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#434580 How Genome Sequencing and Senolytics Can ...
The causes of aging are extremely complex and unclear. With the dramatic demonetization of genome reading and editing over the past decade, and Big Pharma, startups, and the FDA starting to face aging as a disease, we are starting to find practical ways to extend our healthspan.
Here, in Part 2 of a series of blogs on longevity and vitality, I explore how genome sequencing and editing, along with new classes of anti-aging drugs, are augmenting our biology to further extend our healthy lives.
In this blog I’ll cover two classes of emerging technologies:
Genome Sequencing and Editing;
Senolytics, Nutraceuticals & Pharmaceuticals.
Let’s dive in.
Genome Sequencing & Editing
Your genome is the software that runs your body.
A sequence of 3.2 billion letters makes you “you.” These base pairs of A’s, T’s, C’s, and G’s determine your hair color, your height, your personality, your propensity to disease, your lifespan, and so on.
Until recently, it’s been very difficult to rapidly and cheaply “read” these letters—and even more difficult to understand what they mean.
Since 2001, the cost to sequence a whole human genome has plummeted exponentially, outpacing Moore’s Law threefold. From an initial cost of $3.7 billion, it dropped to $10 million in 2006, and to $5,000 in 2012.
Today, the cost of genome sequencing has dropped below $500, and according to Illumina, the world’s leading sequencing company, the process will soon cost about $100 and take about an hour to complete.
This represents one of the most powerful and transformative technology revolutions in healthcare.
When we understand your genome, we’ll be able to understand how to optimize “you.”
We’ll know the perfect foods, the perfect drugs, the perfect exercise regimen, and the perfect supplements, just for you.
We’ll understand what microbiome types, or gut flora, are ideal for you (more on this in a later blog).
We’ll accurately predict how specific sedatives and medicines will impact you.
We’ll learn which diseases and illnesses you’re most likely to develop and, more importantly, how to best prevent them from developing in the first place (rather than trying to cure them after the fact).
CRISPR Gene Editing
In addition to reading the human genome, scientists can now edit a genome using a naturally-occurring biological system discovered in 1987 called CRISPR/Cas9.
Short for Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated protein 9, the editing system was adapted from a naturally-occurring defense system found in bacteria.
Here’s how it works:
The bacteria capture snippets of DNA from invading viruses (or bacteriophage) and use them to create DNA segments known as CRISPR arrays.
The CRISPR arrays allow the bacteria to “remember” the viruses (or closely related ones), and defend against future invasions.
If the viruses attack again, the bacteria produce RNA segments from the CRISPR arrays to target the viruses’ DNA. The bacteria then use Cas9 to cut the DNA apart, which disables the virus.
Most importantly, CRISPR is cheap, quick, easy to use, and more accurate than all previous gene editing methods. As a result, CRISPR/Cas9 has swept through labs around the world as the way to edit a genome.
A short search in the literature will show an exponential rise in the number of CRISPR-related publications and patents.
2018: Filled With CRISPR Breakthroughs
Early results are impressive. Researchers from the University of Chicago recently used CRISPR to genetically engineer cocaine resistance into mice.
Researchers at the University of Texas Southwestern Medical Center used CRISPR to reverse the gene defect causing Duchenne muscular dystrophy (DMD) in dogs (DMD is the most common fatal genetic disease in children).
With great power comes great responsibility, and moral and ethical dilemmas.
In 2015, Chinese scientists sparked global controversy when they first edited human embryo cells in the lab with the goal of modifying genes that would make the child resistant to smallpox, HIV, and cholera.
Three years later, in November 2018, researcher He Jiankui informed the world that the first set of CRISPR-engineered female twins had been delivered.
To accomplish his goal, Jiankui deleted a region of a receptor on the surface of white blood cells known as CCR5, introducing a rare, natural genetic variation that makes it more difficult for HIV to infect its favorite target, white blood cells.
Setting aside the significant ethical conversations, CRISPR will soon provide us the tools to eliminate diseases, create hardier offspring, produce new environmentally resistant crops, and even wipe out pathogens.
Senolytics, Nutraceuticals & Pharmaceuticals
Over the arc of your life, the cells in your body divide until they reach what is known as the Hayflick limit, or the number of times a normal human cell population will divide before cell division stops, which is typically about 50 divisions.
What normally follows next is programmed cell death or destruction by the immune system. A very small fraction of cells, however, become senescent cells and evade this fate to linger indefinitely.
These lingering cells secrete a potent mix of molecules that triggers chronic inflammation, damages the surrounding tissue structures, and changes the behavior of nearby cells for the worse.
Senescent cells appear to be one of the root causes of aging, causing everything from fibrosis and blood vessel calcification, to localized inflammatory conditions such as osteoarthritis, to diminished lung function.
Fortunately, both the scientific and entrepreneurial communities have begun to work on senolytic therapies, moving the technology for selectively destroying senescent cells out of the laboratory and into a half-dozen startup companies.
Prominent companies in the field include the following:
Unity Biotechnology is developing senolytic medicines to selectively eliminate senescent cells with an initial focus on delivering localized therapy in osteoarthritis, ophthalmology and pulmonary disease.
Oisin Biotechnologiesis pioneering a programmable gene therapy that can destroy cells based on their internal biochemistry.
SIWA Therapeuticsis working on an immunotherapy approach to the problem of senescent cells.
In recent years, researchers have identified or designed a handful of senolytic compounds that can curb aging by regulating senescent cells. Two of these drugs that have gained mainstay research traction are rapamycin and metformin.
Rapamycin
Originally extracted from bacteria found on Easter Island, Rapamycin acts on the m-TOR (mechanistic target of rapamycin) pathway to selectively block a key protein that facilitates cell division.
Currently, rapamycin derivatives are widely used as immunosuppression in organ and bone marrow transplants. Research now suggests that use results in prolonged lifespan and enhanced cognitive and immune function.
PureTech Health subsidiary resTORbio (which started 2018 by going public) is working on a rapamycin-based drug intended to enhance immunity and reduce infection. Their clinical-stage RTB101 drug works by inhibiting part of the mTOR pathway.
Results of the drug’s recent clinical trial include:
Decreased incidence of infection
Improved influenza vaccination response
A 30.6 percent decrease in respiratory tract infections
Impressive, to say the least.
Metformin
Metformin is a widely-used generic drug for mitigating liver sugar production in Type 2 diabetes patients.
Researchers have found that Metformin also reduces oxidative stress and inflammation, which otherwise increase as we age.
There is strong evidence that Metformin can augment cellular regeneration and dramatically mitigate cellular senescence by reducing both oxidative stress and inflammation.
Over 100 studies registered on ClinicalTrials.gov are currently following up on strong evidence of Metformin’s protective effect against cancer.
Nutraceuticals and NAD+
Beyond cellular senescence, certain critical nutrients and proteins tend to decline as a function of age. Nutraceuticals combat aging by supplementing and replenishing these declining nutrient levels.
NAD+ exists in every cell, participating in every process from DNA repair to creating the energy vital for cellular processes. It’s been shown that NAD+ levels decline as we age.
The Elysium Health Basis supplement aims to elevate NAD+ levels in the body to extend one’s lifespan. Elysium’s clinical study reports that Basis increases NAD+ levels consistently by a sustained 40 percent.
Conclusion
These are just a taste of the tremendous momentum that longevity and aging technology has right now. As artificial intelligence and quantum computing transform how we decode our DNA and how we discover drugs, genetics and pharmaceuticals will become truly personalized.
The next blog in this series will demonstrate how artificial intelligence is converging with genetics and pharmaceuticals to transform how we approach longevity, aging, and vitality.
We are edging closer to a dramatically extended healthspan—where 100 is the new 60. What will you create, where will you explore, and how will you spend your time if you are able to add an additional 40 healthy years to your life?
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#433928 The Surprising Parallels Between ...
The human mind can be a confusing and overwhelming place. Despite incredible leaps in human progress, many of us still struggle to make our peace with our thoughts. The roots of this are complex and multifaceted. To find explanations for the global mental health epidemic, one can tap into neuroscience, psychology, evolutionary biology, or simply observe the meaningless systems that dominate our modern-day world.
This is not only the context of our reality but also that of the critically-acclaimed Netflix series, Maniac. Psychological dark comedy meets science fiction, Maniac is a retro, futuristic, and hallucinatory trip that is filled with hidden symbols. Directed by Cary Joji Fukunaga, the series tells the story of two strangers who decide to participate in the final stage of a “groundbreaking” pharmaceutical trial—one that combines novel pharmaceuticals with artificial intelligence, and promises to make their emotional pain go away.
Naturally, things don’t go according to plan.
From exams used for testing defense mechanisms to techniques such as cognitive behavioral therapy, the narrative infuses genuine psychological science. As perplexing as the series may be to some viewers, many of the tools depicted actually have a strong grounding in current technological advancements.
Catalysts for Alleviating Suffering
In the therapy of Maniac, participants undergo a three-day trial wherein they ingest three pills and appear to connect their consciousness to a superintelligent AI. Each participant is hurled into the traumatic experiences imprinted in their subconscious and forced to cope with them in a series of hallucinatory and dream-like experiences.
Perhaps the most recognizable parallel that can be drawn is with the latest advancements in psychedelic therapy. Psychedelics are a class of drugs that alter the experience of consciousness, and often cause radical changes in perception and cognitive processes.
Through a process known as transient hypofrontality, the executive “over-thinking” parts of our brains get a rest, and deeper areas become more active. This experience, combined with the breakdown of the ego, is often correlated with feelings of timelessness, peacefulness, presence, unity, and above all, transcendence.
Despite being not addictive and extremely difficult to overdose on, regulators looked down on the use of psychedelics for decades and many continue to dismiss them as “party drugs.” But in the last few years, all of this began to change.
Earlier this summer, the FDA granted breakthrough therapy designation to MDMA for the treatment of PTSD, after several phases of successful trails. Similar research has discovered that Psilocybin (also known as magic mushrooms) combined with therapy is far more effective than traditional forms of treatment to treat depression and anxiety. Today, there is a growing and overwhelming body of research that proves that not only are psychedelics such as LSD, MDMA, or Psylicybin effective catalysts to alleviate suffering and enhance the human condition, but they are potentially the most effective tools out there.
It’s important to realize that these substances are not solutions on their own, but rather catalysts for more effective therapy. They can be groundbreaking, but only in the right context and setting.
Brain-Machine Interfaces
In Maniac, the medication-assisted therapy is guided by what appears to be a super-intelligent form of artificial intelligence called the GRTA, nicknamed Gertie. Gertie, who is a “guide” in machine form, accesses the minds of the participants through what appears to be a futuristic brain-scanning technology and curates customized hallucinatory experiences with the goal of accelerating the healing process.
Such a powerful form of brain-scanning technology is not unheard of. Current levels of scanning technology are already allowing us to decipher dreams and connect three human brains, and are only growing exponentially. Though they are nowhere as advanced as Gertie (we have a long way to go before we get to this kind of general AI), we are also seeing early signs of AI therapy bots, chatbots that listen, think, and communicate with users like a therapist would.
The parallels between current advancements in mental health therapy and the methods in Maniac can be startling, and are a testament to how science fiction and the arts can be used to explore the existential implications of technology.
Not Necessarily a Dystopia
While there are many ingenious similarities between the technology in Maniac and the state of mental health therapy, it’s important to recognize the stark differences. Like many other blockbuster science fiction productions, Maniac tells a fundamentally dystopian tale.
The series tells the story of the 73rd iteration of a controversial drug trial, one that has experienced many failures and even led to various participants being braindead. The scientists appear to be evil, secretive, and driven by their own superficial agendas and deep unresolved emotional issues.
In contrast, clinicians and researchers are not only required to file an “investigational new drug application” with the FDA (and get approval) but also update the agency with safety and progress reports throughout the trial.
Furthermore, many of today’s researchers are driven by a strong desire to contribute to the well-being and progress of our species. Even more, the results of decades of research by organizations like MAPS have been exceptionally promising and aligned with positive values. While Maniac is entertaining and thought-provoking, viewers must not forget the positive potential of such advancements in mental health therapy.
Science, technology, and psychology aside, Maniac is a deep commentary on the human condition and the often disorienting states that pain us all. Within any human lifetime, suffering is inevitable. It is the disproportionate, debilitating, and unjust levels of suffering that we ought to tackle as a society. Ultimately, Maniac explores whether advancements in science and technology can help us live not a life devoid of suffering, but one where it is balanced with fulfillment.
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#433901 The SpiNNaker Supercomputer, Modeled ...
We’ve long used the brain as inspiration for computers, but the SpiNNaker supercomputer, switched on this month, is probably the closest we’ve come to recreating it in silicon. Now scientists hope to use the supercomputer to model the very thing that inspired its design.
The brain is the most complex machine in the known universe, but that complexity comes primarily from its architecture rather than the individual components that make it up. Its highly interconnected structure means that relatively simple messages exchanged between billions of individual neurons add up to carry out highly complex computations.
That’s the paradigm that has inspired the ‘Spiking Neural Network Architecture” (SpiNNaker) supercomputer at the University of Manchester in the UK. The project is the brainchild of Steve Furber, the designer of the original ARM processor. After a decade of development, a million-core version of the machine that will eventually be able to simulate up to a billion neurons was switched on earlier this month.
The idea of splitting computation into very small chunks and spreading them over many processors is already the leading approach to supercomputing. But even the most parallel systems require a lot of communication, and messages may have to pack in a lot of information, such as the task that needs to be completed or the data that needs to be processed.
In contrast, messages in the brain consist of simple electrochemical impulses, or spikes, passed between neurons, with information encoded primarily in the timing or rate of those spikes (which is more important is a topic of debate among neuroscientists). Each neuron is connected to thousands of others via synapses, and complex computation relies on how spikes cascade through these highly-connected networks.
The SpiNNaker machine attempts to replicate this using a model called Address Event Representation. Each of the million cores can simulate roughly a million synapses, so depending on the model, 1,000 neurons with 1,000 connections or 100 neurons with 10,000 connections. Information is encoded in the timing of spikes and the identity of the neuron sending them. When a neuron is activated it broadcasts a tiny packet of data that contains its address, and spike timing is implicitly conveyed.
By modeling their machine on the architecture of the brain, the researchers hope to be able to simulate more biological neurons in real time than any other machine on the planet. The project is funded by the European Human Brain Project, a ten-year science mega-project aimed at bringing together neuroscientists and computer scientists to understand the brain, and researchers will be able to apply for time on the machine to run their simulations.
Importantly, it’s possible to implement various different neuronal models on the machine. The operation of neurons involves a variety of complex biological processes, and it’s still unclear whether this complexity is an artefact of evolution or central to the brain’s ability to process information. The ability to simulate up to a billion simple neurons or millions of more complex ones on the same machine should help to slowly tease out the answer.
Even at a billion neurons, that still only represents about one percent of the human brain, so it’s still going to be limited to investigating isolated networks of neurons. But the previous 500,000-core machine has already been used to do useful simulations of the Basal Ganglia—an area affected in Parkinson’s disease—and an outer layer of the brain that processes sensory information.
The full-scale supercomputer will make it possible to study even larger networks previously out of reach, which could lead to breakthroughs in our understanding of both the healthy and unhealthy functioning of the brain.
And while neurological simulation is the main goal for the machine, it could also provide a useful research tool for roboticists. Previous research has already shown a small board of SpiNNaker chips can be used to control a simple wheeled robot, but Furber thinks the SpiNNaker supercomputer could also be used to run large-scale networks that can process sensory input and generate motor output in real time and at low power.
That low power operation is of particular promise for robotics. The brain is dramatically more power-efficient than conventional supercomputers, and by borrowing from its principles SpiNNaker has managed to capture some of that efficiency. That could be important for running mobile robotic platforms that need to carry their own juice around.
This ability to run complex neural networks at low power has been one of the main commercial drivers for so-called neuromorphic computing devices that are physically modeled on the brain, such as IBM’s TrueNorth chip and Intel’s Loihi. The hope is that complex artificial intelligence applications normally run in massive data centers could be run on edge devices like smartphones, cars, and robots.
But these devices, including SpiNNaker, operate very differently from the leading AI approaches, and its not clear how easy it would be to transfer between the two. The need to adopt an entirely new programming paradigm is likely to limit widespread adoption, and the lack of commercial traction for the aforementioned devices seems to back that up.
At the same time, though, this new paradigm could potentially lead to dramatic breakthroughs in massively parallel computing. SpiNNaker overturns many of the foundational principles of how supercomputers work that make it much more flexible and error-tolerant.
For now, the machine is likely to be firmly focused on accelerating our understanding of how the brain works. But its designers also hope those findings could in turn point the way to more efficient and powerful approaches to computing.
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Posted in Human Robots