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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
#434559 Can AI Tell the Difference Between a ...
Scarcely a day goes by without another headline about neural networks: some new task that deep learning algorithms can excel at, approaching or even surpassing human competence. As the application of this approach to computer vision has continued to improve, with algorithms capable of specialized recognition tasks like those found in medicine, the software is getting closer to widespread commercial use—for example, in self-driving cars. Our ability to recognize patterns is a huge part of human intelligence: if this can be done faster by machines, the consequences will be profound.
Yet, as ever with algorithms, there are deep concerns about their reliability, especially when we don’t know precisely how they work. State-of-the-art neural networks will confidently—and incorrectly—classify images that look like television static or abstract art as real-world objects like school-buses or armadillos. Specific algorithms could be targeted by “adversarial examples,” where adding an imperceptible amount of noise to an image can cause an algorithm to completely mistake one object for another. Machine learning experts enjoy constructing these images to trick advanced software, but if a self-driving car could be fooled by a few stickers, it might not be so fun for the passengers.
These difficulties are hard to smooth out in large part because we don’t have a great intuition for how these neural networks “see” and “recognize” objects. The main insight analyzing a trained network itself can give us is a series of statistical weights, associating certain groups of points with certain objects: this can be very difficult to interpret.
Now, new research from UCLA, published in the journal PLOS Computational Biology, is testing neural networks to understand the limits of their vision and the differences between computer vision and human vision. Nicholas Baker, Hongjing Lu, and Philip J. Kellman of UCLA, alongside Gennady Erlikhman of the University of Nevada, tested a deep convolutional neural network called VGG-19. This is state-of-the-art technology that is already outperforming humans on standardized tests like the ImageNet Large Scale Visual Recognition Challenge.
They found that, while humans tend to classify objects based on their overall (global) shape, deep neural networks are far more sensitive to the textures of objects, including local color gradients and the distribution of points on the object. This result helps explain why neural networks in image recognition make mistakes that no human ever would—and could allow for better designs in the future.
In the first experiment, a neural network was trained to sort images into 1 of 1,000 different categories. It was then presented with silhouettes of these images: all of the local information was lost, while only the outline of the object remained. Ordinarily, the trained neural net was capable of recognizing these objects, assigning more than 90% probability to the correct classification. Studying silhouettes, this dropped to 10%. While human observers could nearly always produce correct shape labels, the neural networks appeared almost insensitive to the overall shape of the images. On average, the correct object was ranked as the 209th most likely solution by the neural network, even though the overall shapes were an exact match.
A particularly striking example arose when they tried to get the neural networks to classify glass figurines of objects they could already recognize. While you or I might find it easy to identify a glass model of an otter or a polar bear, the neural network classified them as “oxygen mask” and “can opener” respectively. By presenting glass figurines, where the texture information that neural networks relied on for classifying objects is lost, the neural network was unable to recognize the objects by shape alone. The neural network was similarly hopeless at classifying objects based on drawings of their outline.
If you got one of these right, you’re better than state-of-the-art image recognition software. Image Credit: Nicholas Baker, Hongjing Lu, Gennady Erlikhman, Philip J. Kelman. “Deep convolutional networks do not classify based on global object shape.” Plos Computational Biology. 12/7/18. / CC BY 4.0
When the neural network was explicitly trained to recognize object silhouettes—given no information in the training data aside from the object outlines—the researchers found that slight distortions or “ripples” to the contour of the image were again enough to fool the AI, while humans paid them no mind.
The fact that neural networks seem to be insensitive to the overall shape of an object—relying instead on statistical similarities between local distributions of points—suggests a further experiment. What if you scrambled the images so that the overall shape was lost but local features were preserved? It turns out that the neural networks are far better and faster at recognizing scrambled versions of objects than outlines, even when humans struggle. Students could classify only 37% of the scrambled objects, while the neural network succeeded 83% of the time.
Humans vastly outperform machines at classifying object (a) as a bear, while the machine learning algorithm has few problems classifying the bear in figure (b). Image Credit: Nicholas Baker, Hongjing Lu, Gennady Erlikhman, Philip J. Kelman. “Deep convolutional networks do not classify based on global object shape.” Plos Computational Biology. 12/7/18. / CC BY 4.0
“This study shows these systems get the right answer in the images they were trained on without considering shape,” Kellman said. “For humans, overall shape is primary for object recognition, and identifying images by overall shape doesn’t seem to be in these deep learning systems at all.”
Naively, one might expect that—as the many layers of a neural network are modeled on connections between neurons in the brain and resemble the visual cortex specifically—the way computer vision operates must necessarily be similar to human vision. But this kind of research shows that, while the fundamental architecture might resemble that of the human brain, the resulting “mind” operates very differently.
Researchers can, increasingly, observe how the “neurons” in neural networks light up when exposed to stimuli and compare it to how biological systems respond to the same stimuli. Perhaps someday it might be possible to use these comparisons to understand how neural networks are “thinking” and how those responses differ from humans.
But, as yet, it takes a more experimental psychology to probe how neural networks and artificial intelligence algorithms perceive the world. The tests employed against the neural network are closer to how scientists might try to understand the senses of an animal or the developing brain of a young child rather than a piece of software.
By combining this experimental psychology with new neural network designs or error-correction techniques, it may be possible to make them even more reliable. Yet this research illustrates just how much we still don’t understand about the algorithms we’re creating and using: how they tick, how they make decisions, and how they’re different from us. As they play an ever-greater role in society, understanding the psychology of neural networks will be crucial if we want to use them wisely and effectively—and not end up missing the woods for the trees.
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Posted in Human Robots