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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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Training a doctor takes years of grueling work in universities and hospitals. Building a doctor may be as easy as teaching an AI how to read.
Artificial intelligence has taken another step towards becoming an integral part of 21st-century medicine. New research out of Guangzhou, China, published February 11th in Nature Medicine Letters, has demonstrated a natural-language processing AI that is capable of out-performing rookie pediatricians in diagnosing common childhood ailments.
The massive study examined the electronic health records (EHR) from nearly 600,000 patients over an 18-month period at the Guangzhou Women and Children’s Medical Center and then compared AI-generated diagnoses against new assessments from physicians with a range of experience.
The verdict? On average, the AI was noticeably more accurate than junior physicians and nearly as reliable as the more senior ones. These results are the latest demonstration that artificial intelligence is on the cusp of becoming a healthcare staple on a global scale.
Less Like a Computer, More Like a Person
To outshine human doctors, the AI first had to become more human. Like IBM’s Watson, the pediatric AI leverages natural language processing, in essence “reading” written notes from EHRs not unlike how a human doctor would review those same records. But the similarities to human doctors don’t end there. The AI is a machine learning classifier (MLC), capable of placing the information learned from the EHRs into categories to improve performance.
Like traditionally-trained pediatricians, the AI broke cases down into major organ groups and infection areas (upper/lower respiratory, gastrointestinal, etc.) before breaking them down even further into subcategories. It could then develop associations between various symptoms and organ groups and use those associations to improve its diagnoses. This hierarchical approach mimics the deductive reasoning human doctors employ.
Another key strength of the AI developed for this study was the enormous size of the dataset collected to teach it: 1,362,559 outpatient visits from 567,498 patients yielded some 101.6 million data points for the MLC to devour on its quest for pediatric dominance. This allowed the AI the depth of learning needed to distinguish and accurately select from the 55 different diagnosis codes across the various organ groups and subcategories.
When comparing against the human doctors, the study used 11,926 records from an unrelated group of children, giving both the MLC and the 20 humans it was compared against an even playing field. The results were clear: while cohorts of senior pediatricians performed better than the AI, junior pediatricians (those with 3-15 years of experience) were outclassed.
Helping, Not Replacing
While the research used a competitive analysis to measure the success of the AI, the results should be seen as anything but hostile to human doctors. The near future of artificial intelligence in medicine will see these machine learning programs augment, not replace, human physicians. The authors of the study specifically call out augmentation as the key short-term application of their work. Triaging incoming patients via intake forms, performing massive metastudies using EHRs, providing rapid ‘second opinions’—the applications for an AI doctor that is better-but-not-the-best are as varied as the healthcare industry itself.
That’s only considering how artificial intelligence could make a positive impact immediately upon implementation. It’s easy to see how long-term use of a diagnostic assistant could reshape the way modern medical institutions approach their work.
Look at how the MLC results fit snugly between the junior and senior physician groups. Essentially, it took nearly 15 years before a physician could consistently out-diagnose the machine. That’s a decade and a half wherein an AI diagnostic assistant would be an invaluable partner—both as a training tool and a safety measure. Likewise, on the other side of the experience curve you have physicians whose performance could be continuously leveraged to improve the AI’s effectiveness. This is a clear opportunity for a symbiotic relationship, with humans and machines each assisting the other as they mature.
Closer to Us, But Still Dependent on Us
No matter the ultimate application, the AI doctors of the future are drawing nearer to us step by step. This latest research is a demonstration that artificial intelligence can mimic the results of human deductive reasoning even in some of the most complex and important decision-making processes. True, the MLC required input from humans to function; both the initial data points and the cases used to evaluate the AI depended on EHRs written by physicians. While every effort was made to design a test schema that removed any indication of the eventual diagnosis, some “data leakage” is bound to occur.
In other words, when AIs use human-created data, they inherit human insight to some degree. Yet the progress made in machine imaging, chatbots, sensors, and other fields all suggest that this dependence on human input is more about where we are right now than where we could be in the near future.
Data, and More Data
That near future may also have some clear winners and losers. For now, those winners seem to be the institutions that can capture and apply the largest sets of data. With a rapidly digitized society gathering incredible amounts of data, China has a clear advantage. Combined with their relatively relaxed approach to privacy, they are likely to continue as one of the driving forces behind machine learning and its applications. So too will Google/Alphabet with their massive medical studies. Data is the uranium in this AI arms race, and everyone seems to be scrambling to collect more.
In a global community that seems increasingly aware of the potential problems arising from this need for and reliance on data, it’s nice to know there’ll be an upside as well. The technology behind AI medical assistants is looking more and more mature—even if we are still struggling to find exactly where, when, and how that technology should first become universal.
Yet wherever we see the next push to make AI a standard tool in a real-world medical setting, I have little doubt it will greatly improve the lives of human patients. Today Doctor AI is performing as well as a human colleague with more than 10 years of experience. By next year or so, it may take twice as long for humans to be competitive. And in a decade, the combined medical knowledge of all human history may be a tool as common as a stethoscope in your doctor’s hands.
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