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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
#433689 The Rise of Dataism: A Threat to Freedom ...
What would happen if we made all of our data public—everything from wearables monitoring our biometrics, all the way to smartphones monitoring our location, our social media activity, and even our internet search history?
Would such insights into our lives simply provide companies and politicians with greater power to invade our privacy and manipulate us by using our psychological profiles against us?
A burgeoning new philosophy called dataism doesn’t think so.
In fact, this trending ideology believes that liberating the flow of data is the supreme value of the universe, and that it could be the key to unleashing the greatest scientific revolution in the history of humanity.
What Is Dataism?
First mentioned by David Brooks in his 2013 New York Times article “The Philosophy of Data,” dataism is an ethical system that has been most heavily explored and popularized by renowned historian, Yuval Noah Harari.
In his 2016 book Homo Deus, Harari described dataism as a new form of religion that celebrates the growing importance of big data.
Its core belief centers around the idea that the universe gives greater value and support to systems, individuals, and societies that contribute most heavily and efficiently to data processing. In an interview with Wired, Harari stated, “Humans were special and important because up until now they were the most sophisticated data processing system in the universe, but this is no longer the case.”
Now, big data and machine learning are proving themselves more sophisticated, and dataists believe we should hand over as much information and power to these algorithms as possible, allowing the free flow of data to unlock innovation and progress unlike anything we’ve ever seen before.
Pros: Progress and Personal Growth
When you let data run freely, it’s bound to be mixed and matched in new ways that inevitably spark progress. And as we enter the exponential future where every person is constantly connected and sharing their data, the potential for such collaborative epiphanies becomes even greater.
We can already see important increases in quality of life thanks to companies like Google. With Google Maps on your phone, your position is constantly updating on their servers. This information, combined with everyone else on the planet using a phone with Google Maps, allows your phone to inform you of traffic conditions. Based on the speed and location of nearby phones, Google can reroute you to less congested areas or help you avoid accidents. And since you trust that these algorithms have more data than you, you gladly hand over your power to them, following your GPS’s directions rather than your own.
We can do the same sort of thing with our bodies.
Imagine, for instance, a world where each person has biosensors in their bloodstreams—a not unlikely or distant possibility when considering diabetic people already wear insulin pumps that constantly monitor their blood sugar levels. And let’s assume this data was freely shared to the world.
Now imagine a virus like Zika or the Bird Flu breaks out. Thanks to this technology, the odd change in biodata coming from a particular region flags an artificial intelligence that feeds data to the CDC (Center for Disease Control and Prevention). Recognizing that a pandemic could be possible, AIs begin 3D printing vaccines on-demand, predicting the number of people who may be afflicted. When our personal AIs tell us the locations of the spreading epidemic and to take the vaccine it just delivered by drone to our homes, are we likely to follow its instructions? Almost certainly—and if so, it’s likely millions, if not billions, of lives will have been saved.
But to quickly create such vaccines, we’ll also need to liberate research.
Currently, universities and companies seeking to benefit humankind with medical solutions have to pay extensively to organize clinical trials and to find people who match their needs. But if all our biodata was freely aggregated, perhaps they could simply say “monitor all people living with cancer” to an AI, and thanks to the constant stream of data coming in from the world’s population, a machine learning program may easily be able to detect a pattern and create a cure.
As always in research, the more sample data you have, the higher the chance that such patterns will emerge. If data is flowing freely, then anyone in the world can suddenly decide they have a hunch they want to explore, and without having to spend months and months of time and money hunting down the data, they can simply test their hypothesis.
Whether garage tinkerers, at-home scientists, or PhD students—an abundance of free data allows for science to progress unhindered, each person able to operate without being slowed by lack of data. And any progress they make is immediately liberated, becoming free data shared with anyone else that may find a use for it.
Any individual with a curious passion would have the entire world’s data at their fingertips, empowering every one of us to become an expert in any subject that inspires us. Expertise we can then share back into the data stream—a positive feedback loop spearheading progress for the entirety of humanity’s knowledge.
Such exponential gains represent a dataism utopia.
Unfortunately, our current incentives and economy also show us the tragic failures of this model.
As Harari has pointed out, the rise of datism means that “humanism is now facing an existential challenge and the idea of ‘free will’ is under threat.”
Cons: Manipulation and Extortion
In 2017, The Economist declared that data was the most valuable resource on the planet—even more valuable than oil.
Perhaps this is because data is ‘priceless’: it represents understanding, and understanding represents control. And so, in the world of advertising and politics, having data on your consumers and voters gives you an incredible advantage.
This was evidenced by the Cambridge Analytica scandal, in which it’s believed that Donald Trump and the architects of Brexit leveraged users’ Facebook data to create psychological profiles that enabled them to manipulate the masses.
How powerful are these psychological models?
A team who built a model similar to that used by Cambridge Analytica said their model could understand someone as well as a coworker with access to only 10 Facebook likes. With 70 likes they could know them as well as a friend might, 150 likes to match their parents’ understanding, and at 300 likes they could even come to know someone better than their lovers. With more likes, they could even come to know someone better than that person knows themselves.
Proceeding With Caution
In a capitalist democracy, do we want businesses and politicians to know us better than we know ourselves?
In spite of the remarkable benefits that may result for our species by freely giving away our information, do we run the risk of that data being used to exploit and manipulate the masses towards a future without free will, where our daily lives are puppeteered by those who own our data?
It’s extremely possible.
And it’s for this reason that one of the most important conversations we’ll have as a species centers around data ownership: do we just give ownership of the data back to the users, allowing them to choose who to sell or freely give their data to? Or will that simply deter the entrepreneurial drive and cause all of the free services we use today, like Google Search and Facebook, to begin charging inaccessible prices? How much are we willing to pay for our freedom? And how much do we actually care?
If recent history has taught us anything, it’s that humans are willing to give up more privacy than they like to think. Fifteen years ago, it would have been crazy to suggest we’d all allow ourselves to be tracked by our cars, phones, and daily check-ins to our favorite neighborhood locations; but now most of us see it as a worthwhile trade for optimized commutes and dating. As we continue navigating that fine line between exploitation and innovation into a more technological future, what other trade-offs might we be willing to make?
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Posted in Human Robots
#431424 A ‘Google Maps’ for the Mouse Brain ...
Ask any neuroscientist to draw you a neuron, and it’ll probably look something like a star with two tails: one stubby with extensive tree-like branches, the other willowy, lengthy and dotted with spindly spikes.
While a decent abstraction, this cartoonish image hides the uncomfortable truth that scientists still don’t know much about what many neurons actually look like, not to mention the extent of their connections.
But without untangling the jumbled mess of neural wires that zigzag across the brain, scientists are stumped in trying to answer one of the most fundamental mysteries of the brain: how individual neuronal threads carry and assemble information, which forms the basis of our thoughts, memories, consciousness, and self.
What if there was a way to virtually trace and explore the brain’s serpentine fibers, much like the way Google Maps allows us to navigate the concrete tangles of our cities’ highways?
Thanks to an interdisciplinary team at Janelia Research Campus, we’re on our way. Meet MouseLight, the most extensive map of the mouse brain ever attempted. The ongoing project has an ambitious goal: reconstructing thousands—if not more—of the mouse’s 70 million neurons into a 3D map. (You can play with it here!)
With map in hand, neuroscientists around the world can begin to answer how neural circuits are organized in the brain, and how information flows from one neuron to another across brain regions and hemispheres.
The first release, presented Monday at the Society for Neuroscience Annual Conference in Washington, DC, contains information about the shape and sizes of 300 neurons.
And that’s just the beginning.
“MouseLight’s new dataset is the largest of its kind,” says Dr. Wyatt Korff, director of project teams. “It’s going to change the textbook view of neurons.”
http://mouselight.janelia.org/assets/carousel/ML-Movie.mp4
Brain Atlas
MouseLight is hardly the first rodent brain atlasing project.
The Mouse Brain Connectivity Atlas at the Allen Institute for Brain Science in Seattle tracks neuron activity across small circuits in an effort to trace a mouse’s connectome—a complete atlas of how the firing of one neuron links to the next.
MICrONS (Machine Intelligence from Cortical Networks), the $100 million government-funded “moonshot” hopes to distill brain computation into algorithms for more powerful artificial intelligence. Its first step? Brain mapping.
What makes MouseLight stand out is its scope and level of detail.
MICrONS, for example, is focused on dissecting a cubic millimeter of the mouse visual processing center. In contrast, MouseLight involves tracing individual neurons across the entire brain.
And while connectomics outlines the major connections between brain regions, the birds-eye view entirely misses the intricacies of each individual neuron. This is where MouseLight steps in.
Slice and Dice
With a width only a fraction of a human hair, neuron projections are hard to capture in their native state. Tug or squeeze the brain too hard, and the long, delicate branches distort or even shred into bits.
In fact, previous attempts at trying to reconstruct neurons at this level of detail topped out at just a dozen, stymied by technological hiccups and sky-high costs.
A few years ago, the MouseLight team set out to automate the entire process, with a few time-saving tweaks. Here’s how it works.
After injecting a mouse with a virus that causes a handful of neurons to produce a green-glowing protein, the team treated the brain with a sugar alcohol solution. This step “clears” the brain, transforming the beige-colored organ to translucent, making it easier for light to penetrate and boosting the signal-to-background noise ratio. The brain is then glued onto a small pedestal and ready for imaging.
Building upon an established method called “two-photon microscopy,” the team then tweaked several parameters to reduce imaging time from days (or weeks) down to a fraction of that. Endearingly known as “2P” by the experts, this type of laser microscope zaps the tissue with just enough photos to light up a single plane without damaging the tissue—sharper plane, better focus, crisper image.
After taking an image, the setup activates its vibrating razor and shaves off the imaged section of the brain—a waspy slice about 200 micrometers thick. The process is repeated until the whole brain is imaged.
This setup increased imaging speed by 16 to 48 times faster than conventional microscopy, writes team leader Dr. Jayaram Chandrashekar, who published a version of the method early last year in eLife.
The resulting images strikingly highlight every crook and cranny of a neuronal branch, popping out against a pitch-black background. But pretty pictures come at a hefty data cost: each image takes up a whopping 20 terabytes of data—roughly the storage space of 4,000 DVDs, or 10,000 hours of movies.
Stitching individual images back into 3D is an image-processing nightmare. The MouseLight team used a combination of computational power and human prowess to complete this final step.
The reconstructed images are handed off to a mighty team of seven trained neuron trackers. With the help of tracing algorithms developed in-house and a keen eye, each member can track roughly a neuron a day—significantly less time than the week or so previously needed.
A Numbers Game
Even with just 300 fully reconstructed neurons, MouseLight has already revealed new secrets of the brain.
While it’s widely accepted that axons, the neurons’ outgoing projection, can span the entire length of the brain, these extra-long connections were considered relatively rare. (In fact, one previously discovered “giant neuron” was thought to link to consciousness because of its expansive connections).
Images captured from two-photon microscopy show an axon and dendrites protruding from a neuron’s cell body (sphere in center). Image Credit: Janelia Research Center, MouseLight project team
MouseLight blows that theory out of the water.
The data clearly shows that “giant neurons” are far more common than previously thought. For example, four neurons normally associated with taste had wiry branches that stretched all the way into brain areas that control movement and process touch.
“We knew that different regions of the brain talked to each other, but seeing it in 3D is different,” says Dr. Eve Marder at Brandeis University.
“The results are so stunning because they give you a really clear view of how the whole brain is connected.”
With a tested and true system in place, the team is now aiming to add 700 neurons to their collection within a year.
But appearance is only part of the story.
We can’t tell everything about a person simply by how they look. Neurons are the same: scientists can only infer so much about a neuron’s function by looking at their shape and positions. The team also hopes to profile the gene expression patterns of each neuron, which could provide more hints to their roles in the brain.
MouseLight essentially dissects the neural infrastructure that allows information traffic to flow through the brain. These anatomical highways are just the foundation. Just like Google Maps, roads form only the critical first layer of the map. Street view, traffic information and other add-ons come later for a complete look at cities in flux.
The same will happen for understanding our ever-changing brain.
Image Credit: Janelia Research Campus, MouseLight project team Continue reading
Posted in Human Robots