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Lizards can regrow entire limbs. Flatworms, starfish, and sea cucumbers regrow entire bodies. Sharks constantly replace lost teeth, often growing over 20,000 teeth throughout their lifetimes. How can we translate these near-superpowers to humans?
The answer: through the cutting-edge innovations of regenerative medicine.
While big data and artificial intelligence transform how we practice medicine and invent new treatments, regenerative medicine is about replenishing, replacing, and rejuvenating our physical bodies.
In Part 5 of this blog series on Longevity and Vitality, I detail three of the regenerative technologies working together to fully augment our vital human organs.
Replenish: Stem cells, the regenerative engine of the body
Replace: Organ regeneration and bioprinting
Rejuvenate: Young blood and parabiosis
Let’s dive in.
Replenish: Stem Cells – The Regenerative Engine of the Body
Stem cells are undifferentiated cells that can transform into specialized cells such as heart, neurons, liver, lung, skin and so on, and can also divide to produce more stem cells.
In a child or young adult, these stem cells are in large supply, acting as a built-in repair system. They are often summoned to the site of damage or inflammation to repair and restore normal function.
But as we age, our supply of stem cells begins to diminish as much as 100- to 10,000-fold in different tissues and organs. In addition, stem cells undergo genetic mutations, which reduce their quality and effectiveness at renovating and repairing your body.
Imagine your stem cells as a team of repairmen in your newly constructed mansion. When the mansion is new and the repairmen are young, they can fix everything perfectly. But as the repairmen age and reduce in number, your mansion eventually goes into disrepair and finally crumbles.
What if you could restore and rejuvenate your stem cell population?
One option to accomplish this restoration and rejuvenation is to extract and concentrate your own autologous adult stem cells from places like your adipose (or fat) tissue or bone marrow.
These stem cells, however, are fewer in number and have undergone mutations (depending on your age) from their original ‘software code.’ Many scientists and physicians now prefer an alternative source, obtaining stem cells from the placenta or umbilical cord, the leftovers of birth.
These stem cells, available in large supply and expressing the undamaged software of a newborn, can be injected into joints or administered intravenously to rejuvenate and revitalize.
Think of these stem cells as chemical factories generating vital growth factors that can help to reduce inflammation, fight autoimmune disease, increase muscle mass, repair joints, and even revitalize skin and grow hair.
Over the last decade, the number of publications per year on stem cell-related research has increased 40x, and the stem cell market is expected to increase to $297 billion by 2022.
Rising research and development initiatives to develop therapeutic options for chronic diseases and growing demand for regenerative treatment options are the most significant drivers of this budding industry.
Biologists led by Kohji Nishida at Osaka University in Japan have discovered a new way to nurture and grow the tissues that make up the human eyeball. The scientists are able to grow retinas, corneas, the eye’s lens, and more, using only a small sample of adult skin.
In a Stanford study, seven of 18 stroke victims who agreed to stem cell treatments showed remarkable motor function improvements. This treatment could work for other neurodegenerative conditions such as Alzheimer’s, Parkinson’s, and ALS.
Doctors from the USC Neurorestoration Center and Keck Medicine of USC injected stem cells into the damaged cervical spine of a recently paralyzed 21-year-old man. Three months later, he showed dramatic improvement in sensation and movement of both arms.
In 2019, doctors in the U.K. cured a patient with HIV for the second time ever thanks to the efficacy of stem cells. After giving the cancer patient (who also had HIV) an allogeneic haematopoietic (e.g. blood) stem cell treatment for his Hodgkin’s lymphoma, the patient went into long-term HIV remission—18 months and counting at the time of the study’s publication.
Replace: Organ Regeneration and 3D Printing
Every 10 minutes, someone is added to the US organ transplant waiting list, totaling over 113,000 people waiting for replacement organs as of January 2019.
Countless more people in need of ‘spare parts’ never make it onto the waiting list. And on average, 20 people die each day while waiting for a transplant.
As a result, 35 percent of all US deaths (~900,000 people) could be prevented or delayed with access to organ replacements.
The excessive demand for donated organs will only intensify as technologies like self-driving cars make the world safer, given that many organ donors result from auto and motorcycle accidents. Safer vehicles mean less accidents and donations.
Clearly, replacement and regenerative medicine represent a massive opportunity.
Enter United Therapeutics CEO, Dr. Martine Rothblatt. A one-time aerospace entrepreneur (she was the founder of Sirius Satellite Radio), Rothblatt changed careers in the 1990s after her daughter developed a rare lung disease.
Her moonshot today is to create an industry of replacement organs. With an initial focus on diseases of the lung, Rothblatt set out to create replacement lungs. To accomplish this goal, her company United Therapeutics has pursued a number of technologies in parallel.
3D Printing Lungs
In 2017, United teamed up with one of the world’s largest 3D printing companies, 3D Systems, to build a collagen bioprinter and is paying another company, 3Scan, to slice up lungs and create detailed maps of their interior.
This 3D Systems bioprinter now operates according to a method called stereolithography. A UV laser flickers through a shallow pool of collagen doped with photosensitive molecules. Wherever the laser lingers, the collagen cures and becomes solid.
Gradually, the object being printed is lowered and new layers are added. The printer can currently lay down collagen at a resolution of around 20 micrometers, but will need to achieve resolution of a micrometer in size to make the lung functional.
Once a collagen lung scaffold has been printed, the next step is to infuse it with human cells, a process called recellularization.
The goal here is to use stem cells that grow on scaffolding and differentiate, ultimately providing the proper functionality. Early evidence indicates this approach can work.
In 2018, Harvard University experimental surgeon Harald Ott reported that he pumped billions of human cells (from umbilical cords and diced lungs) into a pig lung stripped of its own cells. When Ott’s team reconnected it to a pig’s circulation, the resulting organ showed rudimentary function.
Humanizing Pig Lungs
Another of Rothblatt’s organ manufacturing strategies is called xenotransplantation, the idea of transplanting an animal’s organs into humans who need a replacement.
Given the fact that adult pig organs are similar in size and shape to those of humans, United Therapeutics has focused on genetically engineering pigs to allow humans to use their organs. “It’s actually not rocket science,” said Rothblatt in her 2015 TED talk. “It’s editing one gene after another.”
To accomplish this goal, United Therapeutics made a series of investments in companies such as Revivicor Inc. and Synthetic Genomics Inc., and signed large funding agreements with the University of Maryland, University of Alabama, and New York Presbyterian/Columbia University Medical Center to create xenotransplantation programs for new hearts, kidneys, and lungs, respectively. Rothblatt hopes to see human translation in three to four years.
In preparation for that day, United Therapeutics owns a 132-acre property in Research Triangle Park and built a 275,000-square-foot medical laboratory that will ultimately have the capability to annually produce up to 1,000 sets of healthy pig lungs—known as xenolungs—from genetically engineered pigs.
Lung Ex Vivo Perfusion Systems
Beyond 3D printing and genetically engineering pig lungs, Rothblatt has already begun implementing a third near-term approach to improve the supply of lungs across the US.
Only about 30 percent of potential donor lungs meet transplant criteria in the first place; of those, only about 85 percent of those are usable once they arrive at the surgery center. As a result, nearly 75 percent of possible lungs never make it to the recipient in need.
What if these lungs could be rejuvenated? This concept informs Dr. Rothblatt’s next approach.
In 2016, United Therapeutics invested $41.8 million in TransMedics Inc., an Andover, Massachusetts company that develops ex vivo perfusion systems for donor lungs, hearts, and kidneys.
The XVIVO Perfusion System takes marginal-quality lungs that initially failed to meet transplantation standard-of-care criteria and perfuses and ventilates them at normothermic conditions, providing an opportunity for surgeons to reassess transplant suitability.
Rejuvenate Young Blood and Parabiosis
In HBO’s parody of the Bay Area tech community, Silicon Valley, one of the episodes (Season 4, Episode 5) is named “The Blood Boy.”
In this installment, tech billionaire Gavin Belson (Matt Ross) is meeting with Richard Hendricks (Thomas Middleditch) and his team, speaking about the future of the decentralized internet. A young, muscled twenty-something disrupts the meeting when he rolls in a transfusion stand and silently hooks an intravenous connection between himself and Belson.
Belson then introduces the newcomer as his “transfusion associate” and begins to explain the science of parabiosis: “Regular transfusions of the blood of a younger physically fit donor can significantly retard the aging process.”
While the sitcom is fiction, that science has merit, and the scenario portrayed in the episode is already happening today.
On the first point, research at Stanford and Harvard has demonstrated that older animals, when transfused with the blood of young animals, experience regeneration across many tissues and organs.
The opposite is also true: young animals, when transfused with the blood of older animals, experience accelerated aging. But capitalizing on this virtual fountain of youth has been tricky.
One company, a San Francisco-based startup called Ambrosia, recently commenced one of the trials on parabiosis. Their protocol is simple: Healthy participants aged 35 and older get a transfusion of blood plasma from donors under 25, and researchers monitor their blood over the next two years for molecular indicators of health and aging.
Ambrosia’s founder Jesse Karmazin became interested in launching a company around parabiosis after seeing impressive data from animals and studies conducted abroad in humans: In one trial after another, subjects experience a reversal of aging symptoms across every major organ system. “The effects seem to be almost permanent,” he said. “It’s almost like there’s a resetting of gene expression.”
Infusing your own cord blood stem cells as you age may have tremendous longevity benefits. Following an FDA press release in February 2019, Ambrosia halted its consumer-facing treatment after several months of operation.
Understandably, the FDA raised concerns about the practice of parabiosis because to date, there is a marked lack of clinical data to support the treatment’s effectiveness.
On the other end of the reputability spectrum is a startup called Elevian, spun out of Harvard University. Elevian is approaching longevity with a careful, scientifically validated strategy. (Full Disclosure: I am both an advisor to and investor in Elevian.)
CEO Mark Allen, MD, is joined by a dozen MDs and Ph.Ds out of Harvard. Elevian’s scientific founders started the company after identifying specific circulating factors that may be responsible for the “young blood” effect.
One example: A naturally occurring molecule known as “growth differentiation factor 11,” or GDF11, when injected into aged mice, reproduces many of the regenerative effects of young blood, regenerating heart, brain, muscles, lungs, and kidneys.
More specifically, GDF11 supplementation reduces age-related cardiac hypertrophy, accelerates skeletal muscle repair, improves exercise capacity, improves brain function and cerebral blood flow, and improves metabolism.
Elevian is developing a number of therapeutics that regulate GDF11 and other circulating factors. The goal is to restore our body’s natural regenerative capacity, which Elevian believes can address some of the root causes of age-associated disease with the promise of reversing or preventing many aging-related diseases and extending the healthy lifespan.
In 1992, futurist Leland Kaiser coined the term “regenerative medicine”:
“A new branch of medicine will develop that attempts to change the course of chronic disease and in many instances will regenerate tired and failing organ systems.”
Since then, the powerful regenerative medicine industry has grown exponentially, and this rapid growth is anticipated to continue.
A dramatic extension of the human healthspan is just over the horizon. Soon, we’ll all have the regenerative superpowers previously relegated to a handful of animals and comic books.
What new opportunities open up when anybody, anywhere, and at anytime can regenerate, replenish, and replace entire organs and metabolic systems on command?
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According to some scientists, humans really do have a sixth sense. There’s nothing supernatural about it: the sense of proprioception tells you about the relative positions of your limbs and the rest of your body. Close your eyes, block out all sound, and you can still use this internal “map” of your external body to locate your muscles and body parts – you have an innate sense of the distances between them, and the perception of how they’re moving, above and beyond your sense of touch.
This sense is invaluable for allowing us to coordinate our movements. In humans, the brain integrates senses including touch, heat, and the tension in muscle spindles to allow us to build up this map.
Replicating this complex sense has posed a great challenge for roboticists. We can imagine simulating the sense of sight with cameras, sound with microphones, or touch with pressure-pads. Robots with chemical sensors could be far more accurate than us in smell and taste, but building in proprioception, the robot’s sense of itself and its body, is far more difficult, and is a large part of why humanoid robots are so tricky to get right.
Simultaneous localization and mapping (SLAM) software allows robots to use their own senses to build up a picture of their surroundings and environment, but they’d need a keen sense of the position of their own bodies to interact with it. If something unexpected happens, or in dark environments where primary senses are not available, robots can struggle to keep track of their own position and orientation. For human-robot interaction, wearable robotics, and delicate applications like surgery, tiny differences can be extremely important.
In the case of hard robotics, this is generally solved by using a series of strain and pressure sensors in each joint, which allow the robot to determine how its limbs are positioned. That works fine for rigid robots with a limited number of joints, but for softer, more flexible robots, this information is limited. Roboticists are faced with a dilemma: a vast, complex array of sensors for every degree of freedom in the robot’s movement, or limited skill in proprioception?
New techniques, often involving new arrays of sensory material and machine-learning algorithms to fill in the gaps, are starting to tackle this problem. Take the work of Thomas George Thuruthel and colleagues in Pisa and San Diego, who draw inspiration from the proprioception of humans. In a new paper in Science Robotics, they describe the use of soft sensors distributed through a robotic finger at random. This placement is much like the constant adaptation of sensors in humans and animals, rather than relying on feedback from a limited number of positions.
The sensors allow the soft robot to react to touch and pressure in many different locations, forming a map of itself as it contorts into complicated positions. The machine-learning algorithm serves to interpret the signals from the randomly-distributed sensors: as the finger moves around, it’s observed by a motion capture system. After training the robot’s neural network, it can associate the feedback from the sensors with the position of the finger detected in the motion-capture system, which can then be discarded. The robot observes its own motions to understand the shapes that its soft body can take, and translate them into the language of these soft sensors.
“The advantages of our approach are the ability to predict complex motions and forces that the soft robot experiences (which is difficult with traditional methods) and the fact that it can be applied to multiple types of actuators and sensors,” said Michael Tolley of the University of California San Diego. “Our method also includes redundant sensors, which improves the overall robustness of our predictions.”
The use of machine learning lets the roboticists come up with a reliable model for this complex, non-linear system of motions for the actuators, something difficult to do by directly calculating the expected motion of the soft-bot. It also resembles the human system of proprioception, built on redundant sensors that change and shift in position as we age.
In Search of a Perfect Arm
Another approach to training robots in using their bodies comes from Robert Kwiatkowski and Hod Lipson of Columbia University in New York. In their paper “Task-agnostic self-modeling machines,” also recently published in Science Robotics, they describe a new type of robotic arm.
Robotic arms and hands are getting increasingly dexterous, but training them to grasp a large array of objects and perform many different tasks can be an arduous process. It’s also an extremely valuable skill to get right: Amazon is highly interested in the perfect robot arm. Google hooked together an array of over a dozen robot arms so that they could share information about grasping new objects, in part to cut down on training time.
Individually training a robot arm to perform every individual task takes time and reduces the adaptability of your robot: either you need an ML algorithm with a huge dataset of experiences, or, even worse, you need to hard-code thousands of different motions. Kwiatkowski and Lipson attempt to overcome this by developing a robotic system that has a “strong sense of self”: a model of its own size, shape, and motions.
They do this using deep machine learning. The robot begins with no prior knowledge of its own shape or the underlying physics of its motion. It then repeats a series of a thousand random trajectories, recording the motion of its arm. Kwiatkowski and Lipson compare this to a baby in the first year of life observing the motions of its own hands and limbs, fascinated by picking up and manipulating objects.
Again, once the robot has trained itself to interpret these signals and build up a robust model of its own body, it’s ready for the next stage. Using that deep-learning algorithm, the researchers then ask the robot to design strategies to accomplish simple pick-up and place and handwriting tasks. Rather than laboriously and narrowly training itself for each individual task, limiting its abilities to a very narrow set of circumstances, the robot can now strategize how to use its arm for a much wider range of situations, with no additional task-specific training.
In a further experiment, the researchers replaced part of the arm with a “deformed” component, intended to simulate what might happen if the robot was damaged. The robot can then detect that something’s up and “reconfigure” itself, reconstructing its self-model by going through the training exercises once again; it was then able to perform the same tasks with only a small reduction in accuracy.
Machine learning techniques are opening up the field of robotics in ways we’ve never seen before. Combining them with our understanding of how humans and other animals are able to sense and interact with the world around us is bringing robotics closer and closer to becoming truly flexible and adaptable, and, eventually, omnipresent.
But before they can get out and shape the world, as these studies show, they will need to understand themselves.
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