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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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Posted in Human Robots
#433506 MIT’s New Robot Taught Itself to Pick ...
Back in 2016, somewhere in a Google-owned warehouse, more than a dozen robotic arms sat for hours quietly grasping objects of various shapes and sizes. For hours on end, they taught themselves how to pick up and hold the items appropriately—mimicking the way a baby gradually learns to use its hands.
Now, scientists from MIT have made a new breakthrough in machine learning: their new system can not only teach itself to see and identify objects, but also understand how best to manipulate them.
This means that, armed with the new machine learning routine referred to as “dense object nets (DON),” the robot would be capable of picking up an object that it’s never seen before, or in an unfamiliar orientation, without resorting to trial and error—exactly as a human would.
The deceptively simple ability to dexterously manipulate objects with our hands is a huge part of why humans are the dominant species on the planet. We take it for granted. Hardware innovations like the Shadow Dexterous Hand have enabled robots to softly grip and manipulate delicate objects for many years, but the software required to control these precision-engineered machines in a range of circumstances has proved harder to develop.
This was not for want of trying. The Amazon Robotics Challenge offers millions of dollars in prizes (and potentially far more in contracts, as their $775m acquisition of Kiva Systems shows) for the best dexterous robot able to pick and package items in their warehouses. The lucrative dream of a fully-automated delivery system is missing this crucial ability.
Meanwhile, the Robocup@home challenge—an offshoot of the popular Robocup tournament for soccer-playing robots—aims to make everyone’s dream of having a robot butler a reality. The competition involves teams drilling their robots through simple household tasks that require social interaction or object manipulation, like helping to carry the shopping, sorting items onto a shelf, or guiding tourists around a museum.
Yet all of these endeavors have proved difficult; the tasks often have to be simplified to enable the robot to complete them at all. New or unexpected elements, such as those encountered in real life, more often than not throw the system entirely. Programming the robot’s every move in explicit detail is not a scalable solution: this can work in the highly-controlled world of the assembly line, but not in everyday life.
Computer vision is improving all the time. Neural networks, including those you train every time you prove that you’re not a robot with CAPTCHA, are getting better at sorting objects into categories, and identifying them based on sparse or incomplete data, such as when they are occluded, or in different lighting.
But many of these systems require enormous amounts of input data, which is impractical, slow to generate, and often needs to be laboriously categorized by humans. There are entirely new jobs that require people to label, categorize, and sift large bodies of data ready for supervised machine learning. This can make machine learning undemocratic. If you’re Google, you can make thousands of unwitting volunteers label your images for you with CAPTCHA. If you’re IBM, you can hire people to manually label that data. If you’re an individual or startup trying something new, however, you will struggle to access the vast troves of labeled data available to the bigger players.
This is why new systems that can potentially train themselves over time or that allow robots to deal with situations they’ve never seen before without mountains of labelled data are a holy grail in artificial intelligence. The work done by MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) is part of a new wave of “self-supervised” machine learning systems—little of the data used was labeled by humans.
The robot first inspects the new object from multiple angles, building up a 3D picture of the object with its own coordinate system. This then allows the robotic arm to identify a particular feature on the object—such as a handle, or the tongue of a shoe—from various different angles, based on its relative distance to other grid points.
This is the real innovation: the new means of representing objects to grasp as mapped-out 3D objects, with grid points and subsections of their own. Rather than using a computer vision algorithm to identify a door handle, and then activating a door handle grasping subroutine, the DON system treats all objects by making these spatial maps before classifying or manipulating them, enabling it to deal with a greater range of objects than in other approaches.
“Many approaches to manipulation can’t identify specific parts of an object across the many orientations that object may encounter,” said PhD student Lucas Manuelli, who wrote a new paper about the system with lead author and fellow student Pete Florence, alongside MIT professor Russ Tedrake. “For example, existing algorithms would be unable to grasp a mug by its handle, especially if the mug could be in multiple orientations, like upright, or on its side.”
Class-specific descriptors, which can be applied to the object features, can allow the robot arm to identify a mug, find the handle, and pick the mug up appropriately. Object-specific descriptors allow the robot arm to select a particular mug from a group of similar items. I’m already dreaming of a robot butler reliably picking my favourite mug when it serves me coffee in the morning.
Google’s robot arm-y was an attempt to develop a general grasping algorithm: one that could identify, categorize, and appropriately grip as many items as possible. This requires a great deal of training time and data, which is why Google parallelized their project by having 14 robot arms feed data into a single neural network brain: even then, the algorithm may fail with highly specific tasks. Specialist grasping algorithms might require less training if they’re limited to specific objects, but then your software is useless for general tasks.
As the roboticists noted, their system, with its ability to identify parts of an object rather than just a single object, is better suited to specific tasks, such as “grasp the racquet by the handle,” than Amazon Robotics Challenge robots, which identify whole objects by segmenting an image.
This work is small-scale at present. It has been tested with a few classes of objects, including shoes, hats, and mugs. Yet the use of these dense object nets as a way for robots to represent and manipulate new objects may well be another step towards the ultimate goal of generalized automation: a robot capable of performing every task a person can. If that point is reached, the question that will remain is how to cope with being obsolete.
Image Credit: Tom Buehler/CSAIL Continue reading
Posted in Human Robots