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widely known, subjects.

Monday, November 14, 2022

The causes of ageing

To get back my youth I would do anything in the world, except take exercise, get up early, or be respectable.

Oscar Wilde, The Picture of Dorian Gray

Detail from Old woman and boy with candles (c. 1616–1617) by Peter Paul Rubens.

EVERLASTING YOUTH is one of humanity’s perpetual aspirations. None of us are impervious to the effects of old age, either in ourselves or in those we love. Yet, more than an inescapable element of the human condition, ageing is in fact a universal biological feature of complex animals, and possibly of all life. Biologically speaking, ageing is a gradual decline in the capacity of the cells and tissues in a body to preserve their integrity and carry out their central physiological functions. The ultimate consequence of this process is the body’s inability to sustain its own existence, leading to an inevitable death from ‘old age’. Regardless of how much effort is devoted to prolonging life, humans and other animals seem to carry an intrinsic ‘expiry date’. But why should this be so? How did such an implacable force of decay come to exist, and why do we humans seem unable to vanquish it?

The question of what causes ageing, which can be traced as far back as Aristotle, is in fact composed of two very distinct questions. The first is the question of why we age: what is the ultimate biological reason for the fact that animals have never evolved the capacity to live forever? The second question is that of how we age: what are the immediate physiological processes which cause bodies gradually to decay over time? The degree to which we understand ageing may be expected to vary between these two levels of analysis — but it may come as a surprise that it should be our understanding of how we age, rather than why we age, which remains very much undeveloped. The following presents our current scientific perspective on these two dimensions of the ageing process.

Why we age: Evolutionary causes of ageing

The universality of ageing among animals was a troublesome fact to early evolutionary biologists. In the mid-nineteenth century, Charles Darwin had proposed that the biological traits of organisms were the outcome of evolution by natural selection, and therefore had probably been useful for the survival and reproduction of previous generations. How is it, then, that evolution has not crafted organisms with the clearly beneficial capacity to maintain their youth indefinitely?

The first evolutionary explanation of ageing was proposed by the nineteenth-century biologist August Weismann. An early supporter of Darwin’s ideas, Weismann was a key figure in the development of early theories of biological heredity. To him, the evolutionary paradox of ageing could be resolved if one assumed that an animal’s longevity is indeed the product of natural selection — but not because of any benefit to the animal itself, but rather to the species as a whole. He proposed that the duration of life — the lifespan — has evolved to an optimal value which spares the population from being smothered by a preponderance of old individuals. In Weismann’s account, ageing is therefore a death mechanism explicitly evolved for the purging of older, less competitive generations, enabling the success of younger individuals. Remarkably, this theory was in fact a Darwinian makeover of the views of the ancient Roman poet and philosopher Lucretius.

Weismann’s explanation of ageing, although intuitively cogent, was found by later evolutionary biologists to be flawed. For one thing, the argument that older individuals should be purged because they are less fit than younger ones immediately invokes an assumption that individuals experience physiological ageing. But to infer the evolutionary origins of ageing, we must begin with a population whose individuals do not age, and thus can only die through extrinsic forces such as predation, infection, starvation or accident. In such a population, there is no reason to assume that older individuals should be at a disadvantage — if anything, the fact that they have survived for longer implies that they are, on average, better survivors. Moreover, older individuals should have amassed precious expertise in the manoeuvres and tactics of living, such that they should offer formidable competition to youngsters. Therefore, without the assumption of an ageing process, the death of older individuals cannot easily be defended as of benefit to the species.

Another powerful argument against Weismann’s theory is the now-established fact that traits which benefit the collective at the expense of the individual are evolutionarily unstable. In most situations, natural selection operates overwhelmingly at the level of the individual: if one deer is, for instance, able to outrun the others, it will be less likely to be preyed upon, and hence more likely to leave offspring, which will inherit its superior speed. In the same manner, if a species were to evolve an ageing process that were beneficial to the species but disadvantageous to the individual, then any individual happening to age more slowly than the rest would be at a considerable advantage, just like the faster-running deer, and so this trait would be favoured by natural selection. Ageing therefore cannot have evolved for the sole benefit of the species; if Weismann appears here to have misjudged the implications of Darwin’s theory, it may be said in his defence that Darwin himself would have fared no better. It is only after one and a half centuries of thought that we have come to understand ageing not as a consequence of the direct action of natural selection — but rather of its failure.

One of the earliest hints at the concept which underlies modern evolutionary theories of ageing was advanced by the influential mathematical geneticist JBS Haldane. During an inspired series of lectures in 1940, Haldane noted in passing that natural selection should have little power to suppress a deleterious trait if such a trait only manifests itself late in life. To see why this is the case, let us consider Haldane’s case of interest — Huntington’s disease. Despite its devastating and fatal effects, this degenerative condition typically has its onset after the age of thirty, and hence has little impact on a person’s ability to have children. By the time the disease is diagnosed, the patient’s children may already have inherited the responsible gene. Haldane correctly saw this as the reason why such a pernicious gene has not been purged by evolution. The impact of Huntington’s disease is confined to adulthood, a period of life in which the strength of natural selection declines dramatically, since reproduction has already taken place. This period is now termed the ‘selection shadow’, because biological effects within it are effectively ‘out of sight’ for evolution.

Diagram illustrating the concept of the ‘selection shadow’, referring to the progressive decline in the strength of natural selection after the age of reproductive maturity (Credit: A Baez-Ortega).

The concept of the selection shadow was first developed into a complete theory of ageing by the Nobel laureate Sir Peter Medawar, who in the 1950s attempted to explain ageing as the combined effect of a collection of ‘mutant genes’ — altered versions of ‘normal’ genes — whose effects only arise late in life. Just as in the case of Huntington’s disease, age-related conditions such as cataracts, arthritis and osteoporosis have a late onset and no impact on reproduction, which precludes natural selection from weeding off the implicated ‘mutant genes’. A large number of these problematic genes will therefore accumulate in the ‘shadow’ of selection, their effects amalgamating into what we call ageing. Medawar also grasped the significance of extrinsic mortality, that is, the rate of death from environmental forces such as predation: the later in life the effects of a gene are realised, the less individuals will remain alive to experience them. Thus, a gene which contributes to prolonging the health of heart muscle for many decades may be very beneficial to an elephant, but it is of no use to a mouse that will almost certainly be preyed upon before the age of two.

Building on Medawar’s work, a later theory proposed that ageing may arise from genes which not only have negative effects in old age, but also have beneficial effects in youth, when natural selection is at its strongest. In this theory, ageing would be a detrimental late by-product of processes which have evolved because they are beneficial earlier in life. The current scientific consensus is that each of these two theories is probably correct in some cases, such that certain components of ageing have arisen through accumulation of purely detrimental mutant genes, while others are late side-effects of advantageous genes.

An important aspect of these two evolutionary theories is that they define ageing as the result of the inability of natural selection to maintain physiological integrity for longer than is actually useful ‘in the wild’. The key insight is that it is not evolutionarily advantageous to live longer than we do, because our species has evolved so that we are able to develop and reproduce long before our bodies succumb to age. Furthermore, because the wild environment of early humans made it very unlikely for them to survive as long as we do, there has been no evolutionary need for greater longevity. Notably, our evolutionary explanation of ageing, which is theoretically and empirically well supported, does not depend on which specific physiological mechanisms are responsible for ageing. In other words, we certainly understand why the process of ageing has evolved in the first place; the scene is rather different, however, when it comes to the question of how this process unfolds in organisms.

How we age: Mechanistic causes of ageing

Luckily for junior scientists, our mechanistic theories of ageing are much more abundant and less clearly supported than our evolutionary theories. Perhaps the most immediate question regarding the actual process of ageing is whether it results from a single physiological mechanism, or from multiple mechanisms whose effects are roughly synchronised. Given the conclusion that ageing is a consequence of the ineffectiveness of natural selection, it follows that it must come about through multiple, possibly many, unrelated mechanisms.

As a crude analogy, let us imagine owning a car in a very unsafe city, where vehicles are constantly being stolen or damaged. In such circumstances, we should be wise to buy a cheap car which might last a few years, and to spend as little as possible in maintenance, as otherwise the return on our investment may never materialise. Nevertheless, if by a stroke of fortune, we find ourselves owning the same car after a good number of years, we should expect it to come apart by virtue of its being cheap and poorly maintained. This analogy unflatteringly exposes the ultimate reason for ageing — insufficient quality and care — yet it sheds no light as to which of the car’s components is expected to fail first. Given that the car’s decay is caused by deficient maintenance, we might expect multiple of its components to misbehave with increasing frequency, up to the point where the machine as a whole cannot function. Moreover, different processes might be responsible for each component’s failure: the transmission may expire out of sheer friction, while the pistons might succumb to soot. Hence, even though the ultimate cause of ageing may be universal, the processes immediately involved are manifold.

As suggested by this analogy, current research on ageing focuses on the challenging task of establishing which physiological processes contribute to ageing, and how significant each is. A large number of distinct processes have indeed been proposed as mechanistic causes of ageing. Among the most interesting of these are ‘nutrient signalling pathways’, which are functional networks of molecules responsible for transmitting the physiological signals produced when we acquire nutrients. The most popular molecule in this network is insulin, essential for the regulation of blood glucose levels. Yet in addition to the well-known relationship between deficient insulin signalling and diabetes, it has been found that interventions which interfere with nutrient signalling can considerably prolong the lifespan of many species, both vertebrate and invertebrate. For instance, a treatment known as ‘dietary restriction’, whereby the supply of food (or of certain nutrients) is permanently reduced, is considered the most reliable way of extending animal lifespan. Furthermore, the deactivation of certain nutrient signalling genes, by either mutation or pharmacological treatment, produces similar effects to those of dietary restriction. In the 1990s, Cynthia Kenyon and her colleagues discovered that mutations in such a gene led to a doubling of lifespan in nematode worms, a finding followed by similar reports in fruit flies by the groups of Dame Linda Partridge and Marc Tatar. On the other hand, nutrient signalling also regulates body growth and development, and animals subjected to these life-prolonging interventions tend to be stunted and ill-developed. Interestingly, although the network of effects whereby nutrient signalling modulates development and longevity is not yet fully characterised, it is believed to be the reason why smaller dog breeds live longer than larger ones.

A second leading candidate among possible mechanisms of ageing is molecular damage. Cells are constantly exposed to many kinds of chemical damage, which can alter their constituent molecules and impair the efficiency of cellular processes. The types of molecules subject to such damage include proteins (which are both the cell’s building blocks and its working tools) and DNA (which carries the organism’s genetic information, including the instructions for protein synthesis). One extensively studied type of DNA modification with potential roles in ageing is the shortening of telomeres — long stretches of DNA which are placed at the ends of chromosomes to protect them from fraying, like the aglet in a shoelace. Telomeres are slightly shortened every time a cell divides into two new cells, and eventually become too short to allow further cell division, which is thought to be an important barrier against the emergence of cancer — but might also be a cause of ageing. Recently, the biologist María Blasco and her team reported the striking finding that the rate of telomere shortening in a species is related to its lifespan, such that telomeres erode faster in shorter-lived species. Nevertheless, this relationship is obscured by the fact that shorter-lived species also tend to be smaller, and body size itself is thought to influence many aspects of animal physiology.

Fluorescence microscopy image showing the location of telomeres (white) at the ends of human chromosomes (grey). Telomeres preserve the integrity of DNA inside chromosomes, and their shortening over time has been proposed as a cause of ageing (Credit: NASA/Wikimedia Commons, public domain).

Working with Alex Cagan, Iñigo Martincorena and other researchers at the Wellcome Sanger Institute, I recently explored the relationship between animal lifespan and another common form of DNA modification — somatic mutations. This term refers to the changes that accrue in our DNA over time; such mutations are not present initially in any of our cells, but are acquired by individual cells as our bodies grow and age. Somatic mutations were first hypothesised to contribute to ageing in the 1960s, but their exact role remains elusive. Cagan and I characterised the rate of mutation across sixteen species of mammals, from mice to giraffes, and found a very similar relationship to that described for telomeres: shorter-lived species mutate faster than longer-lived ones, such that a mouse cell acquires as many mutations in two years as a human cell might do in eighty. Crucially, we determined this result to be unaffected by the relationship between longevity and body size: at least in mammals, the mutation rate can be used to predict a species’ lifespan, regardless of its size. The fact that the rates of different forms of molecular damage present similar relationships with lifespan suggests — but does not prove — that these forms of damage may be involved in ageing.

Diagram showing the inverse relationship between lifespan and the rate of somatic mutation in 16 species of mammals. The mutation rate of each species is inversely proportional to its lifespan, such that all species carry a similar number of mutations in their cells’ DNA at the end of their respective lifespans. This relationship is indicated by the blue line, with the shaded area marking a two-fold deviation from this line (Source: Cagan, Baez-Ortega et al., 2022).

It might seem inconsistent that processes as unrelated as nutrient signalling and molecular damage might all contribute to ageing. But these processes are not so distant when viewed in the light of a theory known as the ‘disposable soma’ theory of ageing. According to this, the physiology of complex organisms includes a central energy trade-off, such that the energy acquired from food is distributed between the processes of somatic maintenance (the preservation of the body via repair of molecular damage) and reproduction (the preservation of genes via their transmission to offspring). Rather than grappling with the evolutionary origin of ageing, this theory provides a framework for its physiological regulation. Because our body (the ‘soma’) is ultimately perishable, the energy trade-off between maintenance and reproduction has presumably been optimised by evolution to favour the expensive process of reproduction in times of nutrient abundance, and to promote maintenance instead when nutrients are limited. It is thus possible that nutrient signalling disruption modifies the speed of ageing by interfering with the ‘gauge’ of this energy allocation system, whereas molecular damage may simply be the force which opposes somatic maintenance processes. Despite the remarkable coherence of the disposable soma theory, the evidence for the existence of a universal energy trade-off in animals is currently inconclusive. It is possible that, like so much else in biology, energy trade-offs are crucial but not universal: they might be relevant only for some species, or in certain organs, or at particular periods in life. Even in this time of unparalleled scientific progress, an immensity of knowledge remains to be discovered regarding the physiological processes involved in ageing.

The battle against ageing

Since the days of Darwin and Weismann, we have come to understand ageing not as a death force evolved for the benefit of the species, but rather as an inextricable consequence of the manner in which evolution works. Animal bodies have not evolved to live forever, but to succeed in surviving and reproducing amidst a ruthless environment. The biology of our bodies is such as it is precisely because our ancestors managed to succeed in these tasks, not because they managed to live forever.

Whatever the causes of ageing, the essential question for humanity is whether we shall ever be able to throttle them — perhaps not with a view to living forever, but at least to enjoying longer-lasting health and a happier old age. It seems clear that this target will remain out of reach so long as we fail to understand what exactly ‘ageing’ means at the molecular level. Someday we might gain the power to manipulate the processes by which our bodies fend off the effects of time, or even to combat such effects directly; we may finally be able to subdue and domesticate the process of ageing. But such miracles lie still beyond the horizon, and for years to come we must keep drawing on the power of conventional medicine to manage individual age-related conditions.

When it comes to growing older, the personal theory of the essayist, poet and former Master of Magdalene College, AC Benson, may be more helpful than those discussed here: ‘I have a theory that one ought to grow older in a tranquil and appropriate way, that one ought to be perfectly contented with one’s time of life, that amusements and pursuits ought to alter naturally and easily, and not be regretfully abandoned’. Too modest a theory, perhaps; he goes on to concede that ‘It is easier said than done’. Yet, even as we feel the gentle, impassive slipping away of youth between our fingers, we should be wise to keep in mind the words of Longfellow:

For age is opportunity no less
Than youth itself, though in another dress,
And as the evening twilight fades away
The sky is filled with stars, invisible by day.

Weismann, A. ‘The duration of life’ (1881). In Essays Upon Heredity and Kindred Biological Problems (tr. Poulton, EB, Schönland, S, Shipley, AE). Clarendon, 1889.
Haldane, JBS. New Paths in Genetics. Allen & Unwin, 1941.
Kenyon, C, Chang, J et al. A C. elegans mutant that lives twice as long as wild type. Nature, 1993.
Hughes, KA, Reynolds, RM. Evolutionary and mechanistic theories of aging. Annual Review of Entomology, 2005.
Kirkwood, TBL. Understanding the odd science of aging. Cell, 2005.
Flatt, T, Partridge, L. Horizons in the evolution of aging. BMC Biology, 2018.
Whittemore, K, Vera, E et al. Telomere shortening rate predicts species life span. Proceedings of the National Academy of Sciences, 2019.
Cagan, A, Baez-Ortega, A et al. Somatic mutation rates scale with lifespan across mammals. Nature, 2022.

This article was originally published in the 2021–22 Magdalene College Magazine.
The author is grateful to James Raven and Aude Fitzsimons for their comments on the original manuscript.

Las causas del envejecimiento

Por recuperar mi juventud haría cualquier cosa en el mundo, salvo hacer ejercicio, madrugar, o ser respetable.

Oscar Wilde, El retrato de Dorian Gray

Detalle de Anciana y niño con velas (c. 1616–1617) de Pedro Pablo Rubens.

LA ETERNA JUVENTUD es una de las aspiraciones perpetuas de la humanidad. Nadie es inmune a los efectos de la vejez, ya sea en nosotros mismos o en nuestros seres queridos. Sin embargo, más que un elemento ineludible de la condición humana, el envejecimiento es, de hecho, una característica biológica universal de los animales complejos, y quizá incluso de todos los seres vivos. Desde el punto de vista biológico, el envejecimiento es una disminución gradual de la capacidad de las células y tejidos del cuerpo para preservar su propia integridad y desempeñar sus funciones fisiológicas esenciales. La consecuencia última de este proceso es la incapacidad del cuerpo para sostener su propia existencia, conduciendo a una inevitable ‘muerte por vejez’. Sin importar cuánto esfuerzo se dedique a prolongar la vida, los seres humanos y otros animales parecen venir con una ‘fecha de caducidad’ intrínseca. Pero, ¿por qué ha de ser esto así? ¿Cuál es el origen de tan implacable fuerza de degeneración, y cómo es posible que los humanos seamos incapaces de derrotarla?

La cuestión de cuáles son las causas del envejecimiento, que se remonta a los días de Aristóteles, está en realidad compuesta por dos preguntas muy diferentes. La primera es la pregunta de por qué envejecemos: ¿cuál es la razón biológica última por la que los animales no han desarrollado la capacidad de vivir para siempre? La segunda pregunta es aquélla de cómo envejecemos: ¿cuáles son los procesos fisiológicos inmediatos que hacen que el cuerpo animal se deteriore con el tiempo? Aunque debería ser esperable que nuestro grado de conocimiento varíe entre estos dos niveles de análisis, quizá resulte sorprendente el que sea nuestra comprensión de cómo envejecemos, y no por qué envejecemos, la que actualmente se encuentra menos avanzada. En este ensayo se resume la perspectiva científica actual con respecto a estas dos dimensiones del proceso de envejecimiento.

Por qué envejecemos: las causas evolutivas del envejecimiento

La universalidad del envejecimiento en especies animales fue un hecho problemático para los primeros biólogos evolutivos. A mediados del siglo XIX, Charles Darwin propuso que los rasgos biológicos de las especies son producto de la evolución por selección natural y, por tanto, probablemente han sido útiles para la supervivencia y reproducción de generaciones pasadas. ¿Cómo es posible, entonces, que la evolución no haya producido organismos con la habilidad, claramente beneficiosa, de preservar su juventud indefinidamente?

La primera explicación evolutiva del envejecimiento fue propuesta por el biólogo August Weismann a finales del siglo XIX. Defensor temprano de las nuevas ideas de Darwin, Weismann fue una figura clave en el desarrollo de las primeras teorías sobre la herencia biológica. Para él, la paradoja evolutiva del envejecimiento podía resolverse a base de asumir que la longevidad de un animal es, en efecto, producto de la selección natural, pero no debido a un beneficio para el animal en sí, sino para la especie en su conjunto. Weismann propuso que la esperanza de vida de una especie ha evolucionado hasta un valor óptimo, el cual previene que la población se vea asfixiada por una preponderancia de individuos ancianos. Por tanto, según esta teoría, el envejecimiento es un mecanismo de mortalidad desarrollado específicamente para purgar a las generaciones más viejas y menos competitivas de la población, permitiendo así el éxito de individuos más jóvenes. Un detalle fascinante de esta teoría es su sorprendente coincidencia con las ideas del poeta y filósofo romano Lucrecio.

La explicación del envejecimiento propuesta por Weismann, pese a ser intuitivamente convincente, ha sido desmentida por los biólogos evolutivos de generaciones posteriores. Por una parte, el argumento de que los individuos ancianos deberían ser eliminados por ser menos competitivos que los individuos jóvenes invoca inmediatamente la suposición de que los animales experimentan un envejecimiento fisiológico. Sin embargo, para inferir los orígenes evolutivos del envejecimiento, es necesario partir de una población hipotética cuyos individuos no envejezcan y, por tanto, sólo puedan morir a causa de fuerzas extrínsecas como la depredación, la infección, el hambre o los accidentes. En dicha población, no hay razón para suponer que los individuos de mayor edad estarán en desventaja; en todo caso, el hecho de que hayan sobrevivido durante más tiempo implica que, en promedio, son mejores supervivientes. Además, los individuos de mayor edad contarán con una valiosa experiencia en lo que respecta a las tácticas y maniobras de la vida, de modo que deberían ofrecer una competencia formidable a los individuos jóvenes. Por tanto, sin la suposición previa de un proceso de envejecimiento, la muerte de los individuos ancianos no puede defenderse fácilmente como beneficiosa para la especie.

Otro poderoso argumento contra la teoría de Weismann es el hecho, ahora establecido, de que los rasgos que benefician al colectivo a expensas del individuo son evolutivamente inestables. En la mayoría de las situaciones, la selección natural opera abrumadoramente a nivel del individuo: si un ciervo, por ejemplo, es capaz de correr más rápido que sus congéneres, tendrá menor riesgo de ser depredado y, por lo tanto, mayor probabilidad de dejar descendencia, la cual heredará su superior velocidad. De la misma manera, si una especie desarrolla un proceso de envejecimiento que sea beneficioso para la especie pero perjudicial para el individuo, cualquier individuo que envejezca más lentamente que el resto tendrá una ventaja considerable —igual que el ciervo que es capaz de correr más rápido—, por lo que este rasgo se verá favorecido por la selección natural. El envejecimiento, por tanto, no puede haber evolucionado en beneficio exclusivo de la especie; si bien Weismann parece haber juzgado mal las implicaciones de la teoría de Darwin, podría alegarse en su defensa que al propio Darwin no le habría ido mejor. Ha sido sólo tras un siglo y medio de pensamiento que hemos llegado a entender el envejecimiento no como una consecuencia de la acción directa de la selección natural, sino más bien de su fracaso.

Una de las primeras versiones del concepto que subyace a las teorías modernas del envejecimiento fue propuesta por el influyente genetista matemático J.B.S. Haldane. Durante una inspirada serie de conferencias en 1940, Haldane señaló de pasada que la selección natural debería tener poco poder para eliminar un rasgo deletéreo si dicho rasgo solamente se manifiesta tarde en la vida del individuo. Para entender por qué esto es así, consideremos el caso de interés para Haldane: la enfermedad de Huntington. Pese a sus efectos devastadores y fatales, esta condición degenerativa generalmente comienza a manifestarse pasados los treinta años y, por tanto, tiene poco impacto en la capacidad de una persona para tener descendencia. Para cuando finalmente se diagnostica la enfermedad, es probable que los hijos del paciente ya hayan heredado el gen responsable. Haldane dedujo correctamente que éste es el motivo por el que la selección natural no ha sido capaz de suprimir un gen tan pernicioso. El impacto de la enfermedad de Huntington está confinado a la edad adulta, un periodo de la vida en el que la fuerza de la selección natural disminuye drásticamente, dado que la reproducción ya ha tenido lugar. Este periodo se denomina la ‘sombra selectiva’, porque los efectos biológicos confinados a esta etapa son prácticamente invisibles para la evolución.

Diagrama que ilustra el concepto de ‘sombra selectiva’ (selection shadow), que se refiere a la disminución progresiva de la fuerza de la selección natural pasada la edad de madurez reproductiva (A. Báez Ortega).

El primero en aplicar el concepto de la sombra selectiva en la forma de una teoría completa del envejecimiento fue Peter Medawar, ganador del Premio Nobel en 1960. En la década de 1950, Medawar intentó explicar el envejecimiento como el efecto combinado de una colección de ‘genes mutantes’ —versiones alteradas de genes ‘normales’— cuyos efectos solamente aparecen relativamente tarde en la vida del individuo. Al igual que en el caso de la enfermedad de Huntington, las afecciones relacionadas con la edad, como las cataratas, la artritis y la osteoporosis, son de aparición tardía y no tienen impacto en la reproducción, lo cual impide que la selección natural elimine los genes mutantes implicados. Con el paso de miles de generaciones, un gran número de estos genes problemáticos se han ido acumulando ‘a la sombra’ de la selección, fusionándose sus efectos individuales para dar lugar a lo que llamamos envejecimiento. Medawar también captó la importancia de la mortalidad extrínseca, es decir, la tasa de muerte por fuerzas ambientales como la depredación: cuanto más tarde en la vida se expresen los efectos de un gen, menos individuos permanecerán vivos para experimentarlos. Por lo tanto, un gen que contribuya a prolongar la salud del músculo cardíaco durante muchas décadas podrá ser beneficioso para un elefante, pero carece de utilidad para un ratón que, con casi absoluta certeza, será depredado antes de cumplir los dos años.

Sobre la base del trabajo de Medawar, una teoría posterior propuso que el envejecimiento puede surgir de genes que no sólo tienen efectos negativos en la vejez, sino que también proporcionan beneficios en la juventud, cuando la selección natural tiene mayor fuerza. Según esta teoría, el envejecimiento sería un subproducto nocivo tardío de procesos que han sido favorecidos por ser beneficiosos en edades tempranas. El consenso científico actual es que cada una de estas teorías es probablemente correcta en ciertos casos, de forma que algunos componentes del envejecimiento se han originado a través de la acumulación de genes mutantes puramente perjudiciales, mientras que otros son efectos secundarios tardíos de genes beneficiosos.

Un aspecto importante de estas dos teorías evolutivas es que ambas definen el envejecimiento como el resultado de la incapacidad de la selección natural para mantener la integridad fisiológica durante más tiempo del que es realmente útil ‘en la naturaleza’. La idea fundamental es que no es ventajoso, evolutivamente hablando, vivir más de lo que ya vivimos, porque nuestra especie ha evolucionado para que podamos desarrollarnos y reproducirnos mucho antes de que nuestros cuerpos sucumban a la edad. Es más, debido a que el entorno natural de los primeros humanos hacía muy improbable que estos sobrevivieran tanto como nosotros lo hacemos, no ha habido ninguna necesidad evolutiva de una mayor longevidad. Hay que resaltar que nuestro modelo evolutivo del envejecimiento, el cual está bien respaldado por resultados teóricos y empíricos, no depende de qué mecanismos fisiológicos concretos sean responsables del envejecimiento. En otras palabras, aunque ciertamente entendemos por qué el proceso de envejecimiento existe en primer lugar, la escena es bastante distinta cuando consideramos la cuestión de cómo se desarrolla este proceso en un organismo dado.

Cómo envejecemos: causas mecánicas del envejecimiento

Afortunadamente para los científicos jóvenes, nuestras teorías mecanicistas del envejecimiento son mucho más abundantes y están peor respaldadas que las teorías evolutivas. Quizás la pregunta más inmediata con respecto al proceso de envejecimiento es si éste es consecuencia de un único mecanismo fisiológico o de múltiples mecanismos cuyos efectos están aproximadamente sincronizados. Dada la conclusión de que el envejecimiento es producto de la ineficacia de la selección natural, parece probable que este proceso debe de involucrar múltiples —posiblemente muchos— mecanismos no relacionados entre sí.

Como analogía rudimentaria, consideremos la situación de poseer un coche en una ciudad muy insegura, donde los vehículos son robados o dañados constantemente. En tales circunstancias, la decisión acertada sería adquirir un automóvil barato que pueda sobrevivir unos pocos años, y gastar lo menos posible en mantenimiento, ya que de lo contrario nuestra inversión bien podría ser un fracaso. No obstante, si por un golpe de suerte nos encontrásemos conduciendo el mismo coche al cabo de un buen número de años, no debería sorprendernos que nuestro vehículo nos decepcione en cualquier momento, debido precisamente a que es barato y está mal mantenido. Aunque esta analogía expone de manera poco halagadora la razón principal del envejecimiento —calidad y cuidado insuficientes—, no arroja luz alguna en lo que respecta a cuál de los componentes del coche se espera que falle primero. Dado que la degradación del coche es consecuencia de un mantenimiento deficiente, habríamos de esperar que muchos de sus componentes fallen con mayor y mayor frecuencia, hasta el punto en que la máquina en su conjunto sea incapaz de funcionar. Y diferentes procesos pueden ser responsables del fallo de distintos componentes: la transmisión podría desgastarse por pura fricción, mientras que los cilindros podrían sucumbir al hollín. Por lo tanto, aunque la causa última del envejecimiento pueda ser universal, los procesos inmediatamente involucrados en el mismo son múltiples y diversos.

Tal como sugiere esta analogía, la investigación actual sobre el envejecimiento se centra en la difícil tarea de establecer qué procesos fisiológicos contribuyen al envejecimiento, y cómo de importante es cada uno. Una gran variedad de procesos ha sido propuesta como causas mecánicas del envejecimiento; entre los más interesantes de estos se encuentran las ‘rutas de señalización de nutrientes’, que son redes funcionales de moléculas responsables de transmitir las señales fisiológicas que se generan cuando adquirimos nutrientes. La molécula más popular de esta red es la insulina, esencial para la regulación de los niveles de glucosa en sangre. Sin embargo, además de la bien conocida relación entre las deficiencias en la señalización de insulina y la diabetes, se ha descubierto que intervenciones biológicas que interfieren con la señalización de nutrientes pueden prolongar considerablemente la esperanza de vida de muchas especies, tanto vertebradas como invertebradas. Por ejemplo, un tratamiento conocido como ‘restricción calórica’, el cual consiste en limitar permanentemente el suministro de alimentos (o de ciertos nutrientes), se considera la forma más fiable de extender la vida en animales. Además, la desactivación de ciertos genes de señalización de nutrientes, ya sea por mutación o por tratamiento farmacológico, produce efectos similares a los de la restricción calórica. En la década de 1990, Cynthia Kenyon y sus compañeros descubrieron que mutaciones en uno de estos genes duplican la esperanza de vida de los gusanos nematodos, un hallazgo seguido de resultados similares en moscas de la fruta por los grupos de Linda Partridge y Marc Tatar. Por otra parte, la señalización de nutrientes también regula el crecimiento y desarrollo corporales, de modo que los animales sometidos a estas intervenciones tienden a estar atrofiados y mal desarrollados. Curiosamente, aunque la red de efectos moleculares mediante la cual la señalización de nutrientes modula el desarrollo y la longevidad aún no está completamente caracterizada, se cree que ésta es la razón de que las razas de perro pequeñas sean más longevas que las grandes.

Otro importante candidato entre los posibles mecanismos del envejecimiento es el daño molecular. Las células del cuerpo están constantemente expuestas a muchos tipos de daño químico, que pueden alterar las moléculas que las constituyen y comprometer la eficiencia de los procesos celulares. Los tipos de moléculas sujetas a este daño incluyen las proteínas (las cuales son tanto los ‘materiales de construcción’ de la célula como sus ‘herramientas de trabajo’) y el ADN (el cual almacena la información genética del organismo, incluidas las instrucciones para sintetizar proteínas). Un tipo de modificación del ADN que podría jugar un papel en el envejecimiento es el acortamiento de los telómeros, largos tramos de ADN que se encuentran en los extremos de los cromosomas para preservar su estructura, como el herrete al final del cordón de un zapato. Los telómeros se acortan ligeramente cada vez que una célula se divide en dos, hasta que, finalmente, se vuelven demasiado cortos para permitir nuevas divisiones celulares. Aunque se cree que esta erosión de los telómeros constituye una barrera importante contra el cáncer, es posible que también sea una causa del envejecimiento. Recientemente, la bióloga María Blasco y su equipo informaron del sorprendente hallazgo de que la tasa de acortamiento de los telómeros en una especie está relacionada con su esperanza de vida, de modo que los telómeros se erosionan más rápido en especies de vida más corta. No obstante, esta relación se ve oscurecida por el hecho de que las especies con menor esperanza de vida también tienden a ser más pequeñas, y se sabe que el tamaño corporal influye en muchos aspectos de la fisiología animal.

Imagen de microscopía de fluorescencia que muestra la ubicación de los telómeros (en blanco) en los extremos de los cromosomas de una célula humana (en gris). Los telómeros preservan la integridad del ADN en cada cromosoma, y se ha propuesto que su acortamiento con el tiempo es una causa del envejecimiento (NASA/Wikimedia Commons, dominio público).

Recientemente, trabajando junto con Alex Cagan, Íñigo Martincorena y otros investigadores del Wellcome Sanger Institute, hemos explorado la relación entre la esperanza de vida y otra forma común de modificación del ADN: las mutaciones somáticas. Este término se refiere a los cambios que se acumulan en nuestro ADN con el tiempo; tales mutaciones no están presentes inicialmente en ninguna de nuestras células, sino que van siendo adquiridas por células individuales a medida que nuestros cuerpos crecen y envejecen. La hipótesis de que las mutaciones somáticas contribuyen al envejecimiento se planteó por primera vez en la década de 1960, pero su papel exacto sigue siendo una incógnita. Tras caracterizar la tasa de mutación en dieciséis especies de mamíferos, desde ratones hasta jirafas, encontramos una relación muy similar a la descrita para los telómeros: las especies de vida corta mutan más rápido que las de vida más larga, de tal modo que una célula de ratón adquiere tantas mutaciones en dos años como una célula humana en ochenta. Concluimos, además, que este resultado no se ve afectado por la relación entre la longevidad y el tamaño corporal: al menos en mamíferos, la tasa de mutación somática puede emplearse para predecir la esperanza de vida de una especie, independientemente de su tamaño. El hecho de que las tasas de diferentes formas de daño molecular presentan relaciones similares con la esperanza de vida sugiere —aunque no demuestra— que estas clases de daño pueden estar involucradas en el envejecimiento.

Diagrama que muestra la relación inversa entre la esperanza de vida (lifespan) y la tasa de mutación somática (mutation rate) en 16 especies de mamíferos. La tasa de mutación de cada especie es inversamente proporcional a su esperanza de vida, tal que todas las especies tienen un número similar de mutaciones en su ADN al final de sus respectivas vidas. Esta relación está indicada por la línea azul, con el área sombreada marcando una desviación de esta línea por un factor de dos (Fuente: Cagan, Baez-Ortega et al., 2022).

Aunque pueda parecer inconsistente que procesos tan dispares como la señalización de nutrientes y el daño molecular contribuyan al envejecimiento, estos procesos no son tan remotos cuando se observan a la luz de una teoría del envejecimiento conocida como la teoría del ‘soma desechable’. Según esta explicación, la fisiología de los organismos complejos incorpora un equilibrio energético central, mediante el cual la energía adquirida de los nutrientes se distribuye entre los procesos de mantenimiento somático (la preservación del cuerpo mediante la reparación del daño molecular) y reproducción (la preservación de los genes mediante su transmisión a la descendencia). En lugar de lidiar con el origen evolutivo del envejecimiento, esta teoría proporciona un marco para entender su regulación fisiológica. Dado que el cuerpo (o ‘soma’) es, en última instancia, perecedero, el equilibrio energético entre el mantenimiento y la reproducción supuestamente ha sido optimizado por la evolución para favorecer el costoso proceso de reproducción en tiempos de abundancia, y promover procesos de mantenimiento cuando hay escasez de nutrientes. Por tanto, es posible que disrupciones en la señalización de nutrientes modifiquen la tasa de envejecimiento por interferir con el ‘medidor’ de este sistema de asignación de energía, mientras que el daño molecular puede ser simplemente la fuerza que se opone a los procesos de mantenimiento somático. A pesar de la notable coherencia de la teoría del soma desechable, la evidencia de la existencia de un equilibrio energético universal en animales todavía no es concluyente. Es posible que, como tantas otras cosas en la biología, los sistemas de distribución de energía sean cruciales pero no universales: puede que sean relevantes sólo en ciertas especies, o en algunos órganos, o en periodos concretos de la vida. Incluso en esta época de progreso científico sin precedentes, existe una inmensidad de conocimiento por descubrir acerca de los procesos fisiológicos que contribuyen al envejecimiento.

La batalla contra el envejecimiento

Desde los días de Darwin y Weismann, hemos llegado a comprender el envejecimiento no como una ‘fuerza mortal’ dedicada al beneficio de la especie, sino como una consecuencia inevitable de la forma en que opera la evolución. Los cuerpos animales no han evolucionado con objeto de vivir para siempre, sino de sobrevivir y reproducirse en un entorno despiadado. Nuestra biología es tal y como es precisamente porque nuestros antepasados tuvieron éxito en estas metas, no porque consiguieron vivir para siempre.

Cualesquiera que sean las causas del envejecimiento, la pregunta fundamental para la humanidad es si alguna vez lograremos controlarlas, quizá no con miras a vivir para siempre, sino a disfrutar, al menos, de una salud más duradera y una vejez más feliz. Está claro que este objetivo habrá de permanecer fuera de nuestro alcance mientras no entendamos qué significa exactamente ‘envejecer’ a nivel molecular. Puede que algún día obtengamos el poder de manipular los procesos mediante los cuales nuestros cuerpos mantienen a raya los efectos del tiempo, o incluso de combatir dichos efectos directamente; puede que finalmente seamos capaces de someter y domesticar el proceso de envejecimiento. Pero tales milagros aguardan aún tras el horizonte; en años venideros, tendremos que seguir aprovechando la capacidad de la medicina moderna para tratar cada una de las aflicciones relacionadas con la edad.

Cuando se trata de hacerse viejo, la teoría personal de A.C. Benson —ensayista, poeta y antiguo director (Master) del Magdalene College de Cambridge— tal vez resulte más provechosa que las aquí discutidas: ‘Tengo la teoría de que uno ha de envejecer de forma tranquila y adecuada, que uno ha de estar perfectamente satisfecho con su época en la vida, que las diversiones y ocupaciones deben cambiar natural y fácilmente, y no ser abandonadas con pesadumbre’. Una teoría algo modesta, quizá; Benson no tarda en admitir que ‘es más fácil decir que hacer’. Sin embargo, aun cuando seamos conscientes de la lenta e impasible fuga de la juventud por entre nuestros dedos, conviene no olvidar las palabras de Longfellow:

Pues la vejez es tanto una oportunidad,
Con otro vestido, como la mocedad,
Y en el crepúsculo se viste el firmamento
De estrellas invisibles hasta ese momento.

Weismann, A. ‘The duration of life’ (1881). In Essays Upon Heredity and Kindred Biological Problems (tr. Poulton, EB, Schönland, S, Shipley, AE). Clarendon, 1889.
Haldane, JBS. New Paths in Genetics. Allen & Unwin, 1941.
Kenyon, C, Chang, J et al. A C. elegans mutant that lives twice as long as wild type. Nature, 1993.
Hughes, KA, Reynolds, RM. Evolutionary and mechanistic theories of aging. Annual Review of Entomology, 2005.
Kirkwood, TBL. Understanding the odd science of aging. Cell, 2005.
Flatt, T, Partridge, L. Horizons in the evolution of aging. BMC Biology, 2018.
Whittemore, K, Vera, E et al. Telomere shortening rate predicts species life span. Proceedings of the National Academy of Sciences, 2019.
Cagan, A, Baez-Ortega, A et al. Somatic mutation rates scale with lifespan across mammals. Nature, 2022.

Este artículo es una traducción de un artículo publicado en el Magdalene College Magazine (2021–22).
El autor agradece a James Raven y Aude Fitzsimons sus comentarios sobre el manuscrito original.

Friday, July 23, 2021

On eternal life

(Image credit: Francis C. Franklin/Wikimedia.)

I WAS WALKING along a canal in Cambridge, when I stopped to watch a moorhen and its young chick. They were swimming among the branches of a small fallen tree. The moorhen dived briefly to pick one of the tree’s seedpods; the chick dashed as lightning to devour it. I thought of how both of them were oblivious to anything that had ever been, and anything that was yet to be. Their attention was devoted entirely to this thin slice of life. The adult moorhen was oblivious to the fact that it must die in a few years, if not sooner; the chick ignored that it would very soon be feeding its own progeny. Yet I could see this all too clearly. The chick was but a young version of its parent, and was to be an old version of its own offspring, and would then cease to be. I could see this process unfolding backwards in time through millions of repetitions, as more and more remote ancestors of the moorhen slowly shifted in shape to resemble early birds, then dinosaurs, then amphibians, then fish, then simpler organisms, down to the one cell whose genetic material now inhabits every life form. It was the evidence of this endless natural cycle of existence which doubtlessly inspired the idea of spiritual reincarnation, on which the weight of so many human religions rests.

We humans lie in a strange place in the path of life. An immensely long process of evolution connects us to the first self-replicating cells that came into existence over three billion years ago. As life became able to build biochemical systems of higher complexity, a certain kind of self-awareness gradually emerged, from the rudimentary proprioceptor systems of microorganisms, to the evident understanding of their own existence which animals (and even plants) display, and then to the capacity of higher animals for conscious decision-making. Then came Homo sapiens, an overbrained primate that is not only aware of its own existence, but is also able to ponder deeply about it, pose questions about the world it inhabits, and speculate on the causes and meaning of its own life. Humanity marks the point where life stood up, looked back upon its own wake, and was left speechless by its own inconceivable magnificence. We are the only form of life capable, to any extent, of understanding what life is. And yet we are subject to the same cycle of birth, reproduction and death. We reincarnate ourselves in our children, imperfect copies of us who, like the moorhen’s chick, are bound to retrace the arc of our own lives, make imperfect copies of themselves, and finally perish. Our children will admire the descendants of the birds we admire today, and history will keep passively unfolding, while we convince ourselves that life revolves around the infinitely short slice of time which we happen to inhabit. By understanding this, we have perhaps come as close as it is possible to grasping the endless miracle and the infinite calamity of our existence.

It is the ceaseless replication of every organism which makes life immortal. Because every living being must inevitably die, be it from predation, disease, or mere accident, the genetic information that allows life to function cannot rely on a single vessel. Life’s vessels must be such that they are able to construct brand-new vessels before succumbing to any of the natural forces which conspire against their existence. Like infinitesimally short segments of an unfathomably long pipe, we transmit the precious information of life to its new recipients, unintentionally ensuring that life itself carries on after we have been pushed off the stage. Vessels make new vessels; proteins and lipids are created, degraded, created again; only the information of life, written in DNA, survives forever. After our own death, every product and every memory of our life will inevitably dissolve in the vastness of time, whether it takes one generation or one hundred. But our genes, and the genes of our parents, our ancestors, our children, may live as long as humanity does.

Our species also holds a special place for a different reason. Even if Homo sapiens were to become extinct, as have the vast majority of species which have ever existed, life itself will certainly persist, in one form or another, until the Sun’s death throes transform our planet into a ball of molten rock, billions of years into the future. The end of the Earth will mark the end of terrestrial life, and no trace whatsoever will be left of its long and grand history. For even though life possesses the instruments to withstand the unrelenting destruction of its vessels over eons, it is entirely unprepared for such an extreme prospect. Among the many millions of living species, only ours has become aware of it. And so, as life which is conscious of itself and of its destiny, only we can avert the ultimate ending of life, by carrying it to a new planetary vessel. Although the idea of colonising planets outside our own solar system is still an utterly unrealistic one, the fact remains that, unless another species of comparable or superior intelligence emerges in the far future, this will be the only opportunity for life to survive the death of our planet. Whether humanity will ever be in a position even to consider embarking in this ultimate task of self-replication, only time knows. By then, you will have finished feeding your children, and you will no longer exist; perhaps your children and grandchildren will have ceased to be; but the information which you all carry will still inhabit self-conscious vessels of flesh and blood, driven by new thoughts, new hopes, new feelings. This is eternal life.

Friday, January 1, 2021

A boundless mind

The life of the polymath Thomas Young reminds us of the staggering potential of the human intellect.

Portrait of Thomas Young by Henry Briggs, after an original painted by Sir Thomas Lawrence c. 1822 (Wikimedia Commons).

THOMAS YOUNG (1773–1829) is mainly remembered today as the scientist who, in the early nineteenth century, demonstrated that light behaves as a wave, using his celebrated ‘double slit’ experiment. Significant as this discovery was, however, remembering Young for it alone is but an extremely poor recognition of his achievements. By the time he died at nearly fifty-six years of age, Young had not only proved that light is a wave, but, among other things, he had also demonstrated how the eye focuses on objects, discovering at the same time the phenomenon of astigmatism; he had advanced the three-colour theory of human vision, which was confirmed experimentally in the mid-twentieth century; he had invented ‘Young’s modulus’, an important measure of the elasticity of materials; and he had made foundational contributions to the decipherment of Egyptian hieroglyphs, in addition to deciphering another ancient Egyptian writing system, the demotic script. Besides these major accomplishments in physics, physiology, engineering and Egyptology, Young was also an experienced physician, a distinguished linguist and antiquarian, and a scholarly authority on an astonishingly wide variety of subjects, from astronomy and calculus to carpentry and life insurance. Rather than approaching all these subjects as a mere diversion, Young mastered and made original contributions to each of them. The extraordinary breadth of his knowledge was arguably on par with that of Leonardo Da Vinci; and it is fair to say, indeed, that Thomas Young might have been the world’s last ‘Renaissance man’.

As the writer Andrew Robinson explains in his superb biography of Young, The Last Man Who Knew Everything, Young not only enjoyed a magnificent intellect, but also possessed the attributes which we now associate with the notion of a ‘good scientist’. In doing his scientific and scholarly work, he did not aspire mainly to fame, wealth or social recognition, but rather to the pure satisfaction that accompanies the pursuit of knowledge. In fact, having been trained as a physician, Young published many of his non-medical works anonymously, in the fear that his extraordinarily broad interests might dissuade patients from attending his medical practice, opting to consult more ‘centred’ doctors instead. Moreover, his knowledge of science and his awareness of the flaws of nineteenth-century medicine precluded him from adopting the air of overconfident authority which was expected of physicians, ironically giving the impression that he lacked in expertise. Young was fanatically committed to truthfulness and transparency in his research, and was swift to acknowledge and praise the work of his colleagues and predecessors in every field he studied. Notably, he also was, in both his professional and his personal life, a distinctly modest and self-deprecating man, attaching plenty of significance to the role of chance in his career. In a letter to his lifelong friend, the antiquary and politician Hudson Gurney, he wrote: “It is well for me that I have not to live over again; I doubt if I should make so good a use of my time as mere accident has compelled me to do”. In Robinson’s words, “Young was keen on the idea that what one man had done, another man could also do; he had only a small belief in individual genius”.

Born in 1773 into a large Quaker family in Somerset, England, Young soon gave early evidence of his intellectual voracity: he could read fluently by the age of two, and before he was four he had already read the Bible twice. As a schoolboy, he learned Greek, Latin, French and Italian, and he independently went on to tackle Hebrew, Arabic, Persian, Chaldee, Syriac and Samaritan, developing a familiarity with languages that would prove invaluable in his adult research. With the assistance of some neighbours and family acquaintances who were appreciative of his precociousness, he also built telescopes and microscopes and conducted chemical experiments. Even at this early age, Young had a clear ambition of mastering as many areas of knowledge as he could reach; and, even more remarkably, such curiosity and determination would not abandon him until his dying day. As the majority of child prodigies, he acquired most of his knowledge directly from books: in a letter to his brother, he remarked that “Masters and mistresses are very necessary to compensate for want of inclination and exertion: but whoever would arrive at excellence must be self-taught”. Perhaps one of his most impressive feats as a boy, besides his study of dozens of languages, is the fact that, by the age of seventeen, he had studied Newton’s great scientific treatises, the Principia and the Opticks, in full depth — and there is evidence that he was able to follow their advanced mathematics. This showcases the extreme versatility of mind that would characterise the adult Young; as the writer Isaac Asimov noted, “He was the best kind of infant prodigy, the kind that matures into an adult prodigy”.

At the age of nineteen, Young moved to London in order to being his medical training at one of the city’s private anatomy schools. There, after a dissection of an ox’s eye, he became interested in the process by which the eye focuses on objects located at different distances, known as accommodation. He read all the previous literature on the subject, including the theories of Johannes Kepler and René Descartes. The former had proposed that accommodation is effected by the movement of the crystalline lens (the lens found inside the eye) back and forth along the horizontal axis of the eye, just like the lens of a camera. Descartes, in contrast, had argued that the crystalline lens is fixed, and that accommodation occurs not through its movement, but through a change in its shape. Young’s examination of the ox’s eye led him to conclude that Descartes’s theory was correct, and that the crystalline lens was able to alter its own curvature because it was muscular. This work soon led to Young’s first scientific publication, a paper titled ‘Observations on Vision’, which was read to the Royal Society of London by his great-uncle, the physician Richard Brocklesby, and published in the society’s Philosophical Transactions when Young was still nineteen years old. Today, we know that Young was right in concluding that accommodation occurs through a change in the curvature of the crystalline lens; but the latter is not, in fact, muscular, as he then claimed, being instead surrounded by a set of radial muscles which effect the deformation.

Diagram of the parts of an ox’s eye from Young’s first article (Young, 1793).

The following year, Young was elected a fellow of the Royal Society, one of the highest scientific honours in Britain. Although his work on vision was certainly extraordinary for someone his age, it should be borne in mind that the standards for admission into the society were less strict at the time. As Robinson notes, “It is inconceivable today that even a young man as gifted as Young could be elected a fellow of the Royal Society on the evidence of one scientific publication”. Despite his appreciation of this honour, Young’s lifelong shunning of official titles is patent in the letter where he informs his mother of his election: “I hope I am not thoughtless enough to be dazzled with empty titles which are often conferred on weak heads and on corrupted hearts”.

At the turn of the nineteenth century, university degrees were increasingly important for trained physicians to distinguish themselves from quacks and charlatans, which were not in short supply in London. Hence, in spite of having no special interest in attending university, Young went on to study medicine at the universities of Edinburgh, Göttingen and Cambridge. Driven by his multifarious interests, however, he also took the opportunity to improve his knowledge and skills in plenty of domains other than medicine; writing from Edinburgh to his mother, he made clear that he “by no means wish to confine the cultivation of my mind to what is absolutely necessary for a trading physician”. While in Edinburgh and Göttingen, Young made the acquaintance of classical scholars and took lessons in music, drawing, dancing, flute playing and horsemanship. In 1796, after a total of four years of training, he defended his thesis in Göttingen and became a doctor of medicine. Nevertheless, upon his return to England he discovered that he did not yet qualify to be a licentiate of the Royal College of Physicians, which now asked candidates to have studied for at least two years at the same university. Since Young had not spent enough time in either Edinburgh or Göttingen, he was forced to return to university for another two years. He chose to pursue the degree of bachelor of medicine at Emmanuel College, Cambridge. As he considered the ancient university to offer him little in terms of medical training which he had not already acquired, he spent most of his time reading, writing and carrying out experiments in his college rooms, as well as making the acquaintance of a variety of scholars from across the university. He certainly did not go unnoticed in Emmanuel College, although few fellows were pleased to meet a student who was able to challenge their knowledge of their own disciplines.

Young returned to London in 1800; now finally able to practice medicine, he opened a private practice and started to look for a consultant position at a hospital. Crucially, he had received a considerable inheritance after the death of his great-uncle in 1797, which alleviated his financial dependence on patients, thus allowing him to extend his earlier research on vision. In a lengthy paper titled ‘On the Mechanism of the Eye’, read to the Royal Society in 1800, Young conclusively established how the eye focuses, and also diagnosed and measured astigmatism for the first time — in his own eyes. To achieve this, he first improved an existing instrument for measuring the focal distance of an eye, known as an optometer. He then performed an extremely ingenious — and sometimes disturbing — series of experiments to ascertain whether the eye alters its length or its curvature during accommodation. To discover if his eye’s length changed, he inserted the ring of a metal key into his eye socket, and fixed it against the back of his eye: “The key was forced in as far as the sensibility of the integuments would admit, and was wedged, by a moderate pressure, between the eye and the bone”. In this position, the pressure of the key against his retina caused him to see a bright spot, or ‘phantom’; even a slight change in the eye’s length, he argued, would modify the pressure against the key, and hence the size of this phantom. In this way, he showed that the eye does not alter its length when focusing on objects at different distances. To see whether the eye changed its curvature, he closely examined the shape of a candle’s reflection on another person’s cornea, concluding that the eye’s curvature was also unaltered during accommodation. Finally, to verify that it was the shape of the crystalline lens itself that mattered, Young used his optometer to test the power of accommodation of five people whose crystalline lens had been removed as a treatment for cataracts. This showed that “in an eye deprived of the crystalline lens, the actual focal distance is totally unchangeable”: people without a crystalline lens could not focus their eyes on objects, and needed to use a series of spectacles for looking at objects at different distances. Nevertheless, Young was careful not to reiterate his earlier hypothesis that the lens itself was muscular, of which he was no longer convinced. In fact, the ciliary muscles that cause the crystalline lens to change its curvature would not be discovered for several decades.

Illustration from Young’s second paper on vision, presenting different images as perceived by the author himself during his experiments (Young, 1800).

In addition to his experiments on the eye, Young immersed himself in an investigation of the nature of light, which would lead to his defence of the wave theory of light in two papers read to the Royal Society in 1801 and 1803. In the early nineteenth century, the leading theory of light was still Newton’s ‘corpuscular’ theory, which proposed light to be a stream of particles that move in straight lines through empty space. Competing against this was the ‘undulatory’ or wave theory of the astronomer Christiaan Huygens, according to which light was a wave that spread through an invisible medium known as the ether. Both theories were equally capable of explaining the reflection of light on surfaces; the corpuscular theory, however, was more successful at explaining the rectilinear propagation of light, while the wave theory was better suited to explain refraction (the bending of light rays when passing from one medium to another).

Young’s means for conclusively demonstrating that light behaves as a wave was a phenomenon known as interference. This is easiest to picture using the example of waves in water: if two stones are dropped simultaneously on a quiet pond, they produce two sets of waves on the pond’s surface, which cross each other as they spread. At the points where the crests (or the throughs) of two waves coincide, their effects reinforce each other to produce a higher crest (or a lower trough); while at the points where the crest of one wave coincides with the trough of another, their effects cancel each other and the surface remains level. These two types of interaction are called constructive and destructive interference. Young realised that, if light were a wave, the interference between two light rays would produce an alternating pattern of light and darkness. Such a phenomenon, where light added to light can result in shadow, would be impossible to explain for the corpuscular theory. In a bold leap of intuition, Young went on to propose that the colours of light correspond to waves of different frequency (or wavelength); this immediately allowed his principle of interference to explain the puzzling iridescent colours emitted by certain objects, such as soap films and some insects’ wings. In his 1803 paper, Young presented an experiment where he directed a beam of light through a small aperture, and then split it into two beams using the edge of a card. Although this was not yet his celebrated double-slit experiment, it showed that the interference between the light rays passing through each side of the card gave rise to parallel fringes of light and shadow on a screen. Due to the enormous weight of Newton’s theory, however, few people accepted Young’s conclusions in 1803. Despite this, he was confident of his work; in a letter to a friend, he wrote: “The theory of light and colours, though it did not occupy a large portion of time, I conceive to be of more importance than all that I have ever done, or ever shall do besides”. Indeed, his demonstration that light behaves as a wave is considered to be his most significant contribution to science.

Diagram illustrating the interference between two sets of waves in water, produced using a device of Young’s invention known as a ripple tank (Young, 1807).

Young’s adherence to the wave theory of light, in turn, led to his second major contribution to the understanding of vision: his theory of three-colour vision, advanced in his 1801 paper. In this case, his proposition was closer to a powerful intuition than to a formal theory. It had by then become established that the palette of colours in light was derived from a small number of so-called primary colours, possibly three or five. Young’s breakthrough, derived from his association of colour with wavelength, was to imagine that the brain could perceive light using three distinct types of ‘receptors’ in the retina: one receptor for red light, corresponding to a long wavelength, another for yellow light, with a middle wavelength, and a third for blue light, with a short wavelength. Intermediate colours (with intermediate wavelengths), such as green, would stimulate two types of receptors to a similar degree, resulting in a composite signal which the brain would interpret as green. In this way, Young implicitly advanced the first theory of vision which suggested that the brain not only receives information, but also processes it in order to generate the sensations that we perceive. This idea is one of the cornerstones of modern neurology, proving just how far ahead of his time Young’s intellect was. In fact, Young’s three-colour theory remained entirely forgotten until the 1850s, when it was rediscovered by the physiologist and physicist Hermann Helmholtz, who developed it into a full-fledged theory that would later be extended by the physicist James Clerk Maxwell. It was only in 1959 that two groups of scientists in the United States experimentally demonstrated that colour is perceived through three kinds of receptors which cover the retina. Notably, Young even went as far as to suggest, correctly, that colour blindness is caused by the dysfunction of one of the three types of receptor.

In the period between 1801 and 1803, Young not only worked as a physician and investigated light and vision, but he was also a public lecturer at the Royal Institution of London, where he was appointed professor of natural philosophy in 1801. In fact, this period was possibly the most strenuous in Young’s life: in 1802, he wrote to a friend that “an immediate repetition of the labour and anxiety that I have undergone for the past twelve months would at least make me an invalid for life”. The Royal Institution, founded in 1799 to promote the application of science to society, already had a tradition of holding public lectures on scientific subjects, which included live demonstrations of phenomena like chemical reactions, electricity and magnetism. Young accepted to deliver a course of lectures which would cover virtually all of the physical sciences, and on whose preparation he toiled feverishly for the best part of a year. Over 1802–03, he delivered more than a hundred lectures at the Royal Institution; one of his particular ambitions in doing so was to educate interested people who had no access to education, including women. As he later observed in the introduction to the written version of his lectures, “the Royal Institution may in some degree supply the place of a subordinate university, to those whose sex or situation in life has denied them the advantage of an academical education in the national seminaries of learning”. According to contemporary accounts, however, Young’s facility as a writer did not translate into an engaging style of lecturing, and he did not distinguish himself in this role, especially when compared to eminent Royal Institution lecturers like Michael Faraday and Sir Humphry Davy.

Young’s lectures were published in 1807, as an imposing two-volume book titled A Course of Lectures on Natural Philosophy and the Mechanical Arts. In terms of its scope, depth and degree of original insight, this work remains unsurpassed by any other general lecture course written by a single author. Remarkably, the Lectures included not only Young’s lectures from 1802–03, but also a magnificent historical catalogue listing some twenty thousand scientific works in a wide variety of languages, and spanning everything from ancient Greece to his own time. As Robinson rightly states in his biography, “Only Young, among the scientists of his day, would have had the command of foreign languages, combined with the range, judgement and industry to compile such a monumental bibliography”. Ironically, although Young was more than satisfied with the book, his publisher went bankrupt shortly after its publication, leaving him no reward for such a colossal amount of work.

The contents of the Lectures include only too many examples of its author’s tremendous intuition and foresight. First of all, the book contains a description of the experiment for which Young is best remembered today, the double-slit experiment that confirmed the wave theory of light. Here, instead of using the edge of a card (as in his 1803 paper), he cut two narrow slits on a piece of card, which he used to split a beam of light into two beams and observe the fringes of light and darkness produced by their interference. In addition to this, the book includes the first recorded use of the word ‘energy’ in its modern scientific sense (a measure of a system’s capacity to perform work), the first experimental estimate of a molecule’s diameter (whose prescience is underscored by the fact that the existence of atoms and molecules was rejected by most physicists at the time), and an early proposal of the modern notion that different forms of radiation belong to a single spectrum of wavelength, ranging from ultraviolet light on one end, through the colours of visible light, to infrared light (which, moreover, he correctly linked to heat) on the other end. Thus the Lectures, which constitute Young’s greatest written work, evidence that the claim that he was well ahead of his time is no exaggeration.

A selection of figures from Young’s Lectures, including illustrations of the double-slit experiment (top left) and a colour palette (top right) (Young, 1807).

Notwithstanding his trailblazing work in physics and physiology, and the monumental achievement of his Lectures, Young, who was barely thirty years old, was well aware that he still needed to secure a reputation as a practicing physician in order to procure a stable income for him and his wife Eliza, whom he had married in 1804. He tried to attain this by further feats of scholarship: in 1813 and 1815 he published two exhaustive medical volumes, An Introduction to Medical Literature and A Practical and Historical Treatise on Consumptive Diseases. Just as he had done for science, he not only condensed contemporary medical knowledge, but also catalogued the literature of the previous two thousand years. Nevertheless, instead of granting him reputation as a respectable physician, these two books promoted an undesirable image of Young as a ‘cold man of science’, and antagonised his colleagues by offering too clear a view of the abundant flaws and failures of nineteenth-century medicine. The disappointment caused by the reception of his books was probably the main factor which gradually pushed him away from his ambition to become a leading physician, leaving increasing room for his vast array of more absorbing interests.

One such interest was the quest to decipher the writings of ancient Egypt, in which Young would be involved from 1814 onwards. The main driver of the decipherment effort was the legendary Rosetta Stone, discovered by Napoleon’s army in Egypt in 1799. The crucial feature of the Rosetta Stone is that it carries an inscription in three different scripts: Egyptian hieroglyphs, a second Egyptian script known as demotic, and ancient Greek. The Greek inscription was soon translated, revealing that the other two inscriptions contained the same text; this meant that it might be possible to identify equivalent words in Greek and Egyptian, and employ them to crack the hieroglyphic and demotic scripts. Given his vast experience with languages modern and ancient, Young was excellently equipped for this task. By studying the inscriptions in the Rosetta Stone, besides tirelessly copying and comparing hieroglyphic and demotic inscriptions from a myriad of other sources, he was able to notice subtle similarities and patterns which had been overlooked by other scholars. In particular, Young was the first to notice parallels between some hieroglyphic signs and their equivalent demotic characters, and he went on to show that the two scripts were not unrelated, with demotic being actually derived from hieroglyphic. From this insight, he realised that the demotic script comprised “imitations of the hieroglyphics … mixed with letters of the alphabet”; it was, in other words, a mixture of symbolic characters representing concepts, and phonetic characters representing sounds.

In 1819, Young published a historic article titled ‘Egypt’ in the Encyclopaedia Britannica, which contained the first systematic attempt at deciphering ancient Egyptian writings. In over thirty thousand words, the article presented Young’s results since he began studying the scripts in 1814, including a dictionary with proposed translations for more than four hundred hieroglyphic and demotic words, as well as a tentative ‘alphabet’ for the demotic script. These unprecedented advances were made possible by an earlier suggestion that non-Egyptian names in the inscriptions might be spelled phonetically, in both the demotic and hieroglyphic scripts. Young proved that this was the case by translating the hieroglyphic inscriptions for the names of King Ptolemy and Queen Berenice (though not all his phonetic guesses were correct). Most notably, this article was published anonymously, as Young had by then started to conceal his non-medical research to avoid damaging his reputation as a physician. And, despite having been the indisputable leader of the decipherment effort until then, his endeavour to remain anonymous would prove more harmful than beneficial once the French Egyptologist Jean-François Champollion came onto the scene in 1821.

A letter written by Young in 1818, where he advances meanings for certain groups of hieroglyphs (including the names of Ptolemy and Berenice), most of which were correct (The British Museum).

Champollion and Young were bound to become rivals. For a start, they had opposite personalities: Champollion, who is now considered the father of Egyptology, was passionately devoted to the civilisation of ancient Egypt, and had long wished to visit the Mediterranean country and explore its monumental ruins. His temper, moreover, matched his zeal: he was prone to displays of extreme emotions, and harboured a burning desire for the glory of deciphering the hieroglyphs. Young could hardly have been more different: an incorrigible polymath, his interest in the scripts of ancient Egypt never extended beyond the itch to crack a philological puzzle; he had a calm and candid disposition and, according to his friend Gurney, he “could not bear, in the most common conversation, the slightest degree of exaggeration”. Significantly, it was Young’s own self-deprecation and his anonymity as a researcher which enabled Champollion to claim the sole credit for the decipherment of the hieroglyphs, despite the plain fact that his technique was built upon Young’s earlier findings and his tentative Egyptian dictionary. In fact, a former teacher of Champollion, Sylvestre de Sacy, warned Young as early as 1815 that he should be careful in sharing his discoveries with the French scholar, for “he may hereafter make pretension to the priority”.

Just how much Champollion benefitted from Young’s work can be appreciated by examining his major publications. The first of these appeared in 1821, while he was still oblivious of Young’s 1819 article. Two facts about this publication are very notable: first, Champollion put forward the seriously mistaken notion that the demotic script was composed entirely of conceptual symbols (while Young had already shown that it included phonetic symbols as well); second, once he had come across Young’s article in Paris, it seems that Champollion made a herculean effort to withdraw every single copy of his own article, and was careful not to refer to it in his subsequent publications of 1822 and 1824. Most tellingly, he also avoided any mention of Young’s previous identification of the meanings of many hieroglyphs, including his partly correct deciphering of the names of King Ptolemy and Queen Berenice, as well as other crucial findings, such as the use of certain symbols to indicate female names. When making use of these previous discoveries in his research, Champollion simply referred to them as part of his deductive process, thus implying that they were either well-known facts or his own findings. In reality, the insights gathered by other scholars served him as an essential stepping stone that allowed him to finally decipher the entire hieroglyphic script; what is most disturbing is not the fact that he built on these earlier results — which is a natural part of research — but rather that he adamantly refused to concede any recognition to their original authors. An understandably irritated Young was swift to point out that Champollion had attained his goal “not by any means as superseding my system, but as fully confirming and extending it”. Their irksome dispute notwithstanding, Young never failed to laud Champollion’s crucial contributions to the decipherment; he simply wanted his own contributions recognised. With the benefit of hindsight, it is clear that Champollion was doing himself no favour by insisting on claiming all the credit for the decipherment of the hieroglyphs: the breakthroughs that he achieved in 1822–24, his pioneering explorations of Egyptian ruins and monuments, and his publication of the definitive statement of the decipherment, would undoubtedly have sufficed to secure his legacy as the founder of Egyptology. Instead, Champollion’s egotism became an indelible stain on his reputation; brilliant and industrious as he was, he is also remembered as an arrogant and somewhat dishonest scholar.

Despite the manner in which Champollion had overtaken him and seized the hieroglyphic laurels, Young did not cease to work on the writings of ancient Egypt; after all, the demotic script remained undeciphered, and he now seemed to be in a position to crack it. This was largely due to a providentially helpful papyrus which he encountered in 1822, containing a Greek translation of a demotic text that Young had already spent much time trying to decipher. Thus he expressed his exhilaration at the sheer improbability of this event: “a most extraordinary chance had brought into my possession a document which was not very likely, in the first place, ever to have existed, still less to have been preserved uninjured, for my information, through a period of near two thousand years: but that this very extraordinary translation should have been brought safely to Europe, to England, and to me, at the very moment when it was most of all desirable to me to possess it…”. Notably, Champollion himself, possibly more relaxed after having become a prestigious curator at the Louvre Museum in 1826, offered Young the use of his private notes on the demotic script. With these new resources in hand, Young finally completed the decipherment, becoming the first person to read a demotic text in more than a thousand years. From that moment until his death, he continued to work on what would be his final opus, Rudiments of an Egyptian Dictionary in the Ancient Enchorial Character, published posthumously in 1831.

Three pages from Young’s Rudiments of an Egyptian Dictionary, presenting the meanings of groups of demotic characters (Young, 1831).

It would be easy to believe that the study of Egyptian writing systems, combined with his medical obligations, absorbed all of Young’s time after 1814; but nothing could be farther from the truth. In fact, his polymathic tendencies became even more evident during this period. To begin with, between 1816 and 1825 Young contributed a total of 63 articles to the Encyclopaedia Britannica, writing on an astonishing variety of topics including languages, ocean tides, hydraulics, bridges, Egypt, carpentry, road-making, steam engines and integrals. Some of these articles went beyond mere reviews of existing knowledge, presenting some notable original insights. In addition to the pioneering work on the hieroglyphs in his article on Egypt, Young’s article on languages is particularly noteworthy. In its thirty-three thousand words, he applied his philological knowledge to examine and compare some four hundred ancient and modern languages from across the globe, and classified them into families on the basis of their degree of similarity. In this analysis, he coined the now-popular term ‘Indo-European’ for the family of languages comprising most of the Indian, West Asiatic and European tongues. Young, however, made anonymity a condition of his contributions to the Encyclopaedia; he would not agree to attach his name to his writings until 1823, by which time he had abandoned his ambition of becoming a leading physician.

One factor, besides the underwhelming reception of his books, which prompted Young to gradually steer away from his medical aspirations, was the increasing financial security brought by the multiple government-funded positions that he fulfilled from 1811 onwards. The bodies in which he was asked to serve included a Royal Navy committee to evaluate the adoption of an improved method for the construction of ships; a Royal Society committee requested by the government to assess the safety of introducing coal gas in London; a government commission for comparing the French and English unit systems, and considering the adoption of a more consistent system throughout the British Empire; and the government’s Board of Longitude, which was in charge of a scheme of prizes for solutions to the problem of determining longitude at sea. Notably, in 1820 Young used the influence of his position at the Board to convince the government to establish a major astronomical observatory at the Cape of Good Hope in South Africa. It was because of this array of services to his country that he felt confident enough to write, with distinctive wittiness: “But I do not owe the public much, and I suppose I shall never be paid much of what the public owes me”. And even all this does not capture the entirety of Young’s activities during the 1820s: he also published technical papers on such disparate subjects as the shape and density of the Earth and the theory of life insurance; and he was hired as ‘inspector of calculations’ and physician to a newly founded life insurance company — a position so well paid that he asked for his salary to be reduced. More remarkably, Young was also considered as a candidate for the presidency of the Royal Society (which he had served as foreign secretary since 1804), and had he been interested in the position — or “if I were foolish enough to wish for the office” — he would certainly have been elected.

After an adult life of notable good health, in 1828 Young felt an unaccountable fatigue while visiting Geneva. Early in the following year, he started suffering apparent attacks of asthma, and developed progressive difficulty to breathe and weakness. Even when confined to bed, he nonetheless continued to work on the final proofs of his Rudiments of an Egyptian Dictionary, up to the point where he had to resort to a pencil for being too weak to hold a pen. According to George Peacock, a contemporary biographer of Young, when a friend advised the dying man not to fatigue himself with this work, “he replied that it was no fatigue, but a great amusement to him”. He had almost finished correcting the proofs of his book when he passed away on 10 May 1829, just a month short of his fifty-sixth birthday. An autopsy of his body revealed ‘ossification of the aorta’, today known as advanced atherosclerosis: his aorta had become calcified, hard and narrow, which in the end probably caused progressive kidney failure and pulmonary edema. Why Young suffered from such an advanced form of this disease in his middle age remains a mystery.

Young’s death attracted very little public response. Eulogies were read at the Royal Society and the National Institute of France (which in 1827 had elected Young as foreign associate, an extremely prestigious honour), and a terse note reporting his death was published in the medical journal The Lancet. It was only thanks to the campaigning of Young’s widow Eliza, and his lifelong friend Hudson Gurney, that a memorial plaque was eventually installed in London’s Westminster Abbey, granting Young an immortal place among some of the greatest scientists and artists in British history. Eliza Young is also to be thanked for convincing Peacock to tackle the daunting task of writing a biography of her late husband.

With an unparalleled range of serious academic interests and original contributions to science and scholarship, there can be no doubt that Young was the greatest polymath of his time, even by admission of many of his own contemporaries. It is truly difficult even to grasp how much knowledge he acquired over his five decades of life. Had Nobel prizes existed in the nineteenth century, Young would probably have been awarded one in physics for his demonstration of the wave theory of light, and possibly a second one in physiology for his work on human vision. History, however, is notoriously unsympathetic to polymaths, and Young is often summarised simply as a ‘physician and physicist’ — or even just one of the two. His lifelong attitude toward science is perhaps best expressed in a letter to his friend Gurney: “Scientific investigations are a sort of warfare, carried on in the closet or on the couch against all one’s contemporaries and predecessors; I have often gained a signal victory when I have been half asleep, but more frequently found, on being thoroughly awake, that the enemy had still the advantage of me when I thought I had him fast in a corner — and all this, you see, keeps one alive”.

Just as extraordinary as his intellectual motivation is the fact that Young, unlike some of the greatest scientists of the last three centuries, was a sociable and sensitive individual, with a genuine interest in the arts and a distinct fondness of human company. Robinson sums him up as “a lively, occasionally caustic, letter writer, a fair conversationalist, a knowledgeable musician, a respectable dancer, a tolerable versifier, an accomplished horseman and gymnast, and, throughout his life, a participant in the leading society of London”. At the same time, Young was deeply private about his personal life; almost nothing is known about his wife Eliza, for instance, although their marriage is reported to have been a happy one. Eliza was probably a major reason why Young did not become embittered by the many disappointments, offences, disputes and rejections which marked his professional life.

Given the gradual professionalisation and specialisation of every branch of science over the last two hundred years, it is unlikely that we shall see the like of Thomas Young again. His life, however, remains an awe-inspiring testament to the unbounded potential of the human mind, and a prime example of the original meaning of the word ‘philosopher’. For it was his sheer love of knowledge, his unremitting longing to understand the world, which above all defined him, and ‘kept him alive’.

Robinson, A. The Last Man Who Knew Everything. Pi Press/Oneworld Publications, 2006.
Peacock, G. Life of Thomas Young: M.D., F.R.S., &c. John Murray, 1855.
Young, T. Observations on Vision. Philosophical Transactions of the Royal Society of London, 1793.
Young, T. On the Mechanism of the Eye. Philosophical Transactions of the Royal Society of London, 1800.
Young, T. A Course of Lectures on Natural Philosophy and the Mechanical Arts. Joseph Johnson, 1807.
Young, T. Rudiments of an Egyptian Dictionary in the Ancient Enchorial Character. J. and A. Arch, 1831.