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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.
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 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.
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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Making sure artificial intelligence does what we want and behaves in predictable ways will be crucial as the technology becomes increasingly ubiquitous. It’s an area frequently neglected in the race to develop products, but DeepMind has now outlined its research agenda to tackle the problem.
AI safety, as the field is known, has been gaining prominence in recent years. That’s probably at least partly down to the overzealous warnings of a coming AI apocalypse from well-meaning, but underqualified pundits like Elon Musk and Stephen Hawking. But it’s also recognition of the fact that AI technology is quickly pervading all aspects of our lives, making decisions on everything from what movies we watch to whether we get a mortgage.
That’s why DeepMind hired a bevy of researchers who specialize in foreseeing the unforeseen consequences of the way we built AI back in 2016. And now the team has spelled out the three key domains they think require research if we’re going to build autonomous machines that do what we want.
In a new blog designed to provide updates on the team’s work, they introduce the ideas of specification, robustness, and assurance, which they say will act as the cornerstones of their future research. Specification involves making sure AI systems do what their operator intends; robustness means a system can cope with changes to its environment and attempts to throw it off course; and assurance involves our ability to understand what systems are doing and how to control them.
A classic thought experiment designed to illustrate how we could lose control of an AI system can help illustrate the problem of specification. Philosopher Nick Bostrom’s posited a hypothetical machine charged with making as many paperclips as possible. Because the creators fail to add what they might assume are obvious additional goals like not harming people, the AI wipes out humanity so we can’t switch it off before turning all matter in the universe into paperclips.
Obviously the example is extreme, but it shows how a poorly-specified goal can lead to unexpected and disastrous outcomes. Properly codifying the desires of the designer is no easy feat, though; often there are not neat ways to encompass both the explicit and implicit goals in ways that are understandable to the machine and don’t leave room for ambiguities, meaning we often rely on incomplete approximations.
The researchers note recent research by OpenAI in which an AI was trained to play a boat-racing game called CoastRunners. The game rewards players for hitting targets laid out along the race route. The AI worked out that it could get a higher score by repeatedly knocking over regenerating targets rather than actually completing the course. The blog post includes a link to a spreadsheet detailing scores of such examples.
Another key concern for AI designers is making their creation robust to the unpredictability of the real world. Despite their superhuman abilities on certain tasks, most cutting-edge AI systems are remarkably brittle. They tend to be trained on highly-curated datasets and so can fail when faced with unfamiliar input. This can happen by accident or by design—researchers have come up with numerous ways to trick image recognition algorithms into misclassifying things, including thinking a 3D printed tortoise was actually a gun.
Building systems that can deal with every possible encounter may not be feasible, so a big part of making AIs more robust may be getting them to avoid risks and ensuring they can recover from errors, or that they have failsafes to ensure errors don’t lead to catastrophic failure.
And finally, we need to have ways to make sure we can tell whether an AI is performing the way we expect it to. A key part of assurance is being able to effectively monitor systems and interpret what they’re doing—if we’re basing medical treatments or sentencing decisions on the output of an AI, we’d like to see the reasoning. That’s a major outstanding problem for popular deep learning approaches, which are largely indecipherable black boxes.
The other half of assurance is the ability to intervene if a machine isn’t behaving the way we’d like. But designing a reliable off switch is tough, because most learning systems have a strong incentive to prevent anyone from interfering with their goals.
The authors don’t pretend to have all the answers, but they hope the framework they’ve come up with can help guide others working on AI safety. While it may be some time before AI is truly in a position to do us harm, hopefully early efforts like these will mean it’s built on a solid foundation that ensures it is aligned with our goals.
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Photo credit Technology sets us apart and puts us at the forefront, and one industry that is definitely embracing automation and robotics readily is the motor industry. Technology has touched every aspect of motoring – from updates to the manufacturing process that produce much safer and more reliable vehicles to black box diagnostics being used …
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