"We are such stuff as dreams are made on." Shakespeare, The Tempest

Friday, June 5, 2015

The Age of Adaline: Death as No Longer Inevitable

In The Age of Adaline (2015), the age-old “fountain of youth” leitmotif springs forth yet again. In this incarnation, Adaline is forced to come to grips with the fact that everyone around her, including her daughter, is aging even as Adaline herself does not. A strong electromagnetic has altered her genes such that her cells do not divide at slower rates as they age. As she becomes aware of the repercussions, we in turn can marvel at what may be just decades away scientifically concerning the expected human life-span. In short, when the film came out, scientists were already openly discussing whether death itself may no longer be inevitable for human beings.

In an article in Biomaterials published in August 2015, scientists from the Ott lab at Harvard University provide the world with the science behind their successful effort to grow a rat’s limb from cells and attach it to a living rat.[1] Harald Ott describes the significance of the scientific feat for human beings. “Limbs contain muscles, bone, cartilage, blood vessels, tendons, ligaments and nerves – each of which has to be rebuilt and requires a specific supporting structure called the matrix. We have shown that we can maintain the matrix of all of these tissues in their natural relationships to each other, that we can culture the entire construct over prolonged periods of time, and that we can repopulate the vascular system and musculature. . . . Additional next steps will be replicating our success in muscle regeneration with human cells and expanding that to other tissue types, such as bone, cartilage and connective tissue.”[2] In other words, a person’s diseased or simply aged organs may one day be replaceable with organs grown with the individual’s own cells.

The Ott lab’s mission statement lays out the rationale. “End organ failure is the leading health care challenge in the Western World. Nearly 6 million Americans suffer from heart failure with about 550,000 new cases diagnosed annually; 25 million Americans suffer from chronic obstructive pulmonary disease (COPD) with an estimated 12 million new yearly diagnoses; 530,000 Americans suffer from end stage renal disease. Organ transplantation is the only potentially curative therapy available. However, its outcomes are limited by donor organ shortage and the side effects of harsh immunosuppressive treatments. Organ engineering is a theoretical alternative to transplantation. Whole organs could be derived from patient’s cells and transplanted similar to donor organs.”[3] If the brain is such an organ and could be grown from a person’s cells, then would such a transplant essentially end one person, or at least consciousness, and begin another? Ethically speaking, who would have access to his or her own personal “replacement organs”? Only the rich, while death is still inevitable for the poor and middle class?

To be sure, a bunch of organs does not a body make; considerably more is involved. So we must look to the research on cellular aging itself before we can anticipate death as not necessarily inevitable. Just to clarify, this is not the same as immortality. In the film, for example, were Adaline to get hit by a truck, she would not continue at the same age; she would be dead.

In 1913, researchers discovered a cause of aging in mammals that may be reversible.[4] “The aging process we discovered is like a married couple—when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down,” said Harvard Medical School Professor of Genetics David Sinclair, senior author on the study. “And just like with a couple, restoring communication solved the problem.”[5] In scientific terms—now that I’ve warmed you up—“The essence of this finding is a series of molecular events that enable communication inside cells between the nucleus and mitochondria. As communication breaks down, aging accelerates. By administering a molecule naturally produced by the human body, scientists restored the communication network in older mice. Subsequent tissue samples showed key biological hallmarks that were comparable to those of much younger animals.”[6] That is, not only can the aging process be slowed down; it can actually be reversed!

The implications of the research both in growing organs and reversing the aging process at a cellular level are nothing short of breathtaking, not to mention paradigm-altering. At the time of the film’s release, some scientists were openly suggesting that death might no longer be inevitable as early as 2050. That is to say, children, young adults, and even people having reached middle-age watching The Age of Adaline in early 2015 might not experience aging themselves, even as they would naturally have memories of grandparents or parents having aged and died.[7] In the film, Adaline must come to grips with her daughter being an old woman; the implication is that Adaline would eventually have to confront the loss of her daughter, and, indeed, anyone else held dear. I believe this is why Adaline keeps herself from getting into a romantic relationship; even more than wanting to avoid the fear of trusting another person with her secret (for fear of being picked apart by government scientists) and being in the awkward situation of being young while one husband after another reaches retirement age, the deaths of one dog after another—a photo of each one being solemnly kept in an album—have taught her that death as not inevitable has a very sad downside.

Even if death is rendered not inevitable (even as taxes remain so) for every person alive, say in 2100, people would experience other living beings aging and dying. Moreover, longevity itself would doubtless have its own downsides. For those to whom life is a terrible struggle, a lifespan of even just two hundred years—the time between 1776 and Jimmy Carter as the U.S. President in the late 1970s—could be felt to be a curse. The whole notion of a life sentence would have to be re-thought, otherwise it would be intolerably cruel. So too would age discrimination need to be reconsidered. Would it even make sense?

Furthermore, would everyone in the world be at the same age? If so, would humanity consist of children and adult-children—Munchkins, as it were, only with a youthful look? Such a sight would doubtless be extremely distressing to any aliens visiting from elsewhere in the galaxy. Perhaps people could decide to stay at any given age—presumably after having reached adulthood.

Moreover, the right to reproduce in an already overpopulated world might become contentious at least as pertaining to those persons who have “opted into” death as not inevitable, though even they could of course die from an accident or natural disaster. Ethicists would likely find work. The Age of Adaline only skims the surface of the implications from what may lie in store for humanity—that is, if our species can survive the climate-change that was already underway at the time of the film’s release. My point here is that we really have no idea what some of the implications would be; the medical advances touched on above, as well as the work on diseases such cancer, may outstrip the capacity, or at least the usual habits, of the human mind to adapt. At the very least, some paradigms with deep ruts may need to be buried and new seeds sowed.

[1] Bernhard Jank et al, “Engineered Composite Tissue as a Bioartificial Limb Graft, Biomaterials (August 2015), 61:246-56. The abstract reads as follows: “The loss of an extremity is a disastrous injury with tremendous impact on a patient's life. Current mechanical prostheses are technically highly sophisticated, but only partially replace physiologic function and aesthetic appearance. As a biologic alternative, approximately 70 patients have undergone allogeneic hand transplantation to date worldwide. While outcomes are favorable, risks and side effects of transplantation and long-term immunosuppression pose a significant ethical dilemma. An autologous, bio-artificial graft based on native extracellular matrix and patient derived cells could be produced on demand and would not require immunosuppression after transplantation. To create such a graft, we decellularized rat and primate forearms by detergent perfusion and yielded acellular scaffolds with preserved composite architecture. We then repopulated muscle and vasculature with cells of appropriate phenotypes, and matured the composite tissue in a perfusion bioreactor under electrical stimulation in vitro. After confirmation of composite tissue formation, we transplanted the resulting bio-composite grafts to confirm perfusion in vivo.”
[2] Nitya Rajan, “Scientists Grow an Entire Limb in the Lab Using a Dead Rat,” The Huffington Post, June 4, 2015.
[3]Our Mission,” The Ott Lab for Organ Engineering and Regeneration, Harvard University (accessed June 5, 2015).
[4] Ana Gomes et al, “Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging,” Cell (19 December 2013) Vol. 155, No. 7, pp. 1624-638. The abstract reads as follows: “Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD+ and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.”
[5] David Cameron, “A New—and Reversible—Cause of Aging,” Harvard Medical School, December 19, 2013.
[6] Ibid.
[7] The matter of brain transplants puts this assumption at risk, for a brain grown out of some cells would not have the memories. Stretching the envelop even more, what if science eventually enables the memories and even consciousness of the “old” brain to be part of the brain being grown? It seems more likely that the experiential continuity of the person would continue.