Mark Humayun, MD, PhD, was recently featured on Trailblazers, an original podcast hosted by former CNN chairman and CEO Walter Isaacson. The Trailblazers podcast features leaders across society who have shaken up their fields, innovated in ways many would think impossible and charged forward to pioneer changes that excite the way our world operates. Isaacson, who has written best-selling books on innovators ranging from Leonardo da Vinci to Steve Jobs, sat with Humayun to discuss his career as a world-renown ophthalmologist and inventor. The episode highlights the challenges and victories Humayun has encountered along his journey to reverse blindness and restore a glimmer of hope to vision loss patients living in complete darkness.
Isaacson opens the podcast episode, entitled “Eyesight: Vision’s Visionaries,” with the story of Humayun succeeding in his first attempt to use electrodes to stimulate vision during eye surgery. He recounts the miraculous moment in 1992 when Humayun confirmed that his patient, blind for 50 years, was able to see a small but encouraging flicker of light while lying on the operating table. That light, which his patient described as looking like “a candle far off in the distance on a dark night,” marked a turning point in Humayun’s career and a monumental step forward in the field of vision science.
Almost three decades later, Humayun continues to pioneer groundbreaking advancements in ophthalmology and vision restoration. Humayun is widely recognized for his invention of the world’s first artificial retina, which has restored partial vision to hundreds of patients who were previously completely blind. Humayun and his team continue working to surmount the challenges of recreating one of our most sophisticated senses using a network of electrodes, and their current studies are focused on increasing clarity and adding color vision to their artificial sight system. But perhaps the truest measure of Humayun’s success as a trailblazer lies in the most basic and human experiences his patients have regained thanks to their implants: patients often share stories of watching fireworks on the Fourth of July, appreciating the lights on a Christmas tree, or experiencing the joy of playing with their young grandchildren thanks to the gift of sight their implants have given them.
“Everyone said, ‘This cannot happen,’” Humayun explains on Trailblazers, referring to the many obstacles that complicate creating a bionic eye implant, such as the delicacy of the human retina and the challenge of developing an electrode array capable of creating signals that the human brain can discern as meaningful images. “This was actually science fiction,” Humayun surmises, “and we made it science reality.”
To listen to the full podcast episode, click here.
The Argus II retinal prosthesis––often referred to as the world’s first “bionic eye” ––revolutionized the treatment of blindness. Throughout the past decade, this artificial retina, developed by Mark Humayun, MD, PhD and colleagues in collaboration with Second Sight Medical Products, has enabled hundreds of patients around the world with complete retinal blindness to regain partial eyesight.
The invention currently allows for black-and-white vision and particularly helps patients detect boundaries between objects in their surroundings. Using a combination of patient feedback and laboratory experiments, Humayun and his team at the USC Dr. Allen and Charlotte Ginsburg Institute for Biomedical Therapeutics continue to enhance the visual information retinal prostheses can offer patients.
In their latest work, USC Ginsburg Institute scientists, in collaboration with USC Institute for Technology and Medical Systems (ITEMS) engineers, have developed detailed computer models of the retina that enable them to test modifications to the prosthetic system with unprecedented ease and speed. These advances in computational modeling have enabled the team to make profound strides forward in understanding how to refine and build upon the device’s capabilities––with the long-term goal of restoring color vision and more precise visual details to patients with progressive blindness.
A look inside the “bionic eye”
At the most basic level, retinal prostheses work by converting visual information from the environment into electrical impulses that stimulate the otherwise blind retina. When these signals reach the vision center of the brain, known as the visual cortex, patients are able to perceive images and shapes from their surroundings.
The Argus II system involves a retinal implant––or, more specifically, a microelectrode array that sits atop and stimulates the retina––coupled with a pair of glasses outfitted with a camera that transmits signals to the implant. When the implant receives visual cues from the camera, it generates small electrical impulses that stimulate the patient’s retinal cells. This stimulation causes the patient to perceive a flash of light that vision scientists refer to as a phosphene.
Phosphenes should ideally appear as small, rounded dots when a single electrode stimulates the retina. In practice, however, patients sometimes perceive a dash instead of a dot––and the reason has to do with the way cells intermesh in the retina.
One of these cell types is the retinal ganglion cell, which plays an essential role in sending visual information from the eye to the brain. Retinal ganglion cells have rounded bodies with many thin projections branching off in different directions and one long projection that feeds information to the brain. These projections overlap and intertwine like the branches of trees in a densely wooded forest, so that when an electrode stimulates one of the retinal cells it often activates the projections of neighboring cells as well.
When electrical signals from the prosthesis stimulate both cell bodies and projections from nearby cells, patients perceive a dash of light, called an elongated phosphene, instead of a discrete dot. Humayun’s team set out to determine how to prevent elongated phosphenes from forming so patients could enjoy more refined, detailed vision. Doing so required devising an approach to target retinal cell bodies without activating neighboring cells in the process.
Computer models probe deeper into cellular behavior
To solve this challenge, the USC Ginsburg Institute and USC ITEMS teams first developed computational models to recreate different types of retinal ganglion cells and the patterns in which they overlap. Their models accounted for the relevant functional properties of retinal ganglion cells and could therefore respond to stimuli in ways that mimicked how real retinal ganglion cells would respond. Using these model systems, the scientists ran through a gamut of simulations to find a stimulation pattern that activated cell bodies while avoiding the large projections, known as axons, that other cells use to send visual information to the brain.
In one recent study, the team reported their discovery that very short-duration electrical pulses, as brief as 0.1 milliseconds, can selectively target the intended retinal ganglion cells’ bodies without activating their axons. Their models also enabled them to more accurately map out patterns of cellular activation that arise when shorter pulses are used to stimulate the retina. The researchers hope these, and future, findings can help resolve the problem of elongated phosphenes to ultimately offer patients enhanced visual resolution with a retinal prosthesis.
USC Ginsburg Institute and USC ITEMS scientists are also currently using their computational models of the retina to study possible ways of programming additional visual components, such as color, into the Argus II system. A 2020 study of theirs showed that a particular subtype of retinal ganglion cell, called a bistratified cell, is more responsive to high frequency stimulation than one of its counterparts known as a monostratified cell. Understanding these types of slight differences in responses may help the team improve the performance of retinal prosthetics to enable patients to detect color, contrast and edges of objects. Such research is still ongoing, but based on their preliminary findings, the team is hopeful for the ways they can continue enhancing visual perception for the hundreds of retinal prosthesis users who once lived in complete darkness.
Javad Paknahad, a PhD candidate at USC and the lead author on the aforementioned studies, emphasized how the “multi-scale” nature of these models, which account for the properties of single cells as well as the behavior of entire cell populations, makes this approach particularly valuable. He added that using computer models to study the retina allows their team to run experiments more efficiently, which ultimately accelerates scientific progress. “These multi-scale computational models end up saving a lot of time when doing experiments, because as you continue refining the model system and designing the right programs, you can more readily determine the best approaches to solving complex problems,” he said. “This makes computational modeling very powerful.”
Disclosure: Mark Humayun, MD, PhD, is a co-inventor of the Argus implant series. He is a minority equity owner in Second Sight Medical Products, Inc. and receives royalty payment.
Disclosures: Regenerative Patch Technologies LLC was founded by Mark Humayun, MD, PhD, and David R. Hinton, MD, from the University of Southern California, and Dennis O. Clegg, PhD, from the University of California, Santa Barbara. The technology to produce the stem cell–based retinal implant is exclusively licensed to Regenerative Patch Technologies LLC from the University of Southern California, the California Institute of Technology and the University of California, Santa Barbara. Humayun has an equity interest in and is a consultant for Regenerative Patch Technologies LLC.
On November 20th, 2020, the USC Dr. Allen and Charlotte Ginsburg Institute for Biomedical Therapeutics awarded its inaugural Mordechai “Mort” Arditti Award for Excellence to Alejandra Gonzalez-Calle, PhD, a postdoctoral researcher working to develop vision science innovations at the USC Ginsburg Institute.
Gonzalez-Calle grew up in Medellín, Colombia, and earned a BS in biomedical engineering at La Escuela de Ingenieria de Antioquia. As an undergraduate student, she planned to dedicate her career to developing affordable prosthetic limbs. After an accident that caused her to lose vision in her right eye, however, she redirected her energy toward advancing the field of vision science.
In 2009, Gonzalez-Calle reached out to Mark Humayun, MD, PhD, with the hope that she could pursue a research internship at his team’s USC lab. Humayun and his colleagues had an impressive record of churning out engineering-based solutions to address the biological anomalies causing vision loss, and Gonzalez-Calle aspired to join the ranks of this innovative team. That internship ultimately blossomed into over a decade and counting of collaboratively pioneering interdisciplinary, translational approaches to address some of the most confounding challenges in vision science. During that time, Gonzalez-Calle received one of the USC Viterbi School of Engineering’s highest research awards to support her pursuit of a master’s degree in biomedical engineering, and she later went on to earn a PhD in biomedical engineering in 2017.
Some of Gonzalez-Calle’s most meaningful experiences working with the USC Ginsburg Institute team include fine-tuning the Argus II retinal prosthesis to restore eyesight to patients suffering from complete retinal blindness and contributing to the development of a novel stem cell-based retinal implant for patients with AMD. Recently, she worked with a multidisciplinary team that was able to demonstrate, for the first time, that noninvasive electrical stimulation could be used to slow retinal degeneration in pre-clinical models.
Throughout the years spent working on these remarkable feats in biomedical engineering, Gonzalez-Calle has remained continuously inspired by seeing how the projects to which she has contributed can tangibly enhance patients’ lives. “Being able to see our projects evolve from the basic research stage to the point where they are implanted in patients, and then ultimately seeing how much of a difference these interventions can make in patients’ lives, is what makes me so passionate about what I’m doing,” Gonzalez-Calle says.
Receiving the inaugural Mordechai Arditti Award for Excellence carries special meaning for Gonzalez-Calle due to the fact that the late Arditti was an important mentor of hers throughout her training. Arditti, an electrical engineer by training, often contributed to and enhanced Gonzalez-Calle’s projects by helping to build circuits and essential electrical components of the biomedical devices on which Gonzalez-Calle worked. “He was such a special person for all of us,” Gonzalez-Calle remembers. “Besides being a mentor, he was also a friend to all the PhD students. I’m very grateful to receive this award and to feel like it’s coming from him, even though he’s not here with us anymore.”
Dry age-related macular degeneration (dry AMD) poses a significant clinical challenge. It is one of the leading causes of progressive blindness, robbing millions of people over the age of 65 of their central vision, and it often hinders patients’ abilities to read books, drive and discern the faces of their loved ones. Although vitamin-based supplements may slow progression, no treatments currently exist.
A team of physicians and scientists at the USC Dr. Allen and Charlotte Ginsburg Institute for Biomedical Therapeutics (Ginsburg Institute) saw in this situation an opportunity to innovate and pioneer a novel treatment approach for dry AMD patients. Theirs has been a feat of scientific and surgical prowess, and over a decade of their diligence and ingenuity has resulted in what may become the first FDA-approved treatment to transform the prospects of regaining vision for millions of patients.
The Ginsburg Institute team, led by vitreoretinal surgeons Amir Kashani, MD, PhD, associate professor of ophthalmology at the Keck School of Medicine, and Mark Humayun, MD, PhD, director of the Ginsburg Institute and co-director of the USC Roski Eye Institute, developed a stem cell-based retinal implant and accompanying surgical procedure to help restore vision to dry AMD patients. Their innovative approach and insights from their phase 1/2a clinical trial are described in the latest print issue of the American Academy of Ophthalmology’s journal Ophthalmology Retina.
DESIGNING THE IMPLANT
The team accomplished a remarkable multi-part feat that required inventiveness at every turn, starting with designing the novel retinal implant. Dry AMD causes a single layer of cells in the retina called the retinal pigment epithelium (RPE) to deteriorate. The Ginsburg Institute team decided to utilize stem cells to grow RPE tissue in the lab, with the ultimate goal of implanting those cells in patients’ eyes to slow or reverse the damage. Other scientists had attempted to inject stem cell-derived RPE cells into the retina, but had trouble getting the cells to evenly disperse; the Ginsburg Institute scientists instead created a thin membrane made of parylene on which to grow the cells in a single, even layer. Once they had created this RPE layer, the next challenge was to successfully implant it in the eye.
“In practice, being able to get underneath the retina, which is only about a quarter of a millimeter thick, to physically replace the RPE cell layer is a challenging task,” explains Kashani, who is lead author of the publication. “Normally we don’t operate underneath the retina. It’s a place you generally try to avoid during surgery, so that has been a very novel, challenging aspect of delivering these stem cells.”
There are very few tools for performing surgery within the subretinal space. Most available tools were designed 30 to 40 years ago, are relatively bulky and are generally meant to remove scar tissue or other lesions rather than insert anything into the subretinal space. The Ginsburg Institute team decided that the most promising option was to start fresh and design a brand-new tool to fit their purpose.
ENGINEERING THE TOOL
This new tool had to fit a number of criteria: it needed to be made of completely non-toxic materials so as not to harm patients, its design had to be easily reproducible, and it had to be small enough—on a scale of millimeters—to perform minimally invasive surgery inside the eye but large enough to prevent crushing the tissue implant it was meant to deliver.
The surgeons worked with materials and design engineers at the Ginsburg Institute to create single-use forceps with an internal compartment to encapsulate the implant and a roller-style thumbwheel to deploy it. The implant itself is shaped much like a champagne bottle, and the forceps grab onto the narrow end. Rolling the implant into the device’s compartment causes it to fold into a curved shape, and the surgeon can ultimately release it to lay flat inside the eye.
PIONEERING THE SURGICAL TECHNIQUE
With the new instrument and implant came an entirely novel surgical approach. Kashani and Humayun needed to figure out how to create space for the implant in the location of geographic atrophy, which is what doctors call the area of tissue degeneration. To do so, the surgeons decided to create an artificial retinal detachment using a technique called bleb formation, in which a small pocket of space is formed under the retina. “Normally we treat retinal detachments, we don’t make them. In this particular case, we had to create a very well-controlled retinal detachment within an area of scar tissue that is very adherent to the surroundings,” says Kashani. “The challenge was to separate it without damaging the retina.”
In pre-clinical models, creating a bleb alone proved insufficient; the surgeons had to innovate again and ultimately used water pressure to dissect one cell layer from another in a process called targeted hydrodissection. To monitor progress during surgery and prevent complications, the team utilized an advanced imaging technique called optical coherence tomography (OCT) to visualize the dissection at the cellular level. “One part of our job was to make this a very doable surgery and I think we have achieved that with this study,” Kashani says.
“Without tools like OCT, it would be very difficult to visualize the damage we need to treat,” Kashani explains. He emphasizes that in addition to using OCT intraoperatively, he sees a promising role for the technology to be used in earlier-stage AMD patients to monitor the progression of their geographic atrophy. “It’s not a standard of practice to use OCT and other diagnostic methods to detect early and subtle disease changes, but that may prove to be really important for classifying disease and treating it in the future.”
Kashani adds that one of the most rewarding aspects of the entire clinical trial process has been working with his patients and witnessing their commitment to making this translation from research lab to clinical practice possible. “None of this is happening by magic. Patients are volunteering, and they’re taking a chance for the sake of advancing medicine and potentially helping countless other patients down the road. We always appreciate that effort and we thank the patients and their families, too.”
This phase 1/2a trial was supported in large part by a $3.73 million grant from the California Institute for Regenerative Medicine (CIRM). Other authors on the study include Jeremy Uang, BS, of the USC Roski Eye Institute, USC Ginsburg Institute for Biomedical Therapeutics and Department of Ophthalmology, Keck School of Medicine of USC; Melissa Mert, MS, of the Southern California Clinical and Translational Science Institute and USC Department of Preventive Medicine (Biostatistics); Firas Rahhal, MD, of the Retina-Vitreous Associates Medical Group; Clement Chan, MD, of the Southern California Desert Retina Consultants, Palm Desert; Robert L. Avery, MD, of the California Retinal Consultants, Santa Barbara; Pravin Dugel, MD of the Retinal Consultants of Arizona, Phoenix; Sanford Chen, MD, of Orange County Retina, Santa Ana; Jane Lebkowski, PhD, of Regenerative Patch Technologies LLC; Dennis O. Clegg, PhD, of the center for Stem Cell Biology and Engineering, University of California; and David R. Hinton, MD, of the Department of Pathology, Keck School of Medicine of USC.
Mark Humayun, MD, PhD, was featured in an episode of LA Stories with Giselle Fernandez, an Emmy Award-winning series on Spectrum News 1 dedicated to highlighting the “change agents” of Southern California who are shaping the future and imparting lasting changes on our community. Humayun, who serves as director of the USC Dr. Allen and Charlotte Ginsburg Institute for Biomedical Therapeutics and co-director of the USC Roski Eye Institute, was recognized for his pioneering work to treat blindness. On the episode, he shared his family history of practicing medicine, his inspiration to pursue a cure for blindness and his scientific achievements that impact a growing number of patients’ lives each day.
Humayun comes from a long lineage of physicians, but it was his grandmother’s progressive vision loss that spurred his interest in ophthalmology. He had originally planned on becoming a neurosurgeon, but watching his grandmother suffer alerted him to the urgency of curing blindness and he has since dedicated his career to that goal. If his late grandmother could see him today, she would be proud of his tireless commitment to advance the treatment for blindness, from developing the world’s first “bionic eye” to pioneering a stem-cell based treatment to revive the health of patients’ otherwise-degenerating retinas.
Humayun is widely recognized for developing the Argus II retinal implant, which uses electrical stimulation from a computer chip to help blind patients regain some of their eyesight. In 2016, he was awarded the National Medal of Technology and Innovation from President Barack Obama for development of the Argus II retinal implant and his profound and lasting contributions to advancing the biomedical sciences.
Humayun says the goal of developing a bionic eye initially seemed impossible to achieve, but memories of his grandmother’s struggle pushed him to stay dedicated despite the many challenges his team faced. Flash forward to today, and the implants have helped over 300 blind patients around the world partially regain their eyesight and enjoy an improved quality of life. “This idea of putting a computer chip in the eye to restore sight was truly science fiction, but we made it science fact,” Humayun says.
In addition to creating bionic eyes, Humayun and his team at the USC Ginsburg Institute have recently developed a stem-cell based retinal implant to treat age-related macular degeneration, the leading cause of blindness in the United States. Humayun hopes to further enhance the existing implants and make them available to more people. His team is currently integrating features such as infrared technology to help partially blind patients notice and avoid objects like a hot stovetop that could burn them. Such features could be seen as gifting patients with “superhuman” abilities, but Humayun quotes one of his patients who said that rather than making him feel like a cyborg, the bionic eye helps him feel more human because it allows him to interact with his surroundings more like everyone else.
Proof of Humayun’s life-changing work lies in his patients’ testimonies. Terry Byland, the only person in the world to have Argus implants in both of his eyes, was able to see the outline of his teenage son for the first time thanks to the devices. Anna Kuehl, one of the first patients to receive the stem-cell based retinal implant for macular degeneration, has regained enough of her eyesight to see her husband’s face again. Witnessing patients like Byland and Kuehl regain many of the lost joys in their lives inspires Humayun and often makes him think back to his own grandmother to appreciate how far treatment for blindness has come –– and how much further it has yet to go.
“Having that understanding of what my grandmother went through and this understanding of what we have been able to do, I’m able to talk to [patients] and provide them with hope,” Humayun says, and his commitment to enhancing the treatment of blindness despite its challenges is evident. “You just have to say, I’m going to solve this problem, I don’t know how long it’s going to take, but however long it takes, we’ll give it the time because it is worth it.”
To watch Humayun’s complete interview on LA Stories with Giselle Fernandez, click here.