"Despite large public investments in genome-wide association studies of common human diseases, so far, few gene discoveries have led to applications for clinical medicine or public health." - Idris Guessous, Marta Gwinn and Muin J Khoury, in 2009 (1)
We like to think that we are living in an era of rapid scientific advancement; more rapid than any prior era in human history. This is nonsense. In the field of medicine, 50-year progress between 1913 and 1963 greatly exceeded progress between 1964 and 2014. By 1921, we had insulin. Over the next four decades, we developed antibiotics effective against an enormous range of infectious diseases, including tuberculosis. Civil engineers prevented a wide range of common diseases using a clean water supply and improved waste management. Safe methods to preserve food, such as canning, refrigeration, and freezing saved countless lives. In 1941, Papanicolaou introduced the smear technique to screen for precancerous cervical lesions, resulting in a 70% drop in the death rate from uterine cervical cancer, one of the leading causes of cancer deaths in women (See Glossary item, Precancer, Precancerous condition). By 1947, we had overwhelming epidemiologic evidence that cigarettes caused lung cancer. The first polio vaccine and the invention of oral contraceptives came in 1954. By the mid 1950s, sterile surgical technique was widely practiced, bringing a precipitous drop in post-surgical and post-partum deaths. The elucidation of the molecular basis of sickle cell anemia came in 1956 (2), (3). The major discoveries of the fundamental chemistry and biology of DNA came in the 1950s.
Perhaps the greatest advances in the common diseases, in the past several decades, have come to the realm of heart disease. The role of statins in the prevention of heart attacks and strokes, improvements in cardiac surgery, and the use of stents to open narrowed arteries are major therapeutic success stories (See Glossary item, Brain attack). Nonetheless, few would argue that the benefits from these interventional measures would be dwarfed by the benefits enjoyed by individuals who adapted healthy eating habits, exercised regularly, attained a trim habitus, and avoided smoking; sensible life-choices available prior to 1950.
The National Cancer Institute is the largest of the research institutes at the National Institutes of Health (NIH), receiving about 10% of the total NIH budget. Despite intense effort by generations of medical scientists, the cancer death rate today is about the same as it was in 1970 (4). Though there has been a drop in the cancer death rate that has extended from the last decade of the twentieth century to the present, that drop was preceded by a rise in the cancer death rate from 1970 to the early 1990s. The two-decade rise followed by a two-decade drop were both shaped by the rise and consequent fall of smoking. Countries that had a drop in smoking prior to the U.S. saw a drop in cancer death rates prior to the U.S. drop. Countries in which smoking is on the increase have increasing rates of cancer death. For the common cancers (lung, colon, prostate, breast, pancreas, esophagus), progress has been impressive, extending survival times after diagnosis; but the overall death rate from the common cancers has not changed appreciably.
The Human Genome Project is a massive bioinformatics project in which multiple laboratories contributed to sequencing the 3 billion base pairs encoding the full, haploid human genome (See Glossary item, Haploid). The project began its work in 1990, a draft human genome was prepared in 2000, and a completed genome was finished in 2003, marking the start of the so-called post-genomics era. One of the purposes of the project was to find the genetic causes of common diseases. Although we have learned much about the genetics of the common diseases, most of what we have learned has only served to teach us that the genetics of common diseases are much more complex than we had anticipated. Common diseases are associated with hundreds of gene variations, and the gene variations that we have found explain only a small portion of the observed heritability of common diseases (5), (6). Early studies using polygenic variants to predict risk of developing common diseases have not been clinically useful (5).
If the rate of scientific accomplishment were dependent upon the number of scientists on the job, you would expect that progress would be accelerating, not decelerating. According to the National Science Foundation, 18,052 science and engineering doctoral degrees were awarded in the U.S., in 1970. By 1997, that number had risen to 26,847, nearly a 50% increase in the number of graduates at the highest level of academic training (7). The growing work force of scientists failed to advance science at rates achieved in an earlier era, with fewer workers.
While overall rate of medical progress has slowed over the past half century, research funding has accelerated. In 1953, according to the National Science Foundation, the total U.S. expenditures on research and development was $5.16 billion, expressed in current dollar values. In 1998, that number has risen to $227.173 billion, greater than a 40-fold increase in research spending (7). There has not been a commensurate 40-fold increase in scientific discoveries.
The U.S. Department of Health and Human Services has published a sobering document, entitled, "Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products. (8) " The authors note that fewer and fewer new medicines and medical devices are reaching the Food and Drug Administration. Significant advances in genomics, proteomics and nanotechnology have not led to equivalent advances in the treatment of common diseases. The last quarter of the 20th century has been described as the "era of Brownian motion in health care" (9). Wurtman and Bettiker, in their review of medical treatments, commented that, "Successes have been surprisingly infrequent during the past three decades. Few effective treatments have been discovered for the diseases that contribute most to mortality and morbidity" (10).
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, jules j berman
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding. Today's blog emphasizes the lack of progress in the commonly occurring diseases of man. Future blogs will emphasize the crucial role of rare disease research in pursuit of treatments for the common diseases.
 Guessous I, Gwinn M, Khoury MJ. Genome-wide association studies in pharmacogenomics: untapped potential for translation. Genome Medicine 1:46, 2009.
 Pauling L, Itano HA, singer SJ, Wells IC. Sickle cell anemia, a molecular disease. Science 110: 543-548, 1949.
 Ingram VM. A specific chemical difference between globins of normal and sickle-cell anemia hemoglobins. Nature 178:792-794, 1956.
 Berman JJ. Precancer: The Beginning and the End of Cancer. Jones and Bartlett, Sudbury, 2010.
 Wade N. A decade later, genetic map yields few new cures. The New York Times June 12, 2010
 Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature 461:747-753, 2009.
 National Science Board, Science & Engineering Indicators - 2000. Arlington, VA: National Science Foundation, 2000 (NSB-00-1).
 Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products. U.S. Department of Health and Human Services, Food and Drug Administration, 2004.
 Crossing the Quality Chasm: A New Health System for the 21st Century. Quality of Health Care in America Committee, editors. Institute of Medicine, Washington, DC., 2001.
 Wurtman RJ, Bettiker RL. The slowing of treatment discovery, 1965-1995. Nat Med 2:5-6, 1996.