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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.
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 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.
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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Last year, a novelist went on a road trip across the USA. The trip was an attempt to emulate Jack Kerouac—to go out on the road and find something essential to write about in the experience. There is, however, a key difference between this writer and anyone else talking your ear off in the bar. This writer is just a microphone, a GPS, and a camera hooked up to a laptop and a whole bunch of linear algebra.
People who are optimistic that artificial intelligence and machine learning won’t put us all out of a job say that human ingenuity and creativity will be difficult to imitate. The classic argument is that, just as machines freed us from repetitive manual tasks, machine learning will free us from repetitive intellectual tasks.
This leaves us free to spend more time on the rewarding aspects of our work, pursuing creative hobbies, spending time with loved ones, and generally being human.
In this worldview, creative works like a great novel or symphony, and the emotions they evoke, cannot be reduced to lines of code. Humans retain a dimension of superiority over algorithms.
But is creativity a fundamentally human phenomenon? Or can it be learned by machines?
And if they learn to understand us better than we understand ourselves, could the great AI novel—tailored, of course, to your own predispositions in fiction—be the best you’ll ever read?
Maybe Not a Beach Read
This is the futurist’s view, of course. The reality, as the jury-rigged contraption in Ross Goodwin’s Cadillac for that road trip can attest, is some way off.
“This is very much an imperfect document, a rapid prototyping project. The output isn’t perfect. I don’t think it’s a human novel, or anywhere near it,” Goodwin said of the novel that his machine created. 1 The Road is currently marketed as the first novel written by AI.
Once the neural network has been trained, it can generate any length of text that the author desires, either at random or working from a specific seed word or phrase. Goodwin used the sights and sounds of the road trip to provide these seeds: the novel is written one sentence at a time, based on images, locations, dialogue from the microphone, and even the computer’s own internal clock.
The results are… mixed.
The novel begins suitably enough, quoting the time: “It was nine seventeen in the morning, and the house was heavy.” Descriptions of locations begin according to the Foursquare dataset fed into the algorithm, but rapidly veer off into the weeds, becoming surreal. While experimentation in literature is a wonderful thing, repeatedly quoting longitude and latitude coordinates verbatim is unlikely to win anyone the Booker Prize.
Data In, Art Out?
Neural networks as creative agents have some advantages. They excel at being trained on large datasets, identifying the patterns in those datasets, and producing output that follows those same rules. Music inspired by or written by AI has become a growing subgenre—there’s even a pop album by human-machine collaborators called the Songularity.
A neural network can “listen to” all of Bach and Mozart in hours, and train itself on the works of Shakespeare to produce passable pseudo-Bard. The idea of artificial creativity has become so widespread that there’s even a meme format about forcibly training neural network ‘bots’ on human writing samples, with hilarious consequences—although the best joke was undoubtedly human in origin.
The AI that roamed from New York to New Orleans was an LSTM (long short-term memory) neural net. By default, information contained in individual neurons is preserved, and only small parts can be “forgotten” or “learned” in an individual timestep, rather than neurons being entirely overwritten.
The LSTM architecture performs better than previous recurrent neural networks at tasks such as handwriting and speech recognition. The neural net—and its programmer—looked further in search of literary influences, ingesting 60 million words (360 MB) of raw literature according to Goodwin’s recipe: one third poetry, one third science fiction, and one third “bleak” literature.
In this way, Goodwin has some creative control over the project; the source material influences the machine’s vocabulary and sentence structuring, and hence the tone of the piece.
The Thoughts Beneath the Words
The problem with artificially intelligent novelists is the same problem with conversational artificial intelligence that computer scientists have been trying to solve from Turing’s day. The machines can understand and reproduce complex patterns increasingly better than humans can, but they have no understanding of what these patterns mean.
Goodwin’s neural network spits out sentences one letter at a time, on a tiny printer hooked up to the laptop. Statistical associations such as those tracked by neural nets can form words from letters, and sentences from words, but they know nothing of character or plot.
When talking to a chatbot, the code has no real understanding of what’s been said before, and there is no dataset large enough to train it through all of the billions of possible conversations.
Unless restricted to a predetermined set of options, it loses the thread of the conversation after a reply or two. In a similar way, the creative neural nets have no real grasp of what they’re writing, and no way to produce anything with any overarching coherence or narrative.
Goodwin’s experiment is an attempt to add some coherent backbone to the AI “novel” by repeatedly grounding it with stimuli from the cameras or microphones—the thematic links and narrative provided by the American landscape the neural network drives through.
Goodwin feels that this approach (the car itself moving through the landscape, as if a character) borrows some continuity and coherence from the journey itself. “Coherent prose is the holy grail of natural-language generation—feeling that I had somehow solved a small part of the problem was exhilarating. And I do think it makes a point about language in time that’s unexpected and interesting.”
AI Is Still No Kerouac
A coherent tone and semantic “style” might be enough to produce some vaguely-convincing teenage poetry, as Google did, and experimental fiction that uses neural networks can have intriguing results. But wading through the surreal AI prose of this era, searching for some meaning or motif beyond novelty value, can be a frustrating experience.
Maybe machines can learn the complexities of the human heart and brain, or how to write evocative or entertaining prose. But they’re a long way off, and somehow “more layers!” or a bigger corpus of data doesn’t feel like enough to bridge that gulf.
Real attempts by machines to write fiction have so far been broadly incoherent, but with flashes of poetry—dreamlike, hallucinatory ramblings.
Neural networks might not be capable of writing intricately-plotted works with charm and wit, like Dickens or Dostoevsky, but there’s still an eeriness to trying to decipher the surreal, Finnegans’ Wake mish-mash.
You might see, in the odd line, the flickering ghost of something like consciousness, a deeper understanding. Or you might just see fragments of meaning thrown into a neural network blender, full of hype and fury, obeying rules in an occasionally striking way, but ultimately signifying nothing. In that sense, at least, the RNN’s grappling with metaphor feels like a metaphor for the hype surrounding the latest AI summer as a whole.
Or, as the human author of On The Road put it: “You guys are going somewhere or just going?”
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