Excerpted from
Precision Medicine and the Reinvention of Human Disease
Despite having the most advanced healthcare technology on the planet, life expectancy in
the United States is not particularly high. Citizens from most of the European countries and
the highly industrialized Asian countries enjoy longer life expectancies than the United
States. According to the World Health Organization, the United States ranks 31st among
nations, trailing behind Greece, Chile, and Costa Rica, and barely edging out Cuba [42].
Similar rankings are reported by the US Central Intelligence Agency [43]. These findings lead
us to infer that access to advanced technologies, such as those offered by Precision Medicine,
will not extend lifespan significantly.
Every healthcare professional knows that most of the deaths occurring in this country can be
attributed to personal lifestyle choices: smoking, drinking, drug abuse, and over-eating. Lifestyle
diseases account for the majority of deaths in the United States and in otherwestern countries,
these being:heartdisease,diabetes, obesity, andcancer.Population-basedtrials that seek to
improve theways inwhichindividuals live, by introducing adaily exercise routine, healthydiet,
and cigarette abstinence, have yielded huge benefits, in terms of extending average lifespans
[44]. At the front end of the human life cycle, it has been demonstrated that infant mortalities
can be markedly reduced with simple measures, focusing on improved maternal education
[45]. It has been credibly argued that cleanwater, clean air, clean housing, clean food, and clean
living yieldgreater societal benefits than clean operating rooms [46,47]. If this be the case, should
we be investing heavily in Precision Medicine, when simple, low-tech public health measures
are likely to provide a greater return on investment, in terms of overallmorbidity andmortality?
In a certain sense, public health is the opposite of personalized medicine. Whereas personalized
medicine involves finding the best possible treatment for individuals, based on
their uniqueness, public health involves finding ways of treating whole populations
based on their collective sameness. Let’s not dwell on these somewhat contrived philosophic
points. Precision Medicine, as viewed in this book, is a new way of understanding
human diseases. As such, Precision Medicine provides opportunities to advance both personalized
medicine and public health.
Precision Medicine tells us that we should think of diseases as developmental process, with
each step in the process representing an opportunity for intervention. Perhaps the most
important function of Precision Medicine will be to give society the opportunity to institute
public health measures aimed at blocking the pathogenesis of human diseases. Here are just a
few examples:
– Population screening for early stages of common diseases.
The successful reduction in deaths from cervical cancer demonstrates the effectiveness of
screening for early stages of disease. Cervical cancer is a type of squamous cell carcinoma that
develops at the junction between the ectocervix (the squamous lined epithelium) and the
endocervix (the glandular lined epithelium) in the os of the uterine cervix of women. Before
the introduction of cervical precancer treatment, cervical carcinoma was one of the leading
causes of cancer deaths in women worldwide. Today, in many countries that have not deployed
precancer treatment, cervical cancer remains the leading cause of cancer deaths in women [48–
50]. In the United States, a 70% drop in cervical cancer deaths followed the adoption of routine
Papsmear screening[51–53].Noeffort aimedat treatinginvasive cancers has providedanequivalent
reduction in the number of cancer deaths. [Glossary Age-adjusted incidence, Pap smear]
Today, we know that cervical carcinogenesis begins with a localized infection by one of
several strains of human papillomavirus, transmitted during sexual intercourse by an
infected male partner. In the late 1940s (and really up until the early 1980s), the viral etiology
of cervical cancer was unknown. We did know that squamous cells sampled from the uterine
os had highly characteristic morphologic appearances that preceded the development of invasive
cancer. Thanks largely to the persistence of Dr. Papanicolaou and his coworkers, a
standard screening test, known as the Pap smear, was developed to detect cervical
precancers. If precancerous changes were found in a smear, a gynecologist could remove a
superficial portion of the affected epithelium, and this would, in the vast majority of cases,
stop the cancer from ever developing.
Morphologic and epidemiologic observations on Pap smears provided clues that eventually
led to the identification of several strains of human papillomavirus as the major causes of
cervical cancer. Today, a vaccine protective against carcinogenic strains of human papilloma
virus is available [54].
As discussed in
Precision Medicine and the Reinvention of Human Disease, Section 7.5, “What Is Precision Diagnosis?” new biomarkers are being developed
for the early stages of disease, often preceding the development of any clinical symptoms.
In general, diseases are easiest to treat in early stages, before they have had the chance to
do any harm to organs. For example, precancers can often be effectively treated by excision,
or, in some cases, by withdrawal of the agents that would otherwise lead to the progression of
the precancer to the cancerous stage (e.g., cessation of hormonal replacement therapy to block
breast cancer, cessation of smoking to block lung cancer, treatment of Helicobacter pylori infection
to block MALToma).
We can hope that in the future advances in the field of Precision Medicine will identify the
intermediate stages of development for common diseases. With this information, public
health measures aimed at detecting and blocking diseases, in an early stage of development,
will be deployed.
– The aggressive prevention and treatment for the most common patterns of diseases that lead to death
As discussed in
Precision Medicine and the Reinvention of Human Disease, Section 2.3, “Cause of Death,” a well-composed death certificate contains a
thoughtful sequence of medical conditions that develop over time, and that ultimately lead to
the death of the patient. This data, if properly recorded and aggregated into a mortality database,
should provide the most frequently occurring chains of events that account for human
deaths. A public health effort aimed at breaking the early steps of these processes has the potential
of extending the life expectancy of the population.
– Aggressive screening for carriers of infectious diseases
As discussed in Section 6.2, “Our Genome Is a Book Titled ‘The History of Human Infections,’”
organisms that were formerly thought to be purely pathogenic are now known to
frequently live quietly within infected humans, without causing symptoms of disease,
and this would include the organisms that cause Chagas disease, leishmaniases, toxoplasmosis,
tuberculosis, viruses such as Herpes viruses and hepatitis viruses B and C, and bacterial
organisms, some of which circulate in the blood without causing disease under normal
circumstances.
Sensitive diagnostic techniques, including genome sequencing of DNA in blood, may provide
us with the opportunity to perform population screening for organisms that are opportunistic
pathogens, or that produce long-term damage to carriers, or that are transmissible
from carriers.
– Finding targets for vaccines that confer effectiveness against more than one target organism.
Thanks in no small part to Precision Medicine, we are learning that organisms play a role in
many diseases that were once thought to have no infectious component. In particular, it is
now widely accepted that infections contribute to at least one-fifth of all cancers occurring
in humans. Examples of cancer causing organisms are:
– Epstein-Barr virus (B-cell lymphomas, Burkitt lymphoma,
nasopharyngeal cancer, Hodgkin disease and T-cell lymphomas)
– Hepatitis B virus (hepatocellular carcinoma)
– Human papillomavirus types 5, 8, 14, 17, 20,
and 47 (skin cancer)
– Human papillomavirus types 16, 18, 31, 33, 35, 39,
45, 52, 56, 58 (cervical cancer, anogenital cancer)
– Human papillomavirus types 6 and 11 (verrucous
carcinoma)
– Human papillomavirus types 16, 18, 33, 57, 73
(cancers of oral cavity, tongue, larynx, nasal cavity,
and esophagus)
– Merkel cell polyomavirus (MCPyV) (Merkel cell carcinoma)
– HTLV-1 (adult T-cell leukemia)
– Human herpesvirus 8 (Kaposi sarcoma)
– Hepatitis C virus—hepatocellular carcinoma
and low-grade lymphomas
– JC, BK, and SV40-like polyoma viruses (tumors
of brain and pancreatic islet tumors, and mesotheliomas)
– Human endogenous retrovirus HERV-K
(seminomas and germ cell tumors)
– Schistosomiasis and squamous cell carcinoma of
bladder
– Opisthorchis viverrini and Clinorchis sinensis,
flatworms (flukes), found in Southeast Asia,
(cholangiocarcinoma)
– Helicobacter pylori and gastric MALToma
(Mucosa-Associated Lympoid tissue
lymphoma) [55]
Carcinogenic viruses profoundly influence the number of cancer deaths, worldwide. These
include hepatitis B virus (associated with an increased incidence of hepatocellular carcinoma)
and human papillomavirus (which causes cervical cancer). Liver cancer is the third leading
cause of cancer deaths worldwide, accounting for 611,000 deaths in 2000 [50]. It is easy to
understand that the importance of vaccine development for infections that contribute
to chronic diseases and cancers cannot be overstated. As we learn more about the biological
steps involved in the infection process, hope looms that vaccines and preventive
drugs will be developed that target different types of organisms, based on shared properties
of infection, invasion, immunologic resistance, persistence, or phylogeny, as discussed
in
Precision Medicine and the Reinvention of Human Disease, Section 4.4,
“Pathway-Directed Treatments for Convergent Diseases,” [56–60].
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Jules Berman
key words: public health, prevention, precision medicine, cancer, cancer vaccines, jules j berman, Ph.D., M.D.
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