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#437209 A Renaissance of Genomics and Drugs Is ...
The causes of aging are extremely complex and unclear. But with longevity clinical trials increasing, more answers—and questions—are emerging than ever before.
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 turn those answers into practical ways to extend our healthspan.
In this article, I’ll explore how genome sequencing and editing, along with new classes of anti-aging drugs, are augmenting our biology to further extend our healthy lives.
Genome Sequencing and 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 for 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 $1,500 in 2015.
Today, the cost of genome sequencing has dropped below $600, 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 article).
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 have used CRISPR to genetically engineer cocaine resistance into mice, reverse the gene defect causing Duchenne muscular dystrophy (DMD) in dogs, and reduce genetic deafness in mice.
Already this year, CRISPR-edited immune cells have been shown to successfully kill cancer cells in human patients. Researchers have discovered ways to activate CRISPR with light and use the gene-editing technology to better understand Alzheimer’s disease progression.
With great power comes great responsibility, and the opportunity for 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. Because Jiankui forged ethical review documents and misled doctors in the process, he was sentenced to three years in prison and fined $429,000 last December.
Coupled with significant ethical conversations necessary for progress, 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, and 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 Biotechnologies is pioneering a programmable gene therapy that can destroy cells based on their internal biochemistry.
SIWA Therapeutics is 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.
(1) 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 for 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 went public in 2018) 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, and a 30.6 percent decrease in respiratory tract infection.
Impressive, to say the least.
(2) 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.
(3) 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 first 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 article 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 toward 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?
Join Me
(1) A360 Executive Mastermind: If you’re an exponentially and abundance-minded entrepreneur who would like coaching directly from me, consider joining my Abundance 360 Mastermind, a highly selective community of 360 CEOs and entrepreneurs who I coach for 3 days every January in Beverly Hills, Ca. Through A360, I provide my members with context and clarity about how converging exponential technologies will transform every industry. I’m committed to running A360 for the course of an ongoing 25-year journey as a “countdown to the Singularity.”
If you’d like to learn more and consider joining our 2021 membership, apply here.
(2) Abundance-Digital Online Community: I’ve also created a Digital/Online community of bold, abundance-minded entrepreneurs called Abundance-Digital. Abundance-Digital is Singularity University’s ‘onramp’ for exponential entrepreneurs—those who want to get involved and play at a higher level. Click here to learn more.
(Both A360 and Abundance-Digital are part of Singularity University—your participation opens you to a global community.)
This article originally appeared on diamandis.com. Read the original article here.
Image Credit: Arek Socha from Pixabay Continue reading
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#437120 The New Indiana Jones? AI. Here’s How ...
Archaeologists have uncovered scores of long-abandoned settlements along coastal Madagascar that reveal environmental connections to modern-day communities. They have detected the nearly indiscernible bumps of earthen mounds left behind by prehistoric North American cultures. Still other researchers have mapped Bronze Age river systems in the Indus Valley, one of the cradles of civilization.
All of these recent discoveries are examples of landscape archaeology. They’re also examples of how artificial intelligence is helping scientists hunt for new archaeological digs on a scale and at a pace unimaginable even a decade ago.
“AI in archaeology has been increasing substantially over the past few years,” said Dylan Davis, a PhD candidate in the Department of Anthropology at Penn State University. “One of the major uses of AI in archaeology is for the detection of new archaeological sites.”
The near-ubiquitous availability of satellite data and other types of aerial imagery for many parts of the world has been both a boon and a bane to archaeologists. They can cover far more ground, but the job of manually mowing their way across digitized landscapes is still time-consuming and laborious. Machine learning algorithms offer a way to parse through complex data far more quickly.
AI Gives Archaeologists a Bird’s Eye View
Davis developed an automated algorithm for identifying large earthen and shell mounds built by native populations long before Europeans arrived with far-off visions of skyscrapers and superhighways in their eyes. The sites still hidden in places like the South Carolina wilderness contain a wealth of information about how people lived, even what they ate, and the ways they interacted with the local environment and other cultures.
In this particular case, the imagery comes from LiDAR, which uses light pulses that can penetrate tree canopies to map forest floors. The team taught the computer the shape, size, and texture characteristics of the mounds so it could identify potential sites from the digital 3D datasets that it analyzed.
“The process resulted in several thousand possible features that my colleagues and I checked by hand,” Davis told Singularity Hub. “While not entirely automated, this saved the equivalent of years of manual labor that would have been required for analyzing the whole LiDAR image by hand.”
In Madagascar—where Davis is studying human settlement history across the world’s fourth largest island over a timescale of millennia—he developed a predictive algorithm to help locate archaeological sites using freely available satellite imagery. His team was able to survey and identify more than 70 new archaeological sites—and potentially hundreds more—across an area of more than 1,000 square kilometers during the course of about a year.
Machines Learning From the Past Prepare Us for the Future
One impetus behind the rapid identification of archaeological sites is that many are under threat from climate change, such as coastal erosion from sea level rise, or other human impacts. Meanwhile, traditional archaeological approaches are expensive and laborious—serious handicaps in a race against time.
“It is imperative to record as many archaeological sites as we can in a short period of time. That is why AI and machine learning are useful for my research,” Davis said.
Studying the rise and fall of past civilizations can also teach modern humans a thing or two about how to grapple with these current challenges.
Researchers at the Institut Català d’Arqueologia Clàssica (ICAC) turned to machine-learning algorithms to reconstruct more than 20,000 kilometers of paleo-rivers along the Indus Valley civilization of what is now part of modern Pakistan and India. Such AI-powered mapping techniques wouldn’t be possible using satellite images alone.
That effort helped locate many previously unknown archaeological sites and unlocked new insights into those Bronze Age cultures. However, the analytics can also assist governments with important water resource management today, according to Hèctor A. Orengo Romeu, co-director of the Landscape Archaeology Research Group at ICAC.
“Our analyses can contribute to the forecasts of the evolution of aquifers in the area and provide valuable information on aspects such as the variability of agricultural productivity or the influence of climate change on the expansion of the Thar desert, in addition to providing cultural management tools to the government,” he said.
Leveraging AI for Language and Lots More
While landscape archaeology is one major application of AI in archaeology, it’s far from the only one. In 2000, only about a half-dozen scientific papers referred to the use of AI, according to the Web of Science, reputedly the world’s largest global citation database. Last year, more than 65 papers were published concerning the use of machine intelligence technologies in archaeology, with a significant uptick beginning in 2015.
AI methods, for instance, are being used to understand the chemical makeup of artifacts like pottery and ceramics, according to Davis. “This can help identify where these materials were made and how far they were transported. It can also help us to understand the extent of past trading networks.”
Linguistic anthropologists have also used machine intelligence methods to trace the evolution of different languages, Davis said. “Using AI, we can learn when and where languages emerged around the world.”
In other cases, AI has helped reconstruct or decipher ancient texts. Last year, researchers at Google’s DeepMind used a deep neural network called PYTHIA to recreate missing inscriptions in ancient Greek from damaged surfaces of objects made of stone or ceramics.
Named after the Oracle at Delphi, PYTHIA “takes a sequence of damaged text as input, and is trained to predict character sequences comprising hypothesised restorations of ancient Greek inscriptions,” the researchers reported.
In a similar fashion, Chinese scientists applied a convolutional neural network (CNN) to untangle another ancient tongue once found on turtle shells and ox bones. The CNN managed to classify oracle bone morphology in order to piece together fragments of these divination objects, some with inscriptions that represent the earliest evidence of China’s recorded history.
“Differentiating the materials of oracle bones is one of the most basic steps for oracle bone morphology—we need to first make sure we don’t assemble pieces of ox bones with tortoise shells,” lead author of the study, associate professor Shanxiong Chen at China’s Southwest University, told Synced, an online tech publication in China.
AI Helps Archaeologists Get the Scoop…
And then there are applications of AI in archaeology that are simply … interesting. Just last month, researchers published a paper about a machine learning method trained to differentiate between human and canine paleofeces.
The algorithm, dubbed CoproID, compares the gut microbiome DNA found in the ancient material with DNA found in modern feces, enabling it to get the scoop on the origin of the poop.
Also known as coprolites, paleo-feces from humans and dogs are often found in the same archaeological sites. Scientists need to know which is which if they’re trying to understand something like past diets or disease.
“CoproID is the first line of identification in coprolite analysis to confirm that what we’re looking for is actually human, or a dog if we’re interested in dogs,” Maxime Borry, a bioinformatics PhD student at the Max Planck Institute for the Science of Human History, told Vice.
…But Machine Intelligence Is Just Another Tool
There is obviously quite a bit of work that can be automated through AI. But there’s no reason for archaeologists to hit the unemployment line any time soon. There are also plenty of instances where machines can’t yet match humans in identifying objects or patterns. At other times, it’s just faster doing the analysis yourself, Davis noted.
“For ‘big data’ tasks like detecting archaeological materials over a continental scale, AI is useful,” he said. “But for some tasks, it is sometimes more time-consuming to train an entire computer algorithm to complete a task that you can do on your own in an hour.”
Still, there’s no telling what the future will hold for studying the past using artificial intelligence.
“We have already started to see real improvements in the accuracy and reliability of these approaches, but there is a lot more to do,” Davis said. “Hopefully, we start to see these methods being directly applied to a variety of interesting questions around the world, as these methods can produce datasets that would have been impossible a few decades ago.”
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#436578 AI Just Discovered a New Antibiotic to ...
Penicillin, one of the greatest discoveries in the history of medicine, was a product of chance.
After returning from summer vacation in September 1928, bacteriologist Alexander Fleming found a colony of bacteria he’d left in his London lab had sprouted a fungus. Curiously, wherever the bacteria contacted the fungus, their cell walls broke down and they died. Fleming guessed the fungus was secreting something lethal to the bacteria—and the rest is history.
Fleming’s discovery of penicillin and its later isolation, synthesis, and scaling in the 1940s released a flood of antibiotic discoveries in the next few decades. Bacteria and fungi had been waging an ancient war against each other, and the weapons they’d evolved over eons turned out to be humanity’s best defense against bacterial infection and disease.
In recent decades, however, the flood of new antibiotics has slowed to a trickle.
Their development is uneconomical for drug companies, and the low-hanging fruit has long been picked. We’re now facing the emergence of strains of super bacteria resistant to one or more antibiotics and an aging arsenal to fight them with. Gone unchallenged, an estimated 700,000 deaths worldwide due to drug resistance could rise to as many as 10 million in 2050.
Increasingly, scientists warn the tide is turning, and we need a new strategy to keep pace with the remarkably quick and boundlessly creative tactics of bacterial evolution.
But where the golden age of antibiotics was sparked by serendipity, human intelligence, and natural molecular weapons, its sequel may lean on the uncanny eye of artificial intelligence to screen millions of compounds—and even design new ones—in search of the next penicillin.
Hal Discovers a Powerful Antibiotic
In a paper published this week in the journal, Cell, MIT researchers took a step in this direction. The team says their machine learning algorithm discovered a powerful new antibiotic.
Named for the AI in 2001: A Space Odyssey, the antibiotic, halicin, successfully wiped out dozens of bacterial strains, including some of the most dangerous drug-resistant bacteria on the World Health Organization’s most wanted list. The bacteria also failed to develop resistance to E. coli during a month of observation, in stark contrast to existing antibiotic ciprofloxacin.
“In terms of antibiotic discovery, this is absolutely a first,” Regina Barzilay, a senior author on the study and computer science professor at MIT, told The Guardian.
The algorithm that discovered halicin was trained on the molecular features of 2,500 compounds. Nearly half were FDA-approved drugs, and another 800 naturally occurring. The researchers specifically tuned the algorithm to look for molecules with antibiotic properties but whose structures would differ from existing antibiotics (as halicin’s does). Using another machine learning program, they screened the results for those likely to be safe for humans.
Early study suggests halicin attacks the bacteria’s cell membranes, disrupting their ability to produce energy. Protecting the cell membrane from halicin might take more than one or two genetic mutations, which could account for its impressive ability to prevent resistance.
“I think this is one of the more powerful antibiotics that has been discovered to date,” James Collins, an MIT professor of bioengineering and senior author told The Guardian. “It has remarkable activity against a broad range of antibiotic-resistant pathogens.”
Beyond tests in petri-dish bacterial colonies, the team also tested halicin in mice. The antibiotic cleared up infections of a strain of bacteria resistant to all known antibiotics in a day. The team plans further study in partnership with a pharmaceutical company or nonprofit, and they hope to eventually prove it safe and effective for use in humans.
This last bit remains the trickiest step, given the cost of getting a new drug approved. But Collins hopes algorithms like theirs will help. “We could dramatically reduce the cost required to get through clinical trials,” he told the Financial Times.
A Universe of Drugs Awaits
The bigger story may be what happens next.
How many novel antibiotics await discovery, and how far can AI screening take us? The initial 6,000 compounds scanned by Barzilay and Collins’s team is a drop in the bucket.
They’ve already begun digging deeper by setting the algorithm loose on 100 million molecules from an online library of 1.5 billion compounds called the ZINC15 database. This first search took three days and turned up 23 more candidates that, like halicin, differ structurally from existing antibiotics and may be safe for humans. Two of these—which the team will study further—appear to be especially powerful.
Even more ambitiously, Barzilay hopes the approach can find or even design novel antibiotics that kill bad bacteria with alacrity while sparing the good guys. In this way, a round of antibiotics would cure whatever ails you without taking out your whole gut microbiome in the process.
All this is part of a larger movement to use machine learning algorithms in the long, expensive process of drug discovery. Other players in the area are also training AI on the vast possibility space of drug-like compounds. Last fall, one of the leaders in the area, Insilico, was challenged by a partner to see just how fast their method could do the job. The company turned out a new a proof-of-concept drug candidate in only 46 days.
The field is still developing, however, and it has yet to be seen exactly how valuable these approaches will be in practice. Barzilay is optimistic though.
“There is still a question of whether machine-learning tools are really doing something intelligent in healthcare, and how we can develop them to be workhorses in the pharmaceuticals industry,” she said. “This shows how far you can adapt this tool.”
Image Credit: Halicin (top row) prevented the development of antibiotic resistance in E. coli, while ciprofloxacin (bottom row) did not. Collins Lab at MIT Continue reading
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