential, the complexity of genetics itself is difficult
and the current barriers to useful treatment will not change. As with oncological
and transplantation technology, great strides are likely to be made, but only
at a measured pace.
INTRODUCTION
In the mid 20th century, antibiotic discoveries revolutionized medicine.
Diseases that once killed thousands could be cured simply and effectively.
In a short time, treatment of infection became part of the everyday practice
of medicine. While the field of infectious disease remains a strong independent
discipline, all physicians—from dermatologists to orthopaedists—have
an antibiotic armamentarium tailored to the needs of their patients.
In essence, this same revolution and infiltration is happening with
genetics. Some medical specialties, like oncology and pediatrics, have felt
the tug of genetics for quite a while because those areas have the largest
burden of easily recognizable genetic disease. Oncologists use cytogenetic
indicators to diagnose and prognosticate for their patients. In pediatrics,
5% of all patients have a birth defect, and birth defects are the leading
cause of infant mortality in the United States.1
Of course, genetics is not limited to chromosome aberrations, Mendelian
conditions, and congenital anomalies. Any medical condition, except trauma,
has a genetic component. Work within the Human Genome Project has demonstrated
the genetic contribution to common adult conditions like cardiovascular disease,2 Alzheimer disease,3
and hypertension.4 Thus, physicians who treat
these patients will have to become familiar with genetics, genetic counseling,
and the mode of action of new genetic treatments.
The genetic revolution will have its turn at reinventing medicine. However,
just as the advent of antibiotics did not cure all ills, neither will genetics.
It is possible that some conditions will never respond to a genetic remedy,
just as there are afflictions not touched by antibiotics. For those conditions
amenable to genetic manipulation, there are 3 considerations when creating
effective genetic treatment of disease: (1) the relative individuality of
genetic problems, (2) the financial disincentive to develop treatment for
rare disease, and (3) the need to affect people's behavior. Each of these
issues is a stumbling block to the effectiveness of genetic medicine.
HETEROGENEITY
For some conditions, the genetic contribution is obvious. These generally
follow Mendel's laws of inheritance: achondroplasia, neurofibromatosis, and
sickle cell anemia. At the other end of the spectrum are the purely acquired
problems like concussion and amputation. Everything else is somewhere in the
middle. In Figure 1, those conditions
to the far right of the scale are genetic, those on the far left are acquired,
and the middle 98% are multifactorial. Some multifactorial conditions will
not happen without the genetic contribution, some will remain silent without
the environmental exposure.
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The spectrum of genetically influenced disease. Those conditions
to the far left of the scale are acquired, those on the far right are genetic,
and those in the middle 98% are multifactorial.
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In Western adult society today, the most common medical conditions are
those on the left half of Figure 1.
As such, the usefulness of genetic medicine will probably come to fruition
first in some types of the common, non–Mendelian diseases such as heart
disease and cancer. These conditions have the force of numbers—more
patients needing the treatment—even though they are less "genetic" than
Mendelian conditions. Treatment may involve direct change of someone's genome,
or it may be indirect like stimulating cells to increase (or decrease) production
of a particular protein.5 Certainly the pharmaceutical
companies will be working from many angles. It is likely that much good will
be done in this area using information from the Human Genome Project.
In decades of study, genetics has become more rather than less complex.
Mendel knew exactly what a gene was, what it did, and how it interacted with
other genes. That certainly is not true today. Genetic manipulation or targeted
vaccines are not going to be "magic bullets". Complexity will work against
genetic treatment: what succeeds for one race, family, or type of disease
may very well have no action outside that context.
Genetic heterogeneity must be dealt with at the population level and
at the disease level. Differences within a disease population may result from
locus heterogeneity, that is, different mutated genes causing the same phenotype,
without even considering environmental variation. It is already clear that
causes of hypertension vary among races.4 One
might expect, then, that any genetic-based hypertensive treatment that works
for blacks will not work for whites and vice versa. Again, the more ubiquitous
the phenotype is in the general population, the greater the possibility that
it is there for myriad reasons.
Heterogeneity of genetic conditions may lead to treatments that are
either very broad or very specific and the problems echo those of antibiotic
therapy: too broad and some patients will be overtreated or have untoward
affects; too specific and many different treatment options will be needed.
Treatments may need to be tailored to ethnic or population groups. An unfortunate
reality is that fear of discrimination or mistreatment has led some groups
to eschew participation in medical research in general6
and genetic research specifically.7 The resulting
catch-22 is that directed genetic treatment for those groups will be delayed,
which is discrimination and mistreatment.
What about diseases that are relatively uniform across groups? These
are more likely to be the Mendelian conditions in which all people affected
with the same condition share a common mutated gene. They are going to affect
smaller overall numbers of persons and the molecular genetic differences will
be fewer, although there will still be mutation heterogeneity. A single gene
may have deletion or duplication mutations, insertions, splice junction, or
nonsense mutations. In sickle cell anemia, the vast majority of patients have
the same exact mutation, but in cystic fibrosis, there are more than 800 mutations
documented to date.8 A gene-level genetic treatment
would have to account for all possible mutations of the gene.
There is also the problem of pleiotropy (a single gene mutation affecting
multiple organ systems). The genome is ubiquitous in the body: all genes are
present everywhere although they may only be active or relevant in some tissues.
When gene mutation in only one organ causes the significant manifestations
of disease, it may be possible to treat that organ and ignore the others.
This becomes a stickier problem when the organs involved are multiple, as
in storage diseases, or difficult to access, like the brain.
The most straightforward conditions to treat will be those with few
causative mutations and a single most-commonly involved organ. There are some
conditions that are both common and accessible like sickle cell anemia (bone
marrow). Some that are common and, though multisystemic, have a primarily
involved tissue that is easily accessible such as cystic fibrosis (lung).
Others are common but with diffuse tissue involvement and no single target
organ like neurofibromatosis. The more organs of the body involved, the more
difficult the management and treatment of disease.
So, the molecular complexity of the genome may itself be an impediment
to providing genetic therapies. Within a single disease, 2 persons may have
different genes involved, different mutations of the same gene, or different
manifestations of the same mutation. Treatments that account for all of this
will be overly broad; tailoring treatments to the individual patient too cumbersome.
As with other types of disease, the most common cause will engender the first
and most accessible treatments, which may not be useful for the remainder
of the affected population.
INCENTIVE TO DEVELOP TREATMENTS
Most Mendelian genetic conditions and birth defects are uncommon to
rare when considered within the whole population; therefore, for many conditions
the patient population may be too small to prompt investment by a pharmaceutical
company. For patients with these rare diseases, the promise of genetic therapy
may be just as distant today as it was before February 2001 when the first
draft of the human genome was announced as completed.
Government-funded research is invaluable and serves as the basis for
research and development in both the public and private realms. It is, however,
the pharmaceutical companies that have the machinery and money to develop
effective treatments. Unfortunately, private development must be rewarded
with a financial gain and not threatened by litigation. If the target population
is deemed too small, the procedure too laborious, or the treatment too dangerous,
the private sector is unlikely to be interested. This is as much a political-financial
problem as it is a scientific one.
The Orphan Drug Act of 1983 established market incentives to pharmaceutical
companies for development of drugs that treat rare diseases.9
The Orphan Drug Act considers pharmaceutical profits and provides government
subsidy ($14 million in 1990) to pharmaceutical companies to produce effective
medications.10 The Orphan Drug Act defines
"rare disease or condition" as:
(1) in the case of a drug, any disease or condition which (A)
affects less than 200,000 persons in the United States, or (B) affects more
than 200,000 in the United States and for which there is no reasonable expectation
that the cost of developing and making available in the United States a drug
for such disease or condition will be recovered from sales in the United States
of such drug, [Pub L No. 97-414, 21 USC  360ee]10
This rather broad definition means that rarity is not solely measured
by how many people are afflicted. The first point supports public health needs,
particularly those outside the United States. Depending on the interpretation,
it may or may not apply to conditions that are more common in the United States,
but rare overall.11 The second sense of "orphan"
relates to the economics of researching, producing, and marketing the medication.
European criteria for the definition of an orphan drug are similar.11 There is concern by a major US consumer rights organization
that the Orphan Drug Act protects pharmaceutical profits at taxpayers' expense
and that it decreases competition among pharmaceutical companies.12
Table 1 and Table 2 list diseases currently targeted by the Food and Drug Administration–designated
as orphan drugs.13 Those conditions that are
Mendelian are reported separately for clarity. Using the argument of the previous
section, some conditions in Table 1
do have genetic components but are only now being thought of in that light.
Not all drugs initially designated as orphans go on to get marketing approval.
Zidovudine for treatment of acquired immunodeficiency syndrome– related
complex and acquired immunodeficiency syndrome is designated as an orphan
drug.
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Table 1. The 189 Orphan Drugs Designated to Prophylax or Treat Multifactorial
Conditions*
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Table 2. The 38 Orphan Drugs Designated to Prophylax or Treat Diseases
That Are Mendelian or Related to a Mendelian or Otherwise Strongly Genetic
Condition10
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As of this writing, there are 227 orphan drug designations. Designations
and approvals are assigned by effectiveness, so some drugs have more than
one target disease or more than one designation within that disease. For example,
a single drug may be designated once for prophylaxis and separately for treatment.
Somatotropin has 21 separate designations based on treatment goals under different
clinical circumstances (one for growth stimulation in growth hormone deficiency,
another for growth stimulation in Turner syndrome, and others). (See the first
footnote for Table 1.) It is important
to note that the majority of conditions for which there are medications covered
under the Orphan Drug Act are not numerically rare diseases. Even most of
the Mendelian genetic disorders are common within the population.
Certainly the current orphan drug situation is better than it was 30
years ago, and there is hope that research in one set of diseases will lead
to treatments in others.14 However, many drugs
being marketed today under the Orphan Drug Act are not for truly rare diseases.
Genetic diseases are truly rare. Some genetic disorders affect only a few
hundred people. Relative to all the other technological and pharmacological
advances, developing a treatment for such a small group is unlikely to happen
because (1) there simply are not enough people demanding the treatment, (2)
pharmaceutical companies are unlikely to allocate time and resources when
they will not realize a profit, and (3) a drug produced for company profit
would be so expensive that patients and/or their insurance companies may be
unable to afford it. Currently, orphan drugs tend to be covered by insurance
companies; however, there is no way to be sure this will continue in the constantly
changing atmosphere of cost cutting.
CHANGING BEHAVIOR
There are already recommendations promulgated to decrease risk for common
adult-onset conditions and some congenital ones: do not smoke, exercise daily,
drink alcohol in moderation and not at all when pregnant, and others. These
reflect only the first steps in our understanding of gene-environment interaction.
Smoking is a risk for lung cancer and heart disease, but we do not understand
why one smoker is affected very young while another lives past 100 in apparently
good health.15 Likewise, we recognize that
risk for spina bifida can be reduced by maternal intake of folic acid.16 However, neural tube defects are multifactorial conditions,
so the risk reduction differs among ethnic groups.17
The discussion in the "Heterogeneity" section showed the difficulty in addressing
the genetic causes of multifactorial conditions. The discoveries and debates
about folic acid represent the difficulty in dealing with environmental causes
of medical conditions.
Folate is a naturally occurring B vitamin found in legumes and leafy
green vegetables. Folic acid is the manufactured synthetic form in multivitamins
and enriched foods. In the body, folate plays a role in remethylation of homocysteine
to methionine; the biosynthesis of nucleosides; the methylation of DNA, proteins,
and lipids; and the levels of homocysteine and methionine. The major circulating
form of folate is 5-methyltetrahydrofolate (5-MTHF). The enzyme that produces
5-MTHF is methyltetrahydrofolate reductase (MTHFR). Complete or severe deficiency
of MTHFR causes a rare form of homocystinuria.18
(The common form of homocystinuria results from cystathionine B synthetase
deficiency.) The enzyme and its gene are being studied for their role in folate
deficiency–related diseases.
The MTHFR gene mutation C677T converts a cytosine to a thymine at base
pair 677 that, in the protein, changes an alanine to a valine at amino acid
222.2 This mutation is associated in some studies
with increased risk for neural tube defects. Homozygous C677T persons have
impaired folate metabolism, decreased levels of 5-MTHF, and increased levels
of homocysteine.19 However, this biochemical
imbalance can be overridden. Someone homozygous for C667T who takes adequate
amounts of folic acid will have normal blood folate levels.20
Thus, we have an environmental compensation for a genetic inadequacy.
Folic acid dietary supplementation has received a large amount of well-deserved
publicity in the past decade. It is increasingly apparent that low blood folate
levels are associated with increased risk of some birth defects, most notably
neural tube defects,12, 21, 22
and of homocysteinemia-associated heart attacks23
and strokes.24
Herein lies another aspect of disease cure that the Human Genome Project
cannot address: preventative behavior. The US Public Health Service, the Institute
of Medicine, and the American Academies of Pediatrics and of Obstetrics and
Gynecology recommend that all women of childbearing age take 400 µg/d
of synthetic folic acid and eat a varied diet with folate-containing foods.18, 25, 26 For various reasons,
the Institute of Medicine does not specifically recommend increased folic
acid intake for all adults but does acknowledge possible cardiovascular health
benefits of the vitamin.
One of medicine's anecdotes is that people do not want to work for improved
health, they just want to take a "magic pill." For some conditions and birth
defects, folic acid appears to be exactly that magic pill, but, despite that,
its use is not increasing dramatically. One difficulty is education. State
public health entities, the March of Dimes Birth Defect Foundation, and numerous
medical societies have ongoing outreach to both physicians and the public,
but these resource-limited agencies have to prioritize their audiences. The
second difficulty is availability. Women of lower socioeconomic class, as
always at greatest risk of poor nutrition, may be unable to afford vitamin
supplements. The value of a $6- to $8-bottle of tablets may be outweighed
by the value of a few pounds of hamburger or gallons of gasoline. Food stamps
cannot be used to purchase vitamins or medicine.27
Both education and availability are resource issues. That does not make
them less daunting, but it does offer the prospect that increased allocation
or redirection of money may solve the problems. The third hurdle to folic
acid supplementation is the hardest to overcome: turning knowledge into action.
Repeated studies show that even people who understand the health benefits
of folic acid still do not avail themselves of it.28, 29, 30
The Texas Behavioral Risk Factor Surveillance Study31
data reveal that, of women of childbearing age who knew that folic acid supplementation
reduces the risk of birth defects, only 49.1% took folic acid daily. The study
also asked women why they do not take vitamins or supplements. The answers
were varied and included both predictable answers such as an inability to
afford the supplements, or forgetting to take them, as well as unpredictable
answers like believing the vitamins cause weight gain and a physician's advising
against taking them (Table 3).
So, aside from resource issues, there is a mythology or behavior pattern that
has to be overcome for the benefit to occur.
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Table 3. Texas Behavioral Risk Factor Surveillance Study31*
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A recent survey of psychosocial factors involved in the use of prenatal
care indicates that unwanted pregnancy is the single largest factor involved
in keeping high-risk mothers out of prenatal care.32
When the pregnancy was wanted, women attended prenatal care, even if there
were transportation or scheduling hardships. This suggests strongly that access
to and understanding of the importance of the care are insufficient to induce
patients to get care, or, in the case of folic acid, to take their vitamins.
Currently available vaccines, vitamins, and medical care are not used
to their full extent. Sequencing the genome, and the discoveries to follow,
will not decrease smoking and speeding or increase mulitvitamin and sunscreen
use. Indeed, one wonders if a misunderstanding about genetics will lead people
to believe that they have neither control over nor responsibility for their
own health.
CONCLUSIONS
The genetic revolution will have a great influence on everyone's practice
of medicine. However, like the antibiotic revolution of the last century,
genetic diagnosis and treatment will have to overcome obstacles that are scientific,
economic, and social. Genome complexity will abrogate simple universal treatments.
The cost of producing intricate medications for small populations will frustrate
either pharmacutical development or a patient's ability to pay for therapy.
It will still be up to the patient to seek out care, participate in treatment,
and finish a course of medicine.
Lastly, one must not expect the sudden appearance of cures announced
in the next journal edition. Cancer therapy has been under development for
decades and, while large advances have been made, and many cures realized,
we have not won that war. The mutation in sickle cell disease has been known
for 30 years, but treatments are still largely supportive rather than preventive.
The first wave of studies in gene therapy were disappointing and no second
wave has really started yet. Certainly change and advances will happen faster
now than they did at the beginning of the last century, thanks to our new
knowledge of genetics, but they will not be happening overnight.
AUTHOR INFORMATION
Accepted for publication June 4, 2001.
This article was corrected November 14, 2001.
From Genetics, Teratology, and Ethics Consulting, Dallas Tex.
Corresponding author: Angela Scheuerle, MD, PA, Genetics, Teratology,
and Ethics Consulting, 9702 Vinewood Dr, Dallas, TX 75228-3772 (e-mail: angela.scheuerle{at}tdh.state.tx.us).
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