Perspectives On Medical Research

Volume 5, 1995

Aping Science

A Critical Analysis of Research at the Yerkes
Regional Primate Research Center

C. Neurobiology (Vision)

Researchers have used cats and rabbits extensively in vision and eye research. However, fundamental anatomical differences between these species and humans severely undermine the clinical applicability of such research projects.^1-4 This species differential has spurred interest in nonhuman primate "models," and the regional primate research centers have focused considerable attention to such research. Nevertheless, despite nonhuman primates' resemblance to humans in certain ways, primate vision research is still compromised by problems inherent in all animal modelling.^5-9 A review of projects at the Yerkes Regional Primate Research Center illustrates difficulties of cross-species research in this area.¹⁰ In fact, such research difficulties would justify wider use of human clinical modalities.^6-9


1. Amblyopia Research

A major research area at Yerkes involves studies of the neurophysiological changes associated with various types of visual deprivation. Disruption of normal vision during a critical period of childhood results in permanent visual loss in all primates. This process, known as amblyopia, has been induced by Yerkes researchers by several means.


Eyelid Suturing

James Wilson and colleagues sutured one eyelid of monkeys, at different times after birth, and maintained this state of monocular deprivation for various periods.¹¹ Some monkeys underwent subsequent lid-closure of the other eye. They concluded, "These results indicate that the effects of monocular deprivation on macaque monkeys are affected by the start, length, and type of deprivation."¹¹ This finding has already been well-established in humans and is hardly surprising in monkeys. Wilson and co-authors also contend that their results relate to theories of amblyopic development, yet it is virtually impossible to apply these findings to humans. Eyelid suturing of primates causes visual deprivation that differs from cataracts, corneal opacities, and other common forms of human visual deprivation in the quality and quantity of light received by the retina.^12,13 Also, while monkey neurophysiology is similar to that of humans, it is not the same. For example, primate data have provided misleading information about the critical period during which amblyopia develops in humans.¹⁴ Without accurate human data, it is not possible to determine whether or not the monkey data could ever be extrapolated to humans. In any case, the monkey data becomes irrelevant.

Nonetheless, Wilson and his co-workers have called for more animal research: "Clearly, more data from monkeys that are reared with systematically varied onsets and lengths of deprivation will be necessary before the relevant factors leading to changes in various parts of the visual field can be isolated."¹¹


Surgical Aphakia (removal of natural lens)

Wilson and colleagues removed the natural lenses of monkeys at 7-14 days of age and corrected the aphakia (lack of lens) of some animals with contact lenses.¹⁵ Some protocols involved occluding the phakic (with lens in place) eye for different periods of time. They have written, "We conclude that aphakic eyes should be treated by providing them with an optical correction, and that occlusion of the opposite eye should be used cautiously."¹⁵ These principles are already part of the standard management of human congenital cataract and were derived from human clinical observations.

Primates "models" of surgical aphakia leave unanswered many questions concerning the human eye condition. For example, can the aphakic eyes ever reach normal adult levels of vision? Are the 50-80% daily patching regiments that have been used most frequently as part of treatment for unilateral cataracts the best way to maintain vision in the aphakic eye? How important is compliance with optical correction and patching? To what distance should aphakic eyes be focused using contact lenses or other means of optical correction? What is the optimal distance for optical correction for the aphakic eyes? These and other critical questions can only be answered by investigations of aphakic human children.

Animal studies are further undermined by differences in the mechanisms of disease induction. Whereas congenital cataracts are present at birth, the Yerkes researchers removed the primates' lenses at 7-14 days of age. They have attributed the monkeys' surprisingly good visual outcomes to the initial days of normal vision.

They have written, "We are now pursuing studies with monkeys that more closely simulate congenital cataracts."¹⁵ Because the monkey data contradicted existing human clinical data, the researchers dismissed that monkey data as an artifact of the unnatural means of disease induction. Because all such research involves artificial means of disease induction, it is impossible to determine without human clinical data whether a given finding reflects laboratory artifact or whether it actually accords with human conditions.

In a report involving both eyelid suture and aphalda, Wilson and colleagues studied monkeys that had undergone eyelid suturing or lens extraction, followed by various kinds of optical correction.¹⁶ They have written, "The major finding was that the effects of various treatments on the aphakic eye varied in degree depending upon the amount of focused pattern input received by the aphakic eye compared to its fellow eye."¹⁶ This conclusion merely accords with human clinical experience and numerous other animal experiments.

Wilson and colleagues also used different parameters to assess visual function. They found, "The behavioral, electrophysiological and anatomical assessments of the treatment effects on the aphakic eyes correlated closely with each other."¹⁶ The behavioral studies involved performance at various visual tasks. These electrophysiological and anatomical experiments, which correlated visual function with single-neuron recordings in the brain and neuronal connections in various parts of the brain, are best described as "basic science;" they attempt to define fundamental principles that have little, if any clinical relevance.¹ Hundreds of such projects have only demonstrated correlations between visual function and brain anatomy or activity. They cannot elucidate the nature of visual perception, which is a psychological phenomenon and requires language to report. As in the case of neurophysiologic study of language, "It is useless to look for physiologic units unless we know what, functionally speaking, they are units of."^16a

Yerkes officials also claim that monkey studies have shown that aggressively patching one eye in order to force an amblyopic eye to see during the "critical period," helped to reverse amblyopia and caused amblyopia in the patched, formerly "good" eye.¹⁰ This is hardly surprising, given that lack of vision underlies amblyopia. Indeed, this "finding" has long been well-documented in the clinical literature.¹⁷

Much of the information sought using animal research can now be gained safely and accurately with non-invasive imaging technologies. For example, modern magnetic resonance imaging technologies can assess visual cortex function with a resolution of 1.4 millimeters.¹⁸ Other powerful clinical research tools that can address such basic science issues include CAT scans,¹⁹ PET scans,²⁰ and autopsy studies.²¹ Such studies are much more likely to elucidate human neuroanatomic questions, because interspecies differences in neuroanatomy, well-documented in the primate literature, undermine nonhuman data. For example, squirrel and owl monkeys have differences in cortical representation of body surfaces.²² In addition to its limited relevance to basic knowledge of visual system neurophysiology, nonhuman primate research is poorly equipped to address clinically relevant issues, such as how to manage amblyopia. For example, nonhuman research cannot determine the optimal time to operate to correct strabismus or congenital cataracts or the best treatment for aphakia.

Although human clinical investigation remains the most appropriate modality by which to answer such questions, Wilson and co-authors have continued to argue for more primate research "to determine if part-time occlusion or other optical correction paradigms can achieve optimal visual acuities and connections along the visual pathways of both eyes. Such results would have significant clinical relevance because similar methods to those used on our monkeys could be used for treating human infants born with monocular cataracts."¹⁶


Strabismus (misalignment of the eyes)

Several Yerkes studies have looked at the effects of amblyopia on eye alignment. For example, Michael Quick and co-workers have reported that various forms of visual deprivation or abnormal visual experience can induce strabismus in infant monkeys.²³ Long before visual deprivation experiments on animals, it was well known that early visual disturbance or deprivation can cause strabismus in humans,^14,24-31 and later cat experiments accorded with the previous human clinical observations.^32,33

Quick and colleague's contribution was primarily that deprivation-induced strabismus can also occur in monkeys: "These results on deprivation-induced strabismus are consistent with previous findings in cats and humans."²³ Quick and co-workers have suggested that their findings are important because previous investigators have failed to induce strabismus in monkeys, a failure that has led Arthur Jampolsky and others to question the value of monkey research in elucidating human ocular alignment.³⁴ By disrupting monkeys' visual input earlier than other investigators, Quick's group merely produced in monkeys a condition that resembles one already well described in humans.

Jampolsky has also noted that common forms of strabismus in humans are rarely, if ever, found naturally in monkeys. Many monkeys exhibit similar problems thought to cause misalignment in humans, such as unequal eye size and visual systems that focus light poorly. Yet, they do not exhibit intermittent exotropia, accommodative esotropia, A and V patterns, dissociated vertical deviation, latent nystagmus, and other common features of human strabismus. Furthermore, it is extremely difficult to create strabismus in monkeys surgically, and the resulting misalignment tends to differ profoundly from human strabismus.³⁴

Quick and colleagues have also claimed that their research addresses the question of whether amblyopia results from imbalanced visual input or from strabismus (which can be induced by imbalanced visual input). However, by surgically inducing strabismus in monkeys, it is impossible to determine whether the eye misalignment is the cause or the consequence of amblyopia. Human clinical studies of different forms of strabismus and amblyopia have shown, on the other hand, that children with congenital strabismus tend to develop amblyopia despite normal visual inputs to their eyes, and children with congenital cataracts can also develop amblyopia despite good ocular alignment. Therefore, both mechanisms appear to be possible in humans. Whether both mechanisms are possible in nonhuman primates, is a different, and irrelevant, issue.

Quick and co-workers have also asserted, "Our results are also important clinically, especially in the case of children who suffer from early visual disorders." Yet, they do not detail how their results apply to management of such children. They have claimed, "Studies with animals have the potential for determining the sufficient conditions for inducing ocular misalignment," but they have failed to explain just how. At best, monkey experiments may suggest conditions that predispose to eye misalignment, but no monkey experiment can determine with confidence and precision the sufficient conditions in humans.

Similarly, Ronald Boothe and colleagues found that two monkeys with congenital esotropia (eyes turned in) had absent or small accessory lateral rectus (ALR) muscles.35 They have speculated that the frequency of human esotropia may reflect the absence of this muscle in humans: "It may be that frequent esodeviations will be found only in genetic lines of primates in which the ALR is small or absent. These could include entire species, such as humans, and also genetic lines within species ..."³⁵ The assumption that animal data can be reliably applied to humans has again proved spurious, for clinically, in humans with esotropia, the lateral rectus appears normal. In the unlikely event clinicians feel inspired to pursue this inter-species hypothesis further, they will have to study human anatomy.

Quick and colleagues also studied various cases of naturally occurring strabismus in monkeys. They have concluded, "These results demonstrate that naturally occurring strabismus in monkeys might be related to syndromes seen in children."³⁶ Of course, they might be related, but this is impossible to determine unless the human and animal conditions are both well known.


2. Onchocerciasis

Yerkes officials have written that a vaccine to prevent onchocerciasis (the causative agent of "river blindness") "may be expedited" by mangabey research at the Yerkes Center. This highly speculative conclusion is based on the recognition that mangabey monkeys may develop antibodies to a certain onchocercosis (O. volvulus) antigen that is also found in humans who appear immune to the parasite.³⁷ The evidence from Yerkes is very tenuous. Of the three mangabeys that became infected, one did not develop this antibody, one that did still became infected with onchocercosis organisms (but had a low skin titer of the organism), and one was evidently free of organisms. Eberhard and colleagues have written about the similarities of certain animal models of onchocerciasis to analogous human conditions:

It would appear that O. volvulus infections in mangabey monkeys behave more like infections in humans who are "immune," or filaria-negative (unpublished data). The infection in chimpanzees, on the other hand, is more like that observed in filaria-positive [infected] persons."³⁷

At this point, all that is known is that some primates exhibit patterns of O. volvulus infection that superficially resemble certain types of human infection patterns. Given differences between humans and nonhuman primates in responses to many other pathogens (see, for example, the previous section on AIDS research), any predictions of clinical value are, at this point, highly speculative.


3. Intraocular Lenses

Yerkes literature has asserted that its primate research is pioneering efforts to use intraocular (inside the eye) lenses or contact lenses to correct aphakia in infants who have had surgery for congenital cataracts. Using contact lenses has been the standard treatment of aphakia in human infants for decades.³⁸ It is also well known that intraocular lenses are poorly tolerated by human babies, who develop intense inflammatory reactions to the lenses (unlike human adults). Furthermore, normal human eye growth adds another problematic variable, because an intraocular lens properly fitted in an infant will likely be too small for an adult. Yerkes researchers have also tried intracorneal lens implants, with little success to date.^39,40 A related procedure in which grafts are sewn onto human corneas has tended to induce permanent cornea! scarring, and it is unlikely that intracorneal lenses on nonhuman primates will fare better. While Yerkes literature suggests that their nonhuman primate studies offer hope for managing aphakic infants, clinical evidence suggests that their approaches will not benefit humans.


4. Myopia (nearsightedness)

Margarete Tigges and colleagues have studied myopia due to eye elongation in normal rhesus monkeys and in monkeys who experienced different kinds of visual deprivation.⁴¹ These projects originated with David Hubel and Torsten Wiesel's observation in the 1960s that kittens' eyes that were sutured shortly after birth grew longer than unmanipulated eyes.⁴² In fact, even prior to Hubel and Wiesel's finding, there had been numerous prior studies with human subjects aimed at determining whether visual deprivation causes an eye to elongate.⁴³ These studies had conflicting results, but more recent clinical studies have shown that certain kinds of visual deprivation do cause human eyes to elongate.^44-47 Several hereditary and environmental factors contribute to human pathological myopia, and, despite a plethora of monkey and cat studies, only human studies will untangle this complex issue. Nonhuman primate studies have been conflicting, making their applicability doubtful. For example, atropine administration prevents eye elongation from eyelid suturing in Macaca arctoides but not Macaca mulatta. This suggests that even closely related primate species can have different mechanisms of eye elongation. Furthermore, in both Macaca species eye elongation was highly variable among individuals in the same species, suggesting that hereditary factors or other factors contribute to the eye's final size, similar to the differences in cortical representation of body surfaces found in squirrel and owl monkeys.²² Given that species-specific as well as individual factors influence eye size in nonhuman primates, it is difficult, if not impossible, to extrapolate such variable experimental findings to humans.

The inadequacy of the animal "model" in studies of myopia have been illustrated by later research by Elio Raviola and Wiesel; their photographs⁴² have revealed the poor correlation of this model with human myopia. One photograph shows a myopic M. mulatta eye with very visible choroidal blood vessels, a common finding in human myopic eyes. However, choroidal blood vessels are also easily visible in the "normal" monkey eye Raviola and Wiesel have provided for comparison. Another supposed parallel between monkey and human myopia is a temporal crescent adjacent to the optic nerve, which represents retinal and choroidal tissues not reaching the nerve during development. But, the photographed myopic monkey has only a small temporal crescent, which is a common finding in non-myopic human eyes, and differs from the large temporal crescent often seen in pathological human myopia. Raviola and Wiesel have not reported in monkeys other common findings of human myopia, such as lacquer cracks, Fuch's spots, or posterior staphylomas. Noting the inconsistent presentation of visible choroidal vessels and temporal crescents in these monkeys, Raviola and Wiesel have remarked, "Similar inconsistency in the appearance of the fundus is a common clinical finding in advanced human myopia." This is not a sound basis for an animal model of human myopia.


5. Corneal Sizes

Christine Zurawski and colleagues measured corneal sizes and curvatures of 76 adult and 10 infant rhesus monkeys as baseline data for further research.⁴⁸ Since rhesus monkeys have smaller and steeper corneas than humans, these data are relevant only to rhesus monkeys. In addition, Zurawski et al. measured the refractive states of the monkeys. However, their data are highly suspect because a previous study had shown that cage-born monkeys are more nearsighted than wild-born,⁴⁹ and Zurawski et al. did not know the birth status of some of the monkeys.


Summary

While the visual systems of all mammals are similar, in its details the human visual system is unique. While animal research can contribute to "basic science" data, it is impossible to determine whether or not these data apply to humans until after human data are obtained. Fortunately, clinical research modalities are recognized as powerful tools. Clinical studies have greatly enhanced medicine's understanding of amblyopia,^26,50-55 and autopsies and non-invasive imaging technologies have significantly elucidated human visual system neuroanatomy and physiology.^{19-21, 56-61} These Yerkes vision studies have illustrated that, in general: 1) clinical hypotheses are generated by clinical studies, 2) monkey data often differs from human data, 3) monkey studies are unnecessary for developing human treatment approaches, and 4) monkey data's applicability to humans is tenuous, at best.


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