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Following the doubling of the
National Institutes of Health (NIH) budget between 1999 and 2003, the agency
has been allocated only minimal funding increases in the last three years.
Faced with competing spending priorities including the war in Iraq, recovery
from natural disasters and rapidly rising health care costs, lawmakers in
Washington have begun to ask what benefits have been derived from the
nation’s nearly $30 billion per year investment in the NIH.
While those in the biomedical research field recognize that research is
cumulative and that it can take years, or even decades, to understand and
develop treatments for a single disease, others lack an appreciation of the
process of scientific research. Less than five years after the completed
doubling of the budget, they have already begun to ask where the cures are.
It is up to the scientific community to advocate for a sustained investment
in biomedical research by communicating both the benefits and the timeline
of research.
It has become clear that simply advocating for biomedical research funding
based on the promise of medical advancements is not enough. In order to
answer questions about how the doubling of the NIH budget will improve human
health both now and in the future, it is necessary to explain how and why
research spans decades. When advocating for more research funding,
scientists must explain the context of the work they currently do, the
scientific discoveries that the work builds upon, and the promise of
breakthroughs and discoveries that lie ahead.
Advocacy groups such as Research!America have already begun to incorporate
this theme in their messaging. Their website (http://www.researchamerica.org)
highlights the “Then-Now-Imagine” Campaign. The messages focus on the state
of medicine in the past, the present and the hopes for future treatments.
NIH Director Dr. Elias Zerhouni has also begun to refocus the agency’s
advocacy efforts, pointing out that based on research discoveries; the
medicine of the future will be preemptive, personalized and predictive.
http://www.nih.gov/about/researchresultsforthepublic/index.htm
Physiology has a rich history of contributing to the development of cures
and treatments for disease, stretching back throughout the history of
science and medicine. Outlined below are examples of physiological research
that have already improved human health and continue to hold significant
promise for advancement—promise built on decades of research. In each case,
a basic understanding of pathophysiology has led to advances in disease
treatment. They are intended to illustrate that a sustained investment in
research is the best way to improve human and animal health, today, tomorrow
and in the future.
Parkinson’s Disease
Parkinson’s disease (PD) is well known today as a disorder that involves the
loss of dopamine producing neurons in the brain. Researchers in the 1950s
and 1960s focused on working out the biosynthetic pathway for dopamine
synthesis, and recognized DOPA as the precursor to dopamine. Early efforts
to treat PD with DOPA were disappointing, and reflected the failure of the
drug to efficiently cross the blood brain barrier. George Cotzias, an NIH-supported
researcher in the 1970s, overcame that limitation by increasing the dosage
and showing that it could be effective in treating the symptoms of PD.
Further refinement of the therapy involved the discovery of
DOPA-decarboxylase, an enzyme in the gut that breaks down DOPA, resulting in
nausea and a lower amount of circulating DOPA. By pharmacologically
inhibiting DOPA-decarboxylase, side effects were reduced and more DOPA was
available to pass into the brain. Cotzias also went on to discover that
amino acid concentration affects uptake of DOPA in the gut, leading to diet
recommendations that further enhanced the therapeutic effect.
However, because DOPA improves the symptoms in PD patients, but does not
halt disease progression or provide permanent relief, other treatment
options have been explored, building on the basic understanding of the
pathophysiology of PD. New pharmaceutical agents, including dopamine
agonists and other inhibitors that prolong the bioavailability of DOPA, have
been developed for use alone or in combination with DOPA therapy. Some of
these therapies may even have a protective effect on dopaminergic neurons
and help slow disease progression. And while most cases of PD are not
genetic, several NIH funded studies investigating the genetic causes of
familial PD have led to the identification of biological pathways involved
in disease onset and progression (reviewed in [6]). Knowing which molecules
are involved in familial PD opens the door to the development of therapies
that may also work for sporadic cases. Understanding the genetic basis of
the disorder also allows for the development of animal models, which are
extremely useful in exploring interventions. And finally, a detailed picture
of the genes involved will also help personalize treatments regimens in the
future.
In addition to the development of pharmacological treatments for PD, decades
of research into the structure and function of the brain has enabled the
development of new surgical interventions. While some of the earliest
treatments for PD were neurosurgical, there was limited success and high
mortality associated with the procedures. More sophisticated instrumentation
has improved the efficacy of older treatments, and contributed to the
development of new ones such as deep brain stimulation, which can
dramatically reduce symptoms in some PD patients.
The promise of these therapies has spawned dozens of NIH-supported clinical
trials to further explore and enhance therapies for PD, offering hope to
patients around the world.
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| Figure 1.
Remaining life expectancy in years at age 65. |
Cholera
Cholera is a disease that has long plagued many regions of the world,
causing significant mortality with each outbreak of disease. Left untreated,
severe cholera infection kills up to 50% of affected patients (reviewed in
[6]. Research into the pathophysiology of cholera infection led scientists
to understand that the rapid dehydration caused by diarrhea is the result of
an imbalance between secretion and absorption of water and electrolytes in
the gut. Early research into sodium-linked glucose transport provided the
scientific basis for the development of oral rehydration therapy, which has
saved millions of lives around the world since its introduction in the
1970s. Oral rehydration therapy has been an extremely effective treatment
because it is both affordable and readily accessible to affected
populations. However, despite the enormous success of oral rehydration
therapy, vulnerable populations such as the very young, the elderly and the
malnourished still often succumb to the disease.
Research funded by the NIH over the last several decades has provided a body
of basic scientific knowledge that will allow for the continued development
of newer and better therapies. Recent scientific efforts have focused on
refining treatment beyond supportive rehydration, and the development of a
preventative vaccine. Detailed knowledge of precisely how cholera toxin
invades cells and disrupts absorption and secretion has led to the
development of several possible drug targets [3]. Current NIH-funded
research focuses on drug development for the treatment of cholera infection
[4], investigation of the genetic determinants of virulence [1], and the
development of more effective vaccines [5], among others topics. With the
looming threat of bioterrorism and the potential use of cholera and other
organisms as biological weapons, these studies will continue to be of value
to human health all over the world.
Cystic Fibrosis
The completion of the human genome sequence in the late 1990s provided an
enormous resource for the study of genetic disease. But more than a decade
before that landmark event, scientists funded in part by the National
Institutes for Diabetes and Digestive and Kidney Diseases identified the
gene responsible for cystic fibrosis (CF) using positional cloning [6].
Identification of the cystic fibrosis transmembrane conductance regulator (CFTR)
was a major discovery that has allowed scientists to study the molecular
events that lead to the development of CF with an eye toward early
intervention and disease therapy.
While cystic fibrosis is a relatively rare disease, CF is one of the most
common human genetic disorders, and approximately 10 million Americans carry
mutations in the CFTR gene. Understanding the genetic basis of the disorder
has led to the development of accurate diagnostic tests which allow at-risk
individuals to be tested for carrier status, as well as the use of prenatal
genetic testing when appropriate.
Numerous studies in the last 17 years have expanded upon our knowledge of
the molecular mechanisms underlying CF, including how the gene is expressed
in its normal and mutant forms, and how the protein product localizes and
functions at the cell membrane as a chloride channel. Treatments including
the use of anti-inflammatory drugs, antibiotics, pancreatic enzymes and
nutrition supplements have all been developed based on knowledge of CF
pathophysiology, and have contributed greatly to reduced morbidity and
mortality in affected individuals. In the past 30 years, the average
lifespan for individuals affected with CF has increased dramatically and now
stands at 36.8 years, compared with 30 years ago when most deaths occurred
during childhood or the teenage years.
Researchers are now focused on the development of gene therapy techniques
that would deliver CFTR to affected tissues, most importantly the lung.
Current research is focused on the development of animal models that can be
used to test gene therapies, as well as testing different viral and
non-viral methods for gene delivery (reviewed in [4]).
In addition, increased knowledge of the molecular underpinnings of CF has
increased the understanding of other related disorders. For example,
researchers have speculated that deleterious mutations in the CF gene are
maintained at such a high rate in the population because they may confer
some degree of resistance to the development of typhoid fever and secretory
diarrheas such as cholera. Investigation of that association led to the
observation that the pathogen responsible for typhoid fever enters cells in
the gut through the CFTR transporter. CF research has also led to insights
into male infertility, idiopathic pancreatitis and primary sclerosing
cholangitis.
The National Institutes of Health continue to sponsor research that explores
CF and the best way to treat problems associated with the disease.
Currently, the agency spends approximately $100 million per year on CF
research, and according to the federal database of clinical trials, there
are currently 69 clinical trials actively recruiting CF patients to study
various aspects of the disease.
Mechanical Ventilation and Lung Damage
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are
serious lung conditions that are associated with high mortality rates.
Patients whose lungs are damaged by injury or illnesses such as pneumonia
sometimes go on to develop severe inflammation and ARDS, which can result in
respiratory failure in a matter of days. These patients require extensive
medical treatment, including being placed on a respirator to help them
breathe. According to one recent study, approximately 200,000 people in the
United States are affected by ALI each year, and the mortality rate is about
40% [5].
In an effort to improve treatment and reduce mortality due to ALI and ARDS,
the National Heart Lung and Blood Institute developed a consortium of
clinical centers to test new therapies. Clinical researchers tested new
drugs that they hoped would improve patient outcome, and also enrolled more
than 800 patients in a study that examined mechanical ventilation.
Physiologists had speculated that the amount of air being passed into the
patient’s lungs might actually be causing damage, so they experimented with
giving the patients less air with each breath. The researchers found that
the results were dramatic, and that patients who were given less air with
each breathe had a mortality rate that was 31% as compared to 40% in the
control patients receiving traditional ventilation therapy. The results were
so convincing that researchers stopped the study early so that more patients
could be treated with the new clinical protocol [3]. Researchers have gone
on to study the biological basis of this phenomenon, and early results in
animals show that higher levels of ventilation lead to increased
inflammation in the lung [3].
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| Figure 2. Life
expectancy in years (at birth) |
Conclusion
As illustrated in the examples given above, progress from basic research to
disease treatment can be slow and arduous. Despite the lengthy process,
there are countless examples of improvements to human health that are built
upon years of research. By making an effort to communicate this to members
of Congress, scientists can enhance the understanding of the research
process, and hopefully increase support for federal funding of biomedical
research. If citing specific examples of diseases doesn’t appear persuasive
enough, perhaps demonstrating a correlation between NIH funding levels and
longevity (either measured as life expectancy from birth [Fig. 1A] or from
age 65 [Fig. 1B]) would be in order. It will be informative to note what the
trends will look like if the NIH funding level remains flat or decrease over
the next several years.
Acknowledgements
We would like to thank members of the APS sections for contributing the
ideas that formed the basis of this article, especially Bill Talman, Michael
Matthay and Hannah Carey. We also thank Ms. Janice Phillips for preparation
of Figure 1.
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