The Role of the WI-38 Cell Strain in Saving Lives and Reducing Morbidity.

The modern success story of vaccinations involves a historical chain of events that transformed the discovery that vaccines worked, to administering them to the population. We estimate the number of lives saved and morbidity reduction associated with the discovery of the first human cell strain used for the production of licensed human virus vaccines, known as WI-38. The diseases studied include poliomyelitis, measles, mumps, rubella, varicella (chicken pox), herpes zoster, adenovirus, rabies and Hepatitis A. The number of preventable cases and deaths in the U.S. and across the globe was assessed by holding prevalence rates and disease-specific death rates constant from 1960-2015. Results indicate that the total number of cases of poliomyelitis, measles, mumps, rubella, varicella, adenovirus, rabies and hepatitis A averted or treated with WI-38 related vaccines was 198 million in the U.S. and 4.5 billion globally (720 million in Africa; 387 million in Latin America and the Caribbean; 2.7 billion in Asia; and 455 million in Europe). The total number of deaths averted from these same diseases was approximately 450,000 in the U.S., and 10.3 million globally (1.6 million in Africa; 886 thousand in Latin America and the Caribbean; 6.2 million in Asia; and 1.0 million in Europe).

Can human biology allow most of us to become centenarians?

Life span is a topic of great interest in science, medicine and among the general public. How long people live has a profound impact on medical costs, intergenerational interactions, and the solvency of age-based entitlement programs around the world. These challenges are already occurring and the magnitude of their impact is, in part, proportional to the fraction of a population that lives the longest. Some demographic forecasts suggest that most babies born since the year 2000 will survive to their 100th birthday. If these forecasts are correct, then there is reason to fear that the financial solvency of even the most prosperous countries are in jeopardy. We argue here that human biology will preclude survival to age 100 for most people.

The future of ageing.

Advances in our knowledge of age-associated diseases have far outpaced advances in our understanding of the fundamental ageing processes that underlie the vulnerability to these pathologies. If we are to increase human life expectancy beyond the fifteen-year limit that would result if today's leading causes of death were resolved, more attention must be paid to basic research on ageing. Determination of longevity must be distinguished from ageing to take us from the common question of why we age to a more revealing question that is rarely posed: why do we live as long as we do? But if the ability to intervene in ageing ever becomes a reality, it will be rife with unintended and undesirable consequences.

The illusion of cell immortality.

Normal cultured cell populations are mortal but cells that are immortal are abnormal and most have properties of cancer cells. Nevertheless, this distinction becomes blurred because the terms 'mortality' and 'immortality' are subject to enormous variations in understanding. Forty years ago we showed that cell mortality and immortality are inextricably linked to longevity determination, ageing and cancer. We suggested that a counting mechanism existed in normal cells and that has now been identified as telomere attrition. This replicometer, in combination with the discovery of the enzyme telomerase, has gone very far in explaining why most normal somatic cells have a finite capacity to replicate both in vivo and in vitro and how immortal cancer cells circumvent this inevitability. It is suggested that telomere attrition may be better understood as a direct measure of longevity determination and to only have an indirect association with age changes.

[A brief overview of the discovery of cell mortality and immortality and of its influence on concepts about aging and cancer]. / Une brève histoire de la découverte de la mortalité et de l'immortalité cellulaire et de son influence sur nos conceptions concernant le vieillissement et le cancer.

After having accomplished the miraculous performance that led us from conception to birth, then to sexual maturity and adulthood, natural selection failed to develop a more elementary mechanism capable of simply maintaining the results of this process forever. This failure is aging. Because few animals age in the wild, evolution could not give an advantage to animals with modifications due to aging. Natural selection benefits those animals that have the highest likelihood of effectively perpetuating their species because their vital systems have the larger reserve capacity they need to resist and survive predators, disease, injury, and extreme environmental conditions. Natural selection decreases after sexual maturity has been reached because at that stage the species would not derive additional advantages from individuals with larger physiological reserves. A species increases its likelihood of survival by investing its resources and energy into increasing its opportunities for fruitful reproduction rather than into prolonging its postreproductive life span. Most animals are mortal and undergo aging because investment of resources into keeping the body eternally youthful does not promote species survival as much as their investment into strategies that make reproduction more successful.

A brief history of the mortality and immortality of cultured cells.

During the first half of this century it was believed that because cultured normal cells were immortal, aging must be caused by extracellular events. Thirty-five years ago we overthrough this dogma when we discovered that normal cells do have a limited capacity to divide and that aging occurs intracellularly. We also observed that only cancer cells are immortal. Normal cells are mortal because telomeres shorten at each division. Immortal cancer cells express the enzyme telomerase that prevents shortening. Recently, it was discovered that the telomerase gene when inserted into normal cells immortalizes them. There appears to be a relationship between these findings and aging, longevity determination and cancer. After performing the miracles that take us from conception to birth, and then to sexual maturation and adulthood, natural selection was unable to favor the development of a more elementary mechanism that would simply maintain those earlier miracles forever. This failure is called aging. Because few feral animals age, evolution could not have favored animals exhibiting age changes. Natural selection favors animals that are most likely to become reproductively successful by developing greater survival skills and reserve capacity in vital systems to better survive predation, disease, accidents and environmental extremes. Natural selection diminishes after sexual maturation because the species will not benefit from members favored for greater development of physiological reserve. A species betters its chances of survival by investing its resources and energy in increasing opportunities for reproductive success rather than on post-reproductive longevity. The level of physiological reserve remaining after reproductive maturity determines potential longevity and evolves incidental to the selection process that acts on earlier developmental events. Physiological reserve does not renew at the same rate that it incurs losses because molecular disorder increases. These age changes increase vulnerability to predation, accidents or disease.

A novel technique for transforming the theft of mortal human cells into praiseworthy federal policy.

A revolution has occurred in the attitude of biologists toward their intellectual property rights. What today is patentable and highly profitable was, 20 years ago, unpatentable and given away for nothing. The history of this revolution began in the early 1960s when we made the first effort to have self-duplicating cell strains patented. The application was denied because patent law at that time did not include living matter. Because of the demand for our normal human diploid cell strain, WI-38, by NIH grantees, NIH support was provided to distribute WI-38 gratis to hundreds of recipients. These included vaccine and cell manufacturers who profited enormously from the direct sale of WI-38 or its use as a substrate for many human virus vaccines. When federal support for the distribution of WI-38 ended, but demand did not, I continued to distribute it for costs similar to those made by the American Type Culture Collection. When I took the first initiative and asked NIH to have the then unique question of title to a self-duplicating system resolved, they sent an accountant who accused me of theft of government property. I replied with a lawsuit that, after six years of litigation, we won with an out-of-court settlement. During these six years the United States Supreme Court ruled that living matter could be patented. Also, the biotechnology industry was launched by biologists who, like me, started companies using cells or microorganisms developed with federal support. This use of intellectual property rights by the nascent biotechnology industry was ultimately embraced by the entire biological community and by a directive from the President of the United States. This revolution has now evolved to the point where government biologists themselves may profit from research in federal laboratories, and the NIH itself aggressively seeks private commercial alliances. Universities have also pursued similar alliances to the extent that today the distinction between a research university and a commercial organization is only in the eyes of the Internal Revenue Service.

How and why we age.

After performing the miracles that takes us from conception to birth, and then to sexual maturation and adulthood, natural selection was unable to favor the development of a more elementary mechanism that would simply maintain those earlier miracles forever. The manifestations of this failure are called aging. Because few feral animals age, evolution could not have favored a genetic program for age changes. Natural selection favors animals that are most likely to become reproductively successful by developing better survival strategies and greater reserve capacity in vital systems to better escape predation, disease, accidents, and environmental extremes. Natural selection diminishes after reproductive success because the species will not benefit from members favored for greater longevity. The level of physiological reserve remaining after reproductive maturity determines longevity and evolves incidental to the selection process that acts on earlier developmental events. Physiological reserve does not renew at the same rate that it incurs losses because molecular disorder increases at a rate greater than the capacity for repair. These are age changes, and they increase vulnerability to predation, accidents, or disease. Failure to distinguish aging from disease has not only blurred our efforts to understand the fundamental biology of aging, but it has profound political and economic consequences that compromise the field of biogerontology. Changes attributable to disease, or pathological change, can be distinguished from age changes for at least four important reasons. Unlike any known disease, (1) age changes occur in every human given sufficient time, (2) age changes cross virtually all species barriers, (3) no disease afflicts all members of a species only after the age of reproductive success, and (4) aging occurs in all feral animals subsequently protected by humans, even when that species probably has not experienced aging for thousands or millions of years. The resolution of age-associated diseases will not advance our knowledge of aging, just as the resolution of the diseases of childhood did not advance our knowledge of childhood development. We have failed to convey that greater support must be given to a question that is rarely posed. It is a question that is applicable to all age-associated diseases, and its resolution will also advance our fundamental knowledge of aging: "Why are old cells more vulnerable to pathology and disease than are young cells?" During the first half of this century it was believed that because cultured normal cells were immortal, aging must be caused by extra-cellular events. Thirty-five years ago we overthrough this dogma when we found that normal cells do have a limited capacity to divide, and that age changes can occur intracellularly. We also observed that only abnormal or cancer cells are immortal. Normal cells are mortal because telomeres shorten at each division. Immortal cancer cells express the enzyme telomerase that prevents shortening. Recently, it was discovered that when the catalytic subunit of the telomerase gene is inserted into normal cells they become immortal.

Mortality and immortality at the cellular level. A review.

A brief history of cell culture as it pertains to aging research had its origins with the thoughts of Weismann and the work of Carrel. Until the early 1960's it was believed that normal cells had an unlimited capacity to replicate. Consequently, aging was thought to have little to do with intracellular events. In the early 1960's we overthrew this dogma after finding that normal cells do have a finite replicative capacity. We interpreted this phenomenon to be aging at the cellular level. In subsequent years the objective was to identify the putative cell division counting mechanism that had been postulated to exist. Efforts to achieve this goal have had a remarkable degree of success only in the last few years with the discovery of the shortening of telomeres at each round of DNA replication that occurs in normal cells both in vivo and in vitro. Immortal abnormal cell populations overcome telomere shortening by activating an enzyme, telomerase, that catalyzes the synthesis of the TTAGGG sequences that compose mammalian telomeres, thus maintaining their length constant. Telomere shortening in normal cells is not a chronometer because time is not measured but rounds of DNA replication are measured. I propose the term replicometer for the device that measures the loss of telomeric sequences in normal cells because the action is that of a meter, and it is counting DNA replications. Telomere shortening and the finite lifetime of normal cells is more likely to represent longevity determination than it is aging. The hundreds of biological changes that herald the loss of replicative capacity in normal cells are more likely age changes.