Clouded history
One of the chief complaints of people as they age is the gradual loss of vision. As humans enter their 4th decade of life, the cornea begins to stiffen and manifests as presbyopia limiting the eye’s ability to focus on close objects. For most people, cataracts begin to emerge in the sixth-to-eighth decade.
By 80, more than half of Americans will have developed cataracts. As we age, the clear protein components that form the lens of our eye begins to degrade. Accelerated by diabetes, hypertension, and UV exposure, we progressively lose vision as the lens of the eye becomes increasingly damaged and cloudy. Cataracts have been recognized as a problem for older adults since antiquity.1
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Cataract surgery is inspired by a singular question: can one restore vision by removing the cloudy lens? The first description of cataract surgery is contested. The first examples of “couching,” or displacement of the cloudy lens to expose the retina to unfocused light, may date to as early as the 6th century BC. Removal of the lens by surgical aspiration was described as early as the 2nd century AD. In the 18th Century, two physicians demonstrated it was possible to remove the lens of the eye.
Samuel Sharp is credited with the first lens extraction, removing the lens and capsule. However, removing the lens does not restore vision.2 Thick refractive glasses can help focus the light, but patients struggled to resolve objects.
Solution: Replacement?
So why not put in a transparent glass lens? The idea of lens replacement is known as pseudophakia.3 Simply, you can! And, it restores vision! But, it has to be the right type of lens. Many materials induce an inflammatory foreign body response in the body.4 But, British physician Sir Harold Ridley had an idea.
During WWII, Ridley observed that British WWII fighter pilots tolerated shards of acrylic (poly(methylmethacrylate), PMMA) in their eyes without an inflammatory immune response. Sir Harold Ridley speculated that if one could create a transparent, biocompatible plastic lens, then one could restore vision. With the help of ophthalmologists John Holt and John Pike, Ridley carefully crafted a plastic lens that mimicked both the shape and refractive properties of human lenses.5
In November of 1949, Ridley implanted the first intraocular lens.6 Handcrafted, he chose plastic because it was light, flexible, and biocompatible. Additionally, the lens could be chemically sterilized with cetrimide. Heat and temperature would distort the plastic lens and gamma-irradiation sterilization had not yet been developed. In creating the plastic lens, he replaced a deteriorated component of the body with a synthetic mimic to restore visual function in patients.
Ridley presented his results in July of 1951 at the American Academy of Ophthalmology in Chicago. He had kept his work private to avoid other surgeons copying his experimental procedure. However, the field received Ridley’s work largely with hostility. Derrik Vail, the former Editor in Chief of the American Journal of Ophthalmology, described Ridley’s lens replacement operation as having “considerable recklessness” indicating that the risk was not worth the benefit and that he wouldn’t advise it for his patients or himself.
Ridley was ostracized from mainstream ophthalmic surgery and abandoned posterior chamber lens implantation research. Ridley also claimed that fellow ophthalmologists threatened to pursue legal charges of malpractice for his experimental work. According to ophthalmic historians Apple and Sims, as late as the 1980s, academic ophthalmologists would recommend against IOL implantation. The head of the British Institute of Ophthalmology, Sir Stewart Duke-Elder, openly derided Ridley’s intraocular lens implantation as “misguided.”
Refinement promotes widespread adoption
However, Ridley’s technique continued to develop. In 1967, American Ophthalmologist and Broadway producer, Charles Kelman developed phacoemulsification. Here, surgeons apply of ultrasonic energy to liquify the lens for easy aspiration. Dissolving the lens prior to extraction minimized the surgical incision transforming the procedure from an inpatient operation to a same-day outpatient operation.
As ophthalmic surgeons further refined the technique with better incision and lens dissolution techniques, cataract surgery was rapidly adopted in the 1980s. When it was introduced into the US in 1970 as an experimental procedure, cataract surgery and the intraocular lens were largely unregulated.7 In 1978, the FDA began tracking cataract surgeries. From 1978 to 1982, the number of intraocular lens implantations nearly tripled to 400,000 annually in the US. Today, nearly two million Americans receive cataract surgery annually.
Today, the operation is fast and low-risk. A fractional percent of patients experience complications. Many patients walk away from the 20 minute operation with at least 20/40 vision the next day. And, innovation hasn’t stopped. Modern surgical techniques and lenses have continued to innovate becoming flexible, multi-focal, and vision enhancing. So, perhaps, one might forgive ophthalmic surgeons for their minor God complexes considering they routinely perform what was once considered a Christ-like miracle.
So, what’s the price of a medical miracle? All-in, about $2,000 per eye.8 Medicare spends about $3.4B annually on cataract surgery.9 For most patients, the synthetic intraocular lens lasts a lifetime. The risk is low as complications appear in <1% of cases for high-volume surgeons. Moreover, cataract surgery can reduce the risk of falls by up to 30%. It also happens to be one of the most cost-effective procedures for the elderly adding 2.8 QALYs over the course of 13 years at a cost of ~$1,500 per QALY. Cataract surgery is, in effect, so cheap that, while pharmaceutical alternatives to preserve the native lens have been explored, no chronic pharmaceutical therapy could compete at the $2000 lifetime price point.10
This, of course, is not to say that vision loss in older adults is solved problem. Age-related macular degeneration (AMD) - e.g. wet AMD, dry AMD or Geographic Atrophy (GA) - remains a leading cause of vision loss in the elderly. However, pharmaceutical innovation has drastically improved outcomes for patients here. VEGF inhibitors (Eylea/Aflibercept, Lucentis/ranibizumab, Vabysmo/Farcimab) and complement inhibitors (Syfovre/pegcetacoplan and Izervay/avacincaptad pegol) effectively halt the progression of wet AMD and GA respectively. The leading VEGF inhibitor for AMD, Eylea, sells about $10B of drug annually. But, unlike cataract surgery, once vision is lost, it’s gone for good… For now.
Vision, unsurprisingly, is a top concern for older adults. By inserting a prosthetic intraocular lens, cataract surgery permanently restores lens function after a single, outpatient intervention. Interventions like cataract surgery offer a template for longevity medicine. Identify the dysfunctional component and replace it. For best results, intervene early before the dysfunction leads to larger, mortality driving complications such as falls and fractures.
What else might we replace?
There are a few replacement-based approaches to managing age-related disorders. Joint replacements (hip, knee) were developed to treat osteoarthritis and mobility limitations. Joint replacements have a similarly fascinating history as a miraculous medical development of mid-1900s, albeit with a less direct path to patients. One could make a similar argument for dentures. Organ transplantation is not presently widely practiced to treat “age-related” disease, although many recipients are older adults. Perhaps if organs become more available with xenotransplantation (Revivicor, eGenesis) or syngeneic organ generation (Renwal), exploration of transplantation for age-related disease might follow a similar arc.
Another opportunity is syngeneic hematopoetic stem cell (HSC) transplantation. Coupled with non-genotoxic conditioning, youthful HSC transplantation could help cure idiopathic anemia of aging. Youthful HSC transplantation could also help cure some severe autoimmune diseases where CAR-T and T-cell-mediated depletion therapies are proving our the “immune reset” concept. Youthful HSC transplantation could also help address emerging clinical phenomena like clonal hematopoesis, the expansion of a single, clonal lineage of progenitor blood cell. Clonal hematopoesis appears to increase the risk of a variety of hematopoietic disorders. Its incidence also increases with age; up to 20% of 80 year-old adults have dominant hematopoietic clones. Clonal hematopoiesis increases CV death and all-cause mortality risk.
Surgical replacement of dysfunctional components is attractive. One big advantage over pharmaceutical solutions is the one-time nature of the procedure. Although many highly skilled surgeons are required to treat an aging population, the one-time expense with lasting benefit is a big win for patients and health systems. However, opportunities for replacement strategies are limited. Some organs - bone, brain, vasculature, skeletal muscle - are not amenable to transplantation. Yet, they still degenerate over time. But, the opportunities to replace failing systems remain large.
How might the next ‘cataract surgery’ emerge today?
One remarkable aspect of the development of cataract surgery is the lack of pre-clinical testing. Ridley, although not a “physician-scientist,” was certainly an experimental physician. No history of cataract surgery I found mentioned animal models of cataract surgery or intraocular lens replacement. Animal models of cataract surgery do exist for cataract surgery research, but these appear recently developed.
What might developing cataract surgery today look like? I’d fathom that the procedure would require extensive non-clinical evaluation in animal models before the FDA would green-light human studies. Perhaps, we’d also want to see a long-term tolerability study in animals, and humans, of the intraocular lens material? Assessment of vision for intraocular lens efficacy can occur shortly after the procedure. In fact, so quickly and with such a large improvement (>20/400 → <20/40), would regulators require an RCT for efficacy? I could see regulators requiring half-decade long safety assessments, perhaps randomized. But, once efficacy is demonstrated, is it ethical (or possible) to maintain a sham-treatment group? All in, an aggressive timeline here might run 10 years from conception to FDA approval?
However, adoption of Ridley’s procedure was quite slow. Concerns from fellow ophthalmic surgeons limited dissemination. While the first presentation of tho operation occurred in 1951, just a couple of years after Ridley’s conception, professional concerns limited dissemination for nearly two decades. Other practitioners eager to advance the practice did harm patients with faulty intraocular lens implants. It wasn’t until the early-1980s that intraocular lens implants became common in ophthalmic surgery.
Would a rigorous pre-approval process have enabled rapid clinical adoption?
The history of cataracts and cataract surgeries is reviewed extensively in Leffler et al. 2020. ATM.
This is contested. Some claim that French ophthalmologist Jaques Daviel developed this technique simultaneously or before Sharp. But, Daviel’s descriptions of the technique are inconsistent and conflicting, so it’s hard adjudicate.
Pseudophakia - false intraocular lens. Pseudo-, from the Greek word "pseudos," means false or fake. -phakia, from the Greek word "phakos," refers to the lens of the eye.
The ophthalmology literature is very proud of Sir Harold Ridley’s invention of the IOL. Most sources cite him as the first person to make the lens, but note that the suggestion came from a Medical Student, Resident, or Fellow observing a cataract extraction. However, surely ophthalmologists pondered this question prior to Ridley’s attempts. Apple and Sims reference sporadic reports of lens transplants (Apple and Sims. Harold Ridley and the Invention of the Intraocular Lens. 1996). Some forms of glass are also biologically inert like PMMA. PMMA, of course, is lighter than glass. I struggled to uncover other attempts. But, I would like to learn more. Specifically, what efforts were made to implant a glass lens prior to Ridley ?
Apple and Sims (1996) suggest that no person involved in the creation of the synthetic intraocular lens filed any patent or sought direct commercialization of the technology. Rather, they claim, the inventors sought to forgo financial reward to avoid conflicts of interest that could compromise the assessment and adoption of the technique.
Ridley formed the lens to conform to estimates of human lenses. However, he could not form an exact replica of the lens before removal. So, the patient had a refractive error of -18D sphere. Without glasses, she likely would have been legally blind.
Today, intraocular lenses are regulated by the FDA as Class III medical devices.
As with everything in US healthcare, the pricing is opaque. Surgeons receive ~$500 per operation, with a slight increase for bi-lateral replacement (less common). All-in, Medicare pays about ~$1600 for outpatient cataract surgery and ~$2600 in hospital cataract surgery.
Cataract surgery is the highest volume procedure at non-hospital ambulatory surgery centers. Cataract surgery facility fees account for 19% of surgery center revenue, more than double that of colonoscopies.
This could be an interesting avenue for dog longevity. Dogs develop cataracts at 5-8 years old, but can live 10-15 years (perhaps longer; rooting for you, Loyal!). There are intraocular lenses for dogs, but cataract surgery for dogs runs $3,000-$4,500. Could a chemical eye-drop or oral cataract treatment restore vision for $100/mo?