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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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#433828 Using Big Data to Give Patients Control ...
Big data, personalized medicine, artificial intelligence. String these three buzzphrases together, and what do you have?
A system that may revolutionize the future of healthcare, by bringing sophisticated health data directly to patients for them to ponder, digest, and act upon—and potentially stop diseases in their tracks.
At Singularity University’s Exponential Medicine conference in San Diego this week, Dr. Ran Balicer, director of the Clalit Research Institute in Israel, painted a futuristic picture of how big data can merge with personalized healthcare into an app-based system in which the patient is in control.
Dr. Ran Balicer at Exponential Medicine
Picture this: instead of going to a physician with your ailments, your doctor calls you with some bad news: “Within six hours, you’re going to have a heart attack. So why don’t you come into the clinic and we can fix that.” Crisis averted.
Following the treatment, you’re at home monitoring your biomarkers, lab test results, and other health information through an app with a clean, beautiful user interface. Within the app, you can observe how various health-influencing life habits—smoking, drinking, insufficient sleep—influence your chance of future cardiovascular disease risks by toggling their levels up or down.
There’s more: you can also set a health goal within the app—for example, stop smoking—which automatically informs your physician. The app will then suggest pharmaceuticals to help you ditch the nicotine and automatically sends the prescription to your local drug store. You’ll also immediately find a list of nearby support groups that can help you reach your health goal.
With this hefty dose of AI, you’re in charge of your health—in fact, probably more so than under current healthcare systems.
Sound fantastical? In fact, this type of preemptive care is already being provided in some countries, including Israel, at a massive scale, said Balicer. By mining datasets with deep learning and other powerful AI tools, we can predict the future—and put it into the hands of patients.
The Israeli Advantage
In order to apply big data approaches to medicine, you first need a giant database.
Israel is ahead of the game in this regard. With decades of electronic health records aggregated within a central warehouse, Israel offers a wealth of health-related data on the scale of millions of people and billions of data points. The data is incredibly multiplex, covering lab tests, drugs, hospital admissions, medical procedures, and more.
One of Balicer’s early successes was an algorithm that predicts diabetes, which allowed the team to notify physicians to target their care. Clalit has also been busy digging into data that predicts winter pneumonia, osteoporosis, and a long list of other preventable diseases.
So far, Balicer’s predictive health system has only been tested on a pilot group of patients, but he is expecting to roll out the platform to all patients in the database in the next few months.
Truly Personalized Medicine
To Balicer, whatever a machine can do better, it should be welcomed to do. AI diagnosticians have already enjoyed plenty of successes—but their collaboration remains mostly with physicians, at a point in time when the patient is already ill.
A particularly powerful use of AI in medicine is to bring insights and trends directly to the patient, such that they can take control over their own health and medical care.
For example, take the problem of tailored drug dosing. Current drug doses are based on average results conducted during clinical trials—the dosing is not tailored for any specific patient’s genetic and health makeup. But what if a doctor had already seen millions of other patients similar to your case, and could generate dosing recommendations more relevant to you based on that particular group of patients?
Such personalized recommendations are beyond the ability of any single human doctor. But with the help of AI, which can quickly process massive datasets to find similarities, doctors may soon be able to prescribe individually-tailored medications.
Tailored treatment doesn’t stop there. Another issue with pharmaceuticals and treatment regimes is that they often come with side effects: potentially health-threatening reactions that may, or may not, happen to you based on your biometrics.
Back in 2017, the New England Journal of Medicine launched the SPRINT Data Analysis Challenge, which urged physicians and data analysts to identify novel clinical findings using shared clinical trial data.
Working with Dr. Noa Dagan at the Clalit Research Institute, Balicer and team developed an algorithm that recommends whether or not a patient receives a particularly intensive treatment regime for hypertension.
Rather than simply looking at one outcome—normalized blood pressure—the algorithm takes into account an individual’s specific characteristics, laying out the treatment’s predicted benefits and harms for a particular patient.
“We built thousands of models for each patient to comprehensively understand the impact of the treatment for the individual; for example, a reduced risk for stroke and cardiovascular-related deaths could be accompanied by an increase in serious renal failure,” said Balicer. “This approach allows a truly personalized balance—allowing patients and their physicians to ultimately decide if the risks of the treatment are worth the benefits.”
This is already personalized medicine at its finest. But Balicer didn’t stop there.
We are not the sum of our biologics and medical stats, he said. A truly personalized approach needs to take a patient’s needs and goals and the sacrifices and tradeoffs they’re willing to make into account, rather than having the physician make decisions for them.
Balicer’s preventative system adds this layer of complexity by giving weights to different outcomes based on patients’ input of their own health goals. Rather than blindly following big data, the system holistically integrates the patient’s opinion to make recommendations.
Balicer’s system is just one example of how AI can truly transform personalized health care. The next big challenge is to work with physicians to further optimize these systems, in a way that doctors can easily integrate them into their workflow and embrace the technology.
“Health systems will not be replaced by algorithms, rest assured,” concluded Balicer, “but health systems that don’t use algorithms will be replaced by those that do.”
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